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Evidence submission templates to support production of core HTA information and rapid assessments: Pharmaceuticals evidence submission template short version

The EUnetHTA JA 2 (2012-2015) has received funding from the European Union, in the framework of the Health Programme

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Joint Action on HTA 2012-2015

Evidence submission templates to support production of core HTA information and rapid assessments: Pharmaceuticals evidence submission template short version

Date: October 2015

Was developed by Work Package Work Package 7: Methodology development and evidence generation: guidelines and pilot production WP 7 Lead Partner: Haute Autorité de Santé (HAS) WP Subgroup Coordinator: National Institute for Health and Care Excellence (NICE)

Disclaimer: EUnetHTA Joint Action 2 is supported by a grant from the European Commission. The sole responsibility for the content of this document lies with the authors and neither the European Commission nor EUnetHTA are responsible for any use that may be made of the information contained therein. © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 2

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

EUnetHTA pharmaceuticals evidence submission template Short version

PTJA0 7

Stelara® (ustekinumab)

For the treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy, a biologic, or have medical contraindications to such therapies

Janssen-Cilag International NV

Contact details for administrative purposes Name of contact person: Andras Borsi Address of contact: 50-100 Holmers Farm Way, High Wycombe, Buckinghamshire, HP12 4DP, UK

Email address: [email protected]

For agency completion Date of receipt: Identifier:

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Abbreviations 5-ASA: 5-aminosalicylic acid 6-MP: 6-mercaptopurine ACCEPT: Advanced care planning evaluation in elderly patients ADA: Adalimumab AEoSI: Adverse events of special interest AE: Adverse events ATC: Anatomical therapeutic chemical AZA: Azathioprine BADBIR: British Association of Dermatologists Biologic Interventions Register BID: Twice a week BSA: Body surface area CI: Confidence interval CD: Crohn’s disease CONSORT: Consolidated standards of reporting trials CRP: C-reactive protein DDW: Digestive Disease Week DGVS: German Society for Digestive and Metabolic Diseases DMARD: Disease-modifying anti-rheumatic drug DSM: Diagnostic and Statistical Manual of Mental Disorders ECCO: European Crohn’s and Colitis Organisation EIM: Extra intestinal manifestation EMA: European Medicines Agency EOW: Every other week EQ-5D-5L: 5-level EQ-5D EPAR: European Public Assessment Report EULAR: European League Against Rheumatism (EULAR) Fcal: Faecal calprotectin FDA: Food and Drug Administration G-BA: Gemeinsamer Bundesausschuss GETECCU: Spanish Group of Ulcerative Colitis and Crohn's disease GOL: Golimumab HAS: Haute Autorité de Santé HC: Health Canada HRQoL: Health-related quality of life HTA: Health technology assessment ICD: International Classification of Diseases IBD: Inflammatory bowel disease IBDQ: Inflammatory bowel disease questionnaire IBD-DSP: Inflammatory Bowel Disease Specific Programmes IBSEN: Inflammatory Bowel Disease in South-Eastern Norway IFX: Infliximab IgG1k: Human immunoglobulin G1 kappa ISGE: Italian Society of Gastroenterology IL: Human interleukin IPD: Individual patient data

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

ISGE: Italian Society of Gastroenterology LTE: Long-term extension ITT: Intention-to-treat IV: Intravenous JAK: Janus kinase MACE: Major adverse cardiac event MOA: mechanism of action MP: Mercaptopurine MTX: Methotrexate NMA: Network meta-analysis NICE: National Institute for Health and Care Excellence OR: Odds ratio PBO: Placebo PGA: Physicians Global Assessment pMAH: Prospective marketing authorisation holder PRISMA: Preferred reporting items for systematic reviews and meta-analyses PRO: Patient reported outcomes PsA: Psoriasis arthritis PsO: Plaque psoriasis PSOLAR: Psoriasis longitudinal assessment and registry PUVA: Psoralen and ultraviolet A QoL: Quality of Life QXW: Every X weeks RCT: Randomised controlled trial RWE: Real world evidence SAE: Serious adverse event SC: Subcutaneous SES: Socioeconomic status SD: standard deviation SF: Steroid-free SF-36: 36-item Short Form Survey SLR: Systematic literature review SmPC: Summary of product characteristics TGA: Therapeutic Goods Administration TNF: Tumour necrosis factor TNF: Tumour necrosis factor-inhibitor TOF: Tofacitinib UC: Ulcerative colitis UEGW: United European Gastroenterology Week UK: United Kingdom USCC: Ulcerative Colitis Symptom Score UST: Ustekinumab VDZ: Vedolizumab VnR: Nordic Article Number

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Contents Joint Action on HTA 2012-2015 ...... 2 Abbreviations ...... 3 Contents ...... 6 Table of Tables ...... 8 Table of Figures ...... 11 1 Description and technical characteristics of the technology ...... 21 Summary of the characteristics of the technology ...... 21 1.1 Characteristics of the technology ...... 23 1.2 Regulatory status of the technology ...... 27 2 Health problem and current clinical practice ...... 31 Summary of issues relating to the health problem and current clinical practice . 31 2.1 Overview of the disease or health condition ...... 33 2.2 Target population ...... 47 2.3 Clinical management of the disease or health condition ...... 48 2.4 Comparators in the assessment ...... 55 3 Current use of the technology...... 57 Summary of issues relating to current use of the technology ...... 57 3.1 Current use of the technology...... 58 3.1.1 Summary of current use of ustekinumab in Crohn’s disease ...... 59 3.1.2 Summary of current use of ustekinumab in plaque psoriasis ...... 60 3.1.3 Summary of current use of ustekinumab in psoriatic arthritis ...... 61 3.1.4 Safety evidence from PSOLAR study for patients with plaque psoriasis . 62 3.1.5 Safety evidence from clinical trials of plaque psoriasis, psoriatic arthritis, and Crohn’s disease ...... 63 3.2 Reimbursement and assessment status of the technology ...... 64 4 Investments and tools required...... 67 Summary of issues relating to the investments and tools required to introduce the technology ...... 67 4.1 Requirements to use the technology ...... 68 4.2 Investments, disinvestments and changes in service organisation ...... 69 5 Clinical effectiveness and safety ...... 70 Guidance on this section ...... 70 Summary of the clinical effectiveness ...... 71 Summary of safety ...... 72 5.1 Identification and selection of relevant studies ...... 74 5.2 Relevant studies ...... 80 5.2.1 Studies identified from the SLR of RCTs ...... 84 5.2.2 Indirect comparison of ustekinumab versus other active treatments in UC 88 5.2.3 Studies included in the NMA ...... 90 5.2.4 Outcomes assessed in the NMA ...... 95 5.2.5 Comparison in design of the relevant studies ...... 97 5.2.6 Comparison of patient characteristics across studies ...... 97 5.3 Methods for the indirect comparison ...... 117 5.3.1 Approach for the Bayesian NMA ...... 117

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5.3.2 Approach to combine induction and maintenance trial results to enable 1- year comparisons across all active treatments ...... 125 5.3.3 Sensitivity analyses (induction and 1-year timepoints) ...... 138 5.4 Individual study results (clinical outcomes and NMA results) ...... 139 5.4.1 Description of relevant efficacy endpoints ...... 139 5.4.2 Results of the technology and comparator trials ...... 142 5.4.3 Results of the clinical efficacy NMAs ...... 161 5.5 Individual study results (safety outcomes and NMA results) ...... 188 5.5.1 Description of the relevant safety outcomes ...... 188 5.5.2 Comparison of safety ...... 197 5.6 Conclusions ...... 202 5.6.1 Conclusions of the trials of the pMAH ...... 202 5.6.2 Conclusions of the comparative efficacy (NMA) ...... 202 5.7 Strengths and limitations ...... 204 5.7.1 Strengths and limitations of the clinical evidence base for ustekinumab in UC ...... 204 5.7.2 Strengths and limitations of the NMAs ...... 205 6. EUnetHTA action point guide ...... 209 References ...... 218 Appendix 1. Clinical effectiveness SLR: Search strategies ...... 231 Appendix 2. Comparison of safety profiles for the comparator treatments based on SmPC ...... 242 Appendix 3. Comparison of baseline characteristics of studies of the technology and comparator treatments ...... 274 Appendix 4. NMA of safety endpoints in maintenance phase ...... 278 Appendix 5. Carry-over effects ...... 282 A5.1 UNIFI trial: Carry-over effect ...... 282 A5.2 Other phase III trials in UC: Carry-over effect ...... 285 Appendix 6 NMA sensitivity analyses ...... 290 A6.1 One-Year NMA results with ustekinumab 130mg induction ...... 290 A6.2 One-Year NMA results with ustekinumab 130mg induction - Asian patient populations ...... 297 A6.3 One-Year NMA results with ustekinumab 130mg induction - approach mimicking response based design ...... 304 Appendix 7. Multiple imputation sensitivity analysis ...... 312 Appendix 8. Flow diagrams of the trials of the technology and comparators ...... 316 A8.1 Flow diagrams of the trials of the technology by the pMAH ...... 316 A8.2 Flow diagram of the comparator trials identified in the SLR ...... 318 A8.3 Infliximab trial flow diagrams ...... 318 A8.4 Adalimumab trial flow diagrams ...... 321 A8.5 Golimumab trial patient flow diagrams ...... 325 A8.6 Vedolizumab trial flow diagrams ...... 328 A8.7 Tofacitinib trial flow diagrams ...... 329 Appendix 9. Results of the induction safety NMA ...... 330

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Table of Tables Table 1 NMA results for clinical response and clinical remission pooled doses – non- biologic failure patients – 1-year – base case mimicking a treat-through approach ...... Table 2. Features of the technology ...... 23 Table 3. Administration and anticipated dosing of the technology in UC indication ...... 23 Table 4. Pack information ...... 24 Table 5. Regulatory status of the technology ...... 30 Table 6. Disease distribution definition ...... 34 Table 7. Incidence and prevalence of UC by European region(56) ...... 37 Table 8. Incidence and prevalence of UC by European country ...... 37 Table 9. Relevant guidelines for diagnosis and management ...... 54 Table 10. Labels of available comparators in Europe...... 56 Table 11. Inclusion of ustekinumab in European guidelines for PsO ...... 61 Table 12. Inclusion of ustekinumab in European PsA guidelines ...... 62 Table 13. Overview of the reimbursement status of the technology for Crohn’s disease in European countries ...... 64 Table 14. Overview of the reimbursement status of the technology for plaque psoriasis in European countries ...... 65 Table 15. Overview of the reimbursement status of the technology for psoriatic arthritis in European countries ...... 66 Table 16. Hand searches ...... 74 Table 17: Inclusion and exclusion criteria ...... 76 Table 18. List of all relevant studies ...... 81 Table 19. Summary of studies related to the technology and the pMAH ...... 86 Table 20. Overview of the number of relevant studies, by treatment ...... 88 Table 21. Summary of studies included in the NMAs by timepoint ...... 92 Table 22. Characteristics of the studies ...... 102 Table 23. Subgroup definitions across trials for prior therapy with the population corresponding to UNIFI ...... 118 Table 24. Induction studies and time points of assessment ...... 121 Table 25. Partial mayo score at weeks 4, 6 and 8 across trials ...... 123 Table 26. Study design - included maintenance trials ...... 132 Table 27 Calculations to mimic a treat-through approach ...... 133 Table 28: Maintenance placebo and active treatment data available for approach including induction responders and induction non-responders (treat-through based approach) ...... 134 Table 29 Efficacy outcomes with placebo at the end of maintenance in UNIFI, ACT I and PURSUIT for induction responders to placebo ...... 136 Table 30. Imputation maintenance data from ACT I and GEMINI I for placebo induction non-responders used in the NMA ...... 137 Table 31. Clinical outcome measures in the UNIFI clinical trial programme ...... 139 Table 32. Central vs. local endoscopic reading ...... 142 Table 33. Methods of data collection and analysis of clinical remission ...... 143 Table 34. Methods of data collection and analysis of clinical response ...... 143 Table 35. Methods of data collection and analysis of mucosal healing ...... 143

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Table 36. Results summary for clinical remission in the full patient population ...... 144 Table 37. Results summary for clinical response in the full patient population ...... 146 Table 38. Results summary for mucosal healing in the full patient population ...... 148 Table 39. Results summary for clinical response in the non-biologic failure population ...... 151 Table 40. Results summary for clinical response in the biologic failure population ..... 153 Table 41. Results summary for clinical remission for the non-biologic failure population ...... 154 Table 42. Results summary for clinical remission for the biologic failure population ... 156 Table 43. Results summary for mucosal healing for the non-biologic failure population ...... 157 Table 44. Results summary for mucosal healing in the biologic failure population ...... 159 Table 45. NMA results for clinical response - non-biologic failure patients (induction) 163 Table 46. NMA results for clinical remission - non-biologic failure patients (induction) 165 Table 47. NMA results for mucosal healing - non-biologic failure patients (induction) 167 Table 48. NMA results for clinical response - biologic failure patients (induction) ...... 169 Table 49. NMA results for clinical remission - biologic failure patients (induction) ...... 171 Table 50. NMA results for mucosal healing - biologic failure patients (induction) ...... 172 Table 51. NMA results for clinical response (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach ...... 175 Table 52. NMA results for clinical remission (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach ...... 177 Table 53. NMA results for mucosal healing (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach ...... 179 Table 54. NMA results for clinical response (unpooled doses) – biologic failure patients – one-year base case mimicking a treat-through approach...... 182 Table 55. NMA results for clinical remission (unpooled doses) – biologic failure patients – one-year base case mimicking a treat-through approach...... 185 Table 56. Methods of data collection and analysis of overall adverse events ...... 189 Table 57. Overview of adverse events: Infliximab trials (Japic CTI060298) ...... 190 Table 58. Overview of adverse events: Infliximab trials (ACT 1, ACT 2, Jiang 2015) . 190 Table 59. Overview of adverse events: Adalimumab trials (ULTRA 1 and NCT00853099) ...... 191 Table 60. Overview of adverse events: Golimumab trials (PURSUIT-SC, PURSUIT-J and PURSUIT-M) ...... 192 Table 61. Overview of adverse events: Vedolizumab trials (GEMINI, NCT02039505) 193 Table 62. Overview of adverse events: Tofacitinib trials (OCTAVE 1, OCTAVE 2, OCTAVE Sustain) ...... 195 Table 63. Summary of adverse events in UNIFI trial programme; Safety Anlaysis Set196 Table 64. Cumulative incidence rates of serious infections per 100 patient-years within 91 days of biologic administration ...... 200 Table 65. Comparison of population stratifications between UNIFI and other key trials ...... 209 Table 66. Common safety concerns for the technology and comparators (SmPC) ..... 214 Table 67. Search terms for MEDLINE and MEDLINE-IN-PROCESS via www.pubmed.com ...... 231 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 9

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Table 68. Search terms for Embase via www.embase.com ...... 235 Table 69. Search terms in Cochrane Library via http://www.cochranelibrary.com/ ..... 239 Table 70. Summary of Warnings and Precautions ...... 242 Table 71. Warnings and precautions with regard to infections ...... 250 Table 72. Infections (Section 4.8 of SmPC) ...... 253 Table 73. Malignancies (Section 4.4 and 4.8 of SmPC) ...... 256 Table 74. Posology...... 262 Table 75. Contraindications ...... 263 Table 76. Adverse events ...... 263 Table 77. Baseline patient characteristics of studies used in NMA ...... 274 Table 78 Clinical response at the end of maintenance for induction responders to placebo (re-randomised arms) by population and chi-squred test ...... 289 Table 79 NMA results for clinical response - non-biologic failure patients –one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 291 Table 80 NMA results for clinical response pooled - non-biologic failure patients – one- year base case mimicking a treat-through approach and including UST 130mg induction ...... 292 Table 81 NMA results for clinical remission - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 293 Table 82 NMA results for clinical remission pooled doses - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 294 Table 83 NMA results for mucosal healing - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 295 Table 84 NMA results for mucosal healing pooled doses - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 296 Table 85 NMA results for clinical response - biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 296 Table 86 NMA results for clinical remission - biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction ...... 297 Table 87. NMA results for clinical response - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 298 Table 88. NMA results for clinical response pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 299 Table 89. NMA results for clinical remission - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 300 Table 90. NMA results for clinical remission pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 301 Table 91. NMA results for mucosal healing - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 302 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 10

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Table 92. NMA results for mucosal healing pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction ...... 303 Table 93. NMA results for clinical response - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ..... 304 Table 94. NMA results for clinical response pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ...... 305 Table 95. NMA results for clinical remission - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ..... 306 Table 96. NMA results for clinical remission pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ...... 307 Table 97. NMA results for mucosal healing - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ..... 308 Table 98. NMA results for mucosal healing pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ...... 308 Table 99. NMA results for clinical response - biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ...... 309 Table 100. NMA results for clinical remission - biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ..... 310 Table 101. NMA results for mucosal healing - biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction ..... 311 Table 102 Clinical response at the end of maintenance for patients receiving placebo from UNIFI, ACT I and PURSUIT for non-biologic failure patients ...... 313 Table 103. Network meta analysis results for overall and serious adverse events (induction) ...... 331 Table 104. NMA results for overall and serious infections ...... 333

Table of Figures Figure 1. Ulcerative colitis phenotypes(27) ...... 34 Figure 2. Percentage of patients with proctitis (anatomically limited disease) over disease course by study ...... 39 Figure 3. UC disease behaviour over time in the IBSEN cohort ...... 40 Figure 4. Number of patients maintaining clinical response through Week 44 by biologic failure status; Primary efficacy analysis set ...... 45 Figure 5 Proportion of patients in clinical response at Week 8 and Week 16 ...... 46 Figure 6. Clinical pathway to induce remission for patients with mild-to-moderate and moderate-to-severe UC from ECCO ...... 49 Figure 7. Recommended treatment for patients with severe UC from ECCO ...... 50 Figure 8. Ustekinumab and the ECCO clinical care pathway for moderately to severely active UC ...... 52

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Figure 9. Ustekinumab and the ECCO clinical care pathway for severe ulcerative colitis ...... 53 Figure 10. PRISMA diagram (Search conducted on 14th August 2018) ...... 78 Figure 11. PRISMA diagram (updated search results conducted on 22nd January 2019; publication date from 01/01/2018-22/01/2019) ...... 78 Figure 12. PRISMA diagram (updated search results conducted on 28th March 2019; publication date from 01/01/2019-28/03/2019) ...... 79 Figure 13. UNIFI phase III trial overview ...... 85 Figure 14. Mean and median disease duration of patients at start of induction ...... 99 Figure 15. Mean and median CRP level of patients at start of induction ...... 100 Figure 16. Mean and median Mayo score of patients at start of induction ...... 101 Figure 17. Treat-through trial design schematic ...... 124 Figure 18. Response-based re-randomised trial design schematic ...... 124 Figure 19 Evidence of carry-over of the induction with ustekinumab vs. anti-TNFs in UC and Crohn’s Disease ...... 127 Figure 20 Clinical response at the end of maintenance for the re-randomised response- based trial arms – Non-biologic failure population ...... 128 Figure 21 Clinical response at the end of maintenance for the re-randomised response- based trial arms – biologic failure population ...... 129 Figure 22. Network of evidence for clinical response - non-biologic failure patients (induction) ...... 161 Figure 23. Data inputs for clinical response - non-biologic failure patients (induction) 162 Figure 24. Network of evidence for clinical remission - non-biologic failure patients (induction) ...... 163 Figure 25. Data inputs for clinical remission - non-biologic failure patients (induction) 164 Figure 26. Network of evidence for mucosal healing - non-biologic failure patients (induction) ...... 165 Figure 27. Data inputs for mucosal healing - non-biologic failure patients (induction) . 166 Figure 28. Network of evidence for clinical response - biologic failure patients (induction) ...... 167 Figure 29. Data inputs for clinical response - biologic failure patients (induction) ...... 168 Figure 30. Network of evidence for clinical remission - biologic failure patients (induction) ...... 169 Figure 31. Data inputs for clinical remission - biologic failure population (induction) ... 170 Figure 32. Network of evidence for mucosal healing - biologic failure patients (induction) ...... 171 Figure 33. Data inputs for mucosal healing – biologic failure patients (induction) ...... 172 Figure 34. Network of evidence for clinical response – non-biologic failure patients – one- year base case mimicking a treat-through approach ...... 174 Figure 35. Data inputs for clinical response – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach ...... 175 Figure 36. Network of evidence for clinical remission – non-biologic failure patients – one- year base case mimicking a treat-through approach ...... 176 Figure 37. Data inputs for clinical remission – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach ...... 177

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Figure 38. Network of evidence for mucosal healing – non-biologic failure patients – one- year base case mimicking a treat-through approach ...... 178 Figure 39. Data inputs for mucosal healing – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach ...... 179 Figure 40. Network of evidence for clinical response – biologic failure patients – one-year base case mimicking a treat-through approach ...... 180 Figure 41. Data inputs for clinical response – biologic failure patients – one-year base case mimicking a treat-through approach ...... 181 Figure 42. Network of evidence for clinical remission – biologic failure patients – one-year base case mimicking a treat-through approach ...... 183 Figure 43. Data inputs for clinical remission – biologic failure patients – one-year base case mimicking a treat-through approach ...... 184 Figure 44. Cumulative Incidence Rates of Serious Infections of Interest per 100 Patient- years ...... 200 Figure 45. Median Faecal Calprotectin Concentration Through Week 44; Primary Efficacy ...... 282 Figure 46. Median Faecal Lactoferrin Concentration Through Week 44 ...... 283 Figure 47. Plot of Mean Partial Mayo Score Through Week 44; Primary Efficacy Analysis Set ...... 284 Figure 48. Proportion of subjects in partial Mayo remission over time through Week 44, Primary efficacy analysis set ...... 285 Figure 49. Median partial mayo score in the maintenance phase of UNIFI ...... 286 Figure 50. Median partial mayo score in the maintenance phase of PURSUIT ...... 286 Figure 51. Mean partial mayo score in the maintenance phase of GEMINI I ...... 287 Figure 52. Proportion of patients in clinical remission in maintenance phase of UNITI 288 Figure 53. Proportion of patients in clinical remission in maintenance phase of CHARM ...... 288 Figure 54 Sampled versus underlying distribution of the imputed values for clinical response at the end of maintenance of induction responders and induction non responders (based on 100 samples) ...... 314 Figure 55 Results of the multiple imputation NMAs for each distribution (beta and normal) for ustekinumab 6mg/kg-ustekinumab pooled versus comparators ...... 315 Figure 56. UNIFI Induction trial flow diagram ...... 316 Figure 57. UNIFI Maintenance trial flow diagram ...... 317 Figure 58. Jiang 2015 flow diagram(150) ...... 318 Figure 59. Japic CTI060298 flow diagram (152) ...... 319 Figure 60. ACT 1 flow diagram(153) ...... 319 Figure 61. ACT 2 flow diagram(153) ...... 320 Figure 62. ULTRA 1 trial (Induction) flow diagram(148) ...... 321 Figure 63. ULTRA 1 trial (Maintenance) flow diagram (Original Protocol)(148) ...... 322 Figure 64. ULTRA 1 trial (Maintenance) flow diagram (Amendment 3)(148) ...... 323 Figure 65. ULTRA 2 trial flow diagram(149) ...... 323 Figure 66. NCT00853099 trial flow diagram(149) ...... 324 Figure 67. PURSUIT-M trial flow diagram(106) ...... 325 Figure 68. PURSUIT-J trial flow diagram(96) ...... 326 Figure 69. PURSUIT-SC trial flow diagram ...... 327 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 13

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Figure 70. NCT02039505 trial (Induction) flow diagram ...... 328 Figure 71. NCT02039505 trial (Induction) flow diagram ...... 328 Figure 72. Data inputs for overall and serious adverse events (induction) ...... 330 Figure 73. Data inputs for overall and serious infections (induction) ...... 332

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Using this evidence submission template This evidence submission template contains suggestions to companies about what information to include, highlighted in blue, which agencies can adapt as necessary. There are also ‘form fields’ that prompt companies for their response, for example [add details here]. To insert a response, a company should click once anywhere within the highlighted text and then type in their response. This overwrites the section that was highlighted. To delete a form field, click anywhere within the highlighted text and press DELETE.

EUnetHTA JA2 EUnetHTA pharmaceuticals evidence submission template short version WP7

Executive Summary: Ustekinumab (Stelara®) for the treatment of moderately to severely active ulcerative colitis Health problem  Ulcerative colitis is a lifelong, progressive disease characterised by the diffuse inflammation of the rectal and colonic mucosa.  Symptoms are diverse, depending on the extent of the disease, and can be severe with profound impact on patients’ lives. Typical symptoms of UC include, rectal bleeding, bowel urgency, tenesmus, proctitis, diarrhoea and abdominal cramping.  UC patients are at risk of hospitalisation and UC-related surgery (i.e. up to 20% of patients eventually need surgical resection) and have an increased mortality risk especially for patients with extensive disease and undergoing surgery (i.e. UC increases the risk of death with a standard mortality ratio (SMR) vs. the general population of 1.192). Ulcerative colitis has negative effects on patients’ quality of life, ability to perform work and leisure activities, mental health and social interaction. Current clinical practice  Current management of UC, as described in both European HTA and ECCO guidelines, has historically followed a step-up approach which includes conventional therapies (e.g. aminosalicylates, thiopurines, and corticosteroids), non-conventional therapies (e.g. biologics and janus kinase inhibitors), and surgical interventions (e.g. colectomy).  Despite the availability of alternative treatments, such as TNF inhibitors, lack of long-term remission is common and associated with poor clinical outcomes (i.e. over 60% of anti-TNF-treated patients fail maintenance at 1 year and 50% discontinue therapy). Dose escalation is also common in both non-biologic failure and biologic failure patients and is associated with poor clinical outcomes.  Given the chronicity, progression, and highly individualised symptom burden of moderately to severely active UC, as well as the current unmet needs faced by both non-biologic failure and biologic failure patients, alternative treatments are required to help patients achieve treatment goals of remission and improve their overall quality of life Summary of clinical evidence for ustekinumab in UC Ustekinumab is an innovative treatment for moderately to severely active UC based on a mechanism of action (IL-12/23) with an established benefit/risk in other indications. Ustekinumab is anticipated to be approved in-line with its expected EMA indication (ultimate best case: August 2019; best case: October 2019): for the treatment of adult patients with moderately to severely active UC who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy, a biologic, or have medical contraindications to such therapies. The anticipated licensed dose of ustekinumab is 6mg/kg for IV induction treatment and 90 mg SC q8w or q12w for maintenance treatment. The efficacy and safety of ustekinumab in the treatment of patients with moderately to severely active UC was demonstrated in the phase III, randomized, double-blind, placebo-controlled, parallel-group, multicentre UNIFI trial. Ustekinumab demonstrated rapid and sustained improvement of disease activity in patients who demonstrated an inadequate response or failure or intolerance to conventional therapy or biologic therapy. The safety profile of ustekinumab in the UNIFI trial was similar to placebo and consistent with clinical experience in established indications, as demonstrated in Crohn’s disease, plaque psoriasis, and psoriasis arthritis clinical trials. Ustekinumab was the first biologic therapy to show statistically significant difference in histologic healing versus placebo in refractory UC patients. Evidence from the UNIFI clinical trial programme Methodology  The UNIFI trial evaluated the efficacy and safety of ustekinumab compared to placebo in patients with moderately to severely active UC in patients for induction and maintenance treatment  Both the induction and maintenance studies are randomized, double-blind, placebo-controlled, parallel group, multi-centre studies:

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o The induction study was of at least 8 weeks duration for each participant, with a primary endpoint of clinical remission at Week 8; participants achieving clinical response in the induction study were eligible for the maintenance study o Responders to induction with ustekinumab treatment were re-randomized 1:1:1 to placebo, ustekinumab 90 mg SC q8w, or ustekinumab 90 mg SC q12w; the maintenance study was 44 weeks in duration with a primary endpoint of clinical remission at Week 44 o Other key endpoints included: clinical response, endoscopic healing, histological healing, mean change from baseline in IBDQ score o Patients not in response after induction with ustekinumab continued on ustekinumab q8w in the blinded, but non re-randomised part of the maintenance trial. o Patients in response after induction with placebo continued on placebo in the blinded, but non- re-randomised part of the maintenance trial Key Results

UNIFI Induction:  Results for all key efficacy endpoints were statistically significant for the full population, and both the non-biologic failure (i.e. patients who are biologic-naïve or biologic-experienced without documented treatment failure) and biologic failure populations, for both induction doses of ustekinumab. These results included clinical remission, clinical response, endoscopic healing, and mucosal healing (a combination of endoscopic healing and histologic healing) at Week 8 (all p- values <0.001). In addition, improvements in clinical outcomes were accompanied by reductions in inflammatory biomarkers and improvements in health-related quality of life measures. UNIFI Maintenance:  Results for all key efficacy endpoints were statistically significant for the full population, and both the non-biologic failure and biologic failure populations, for both dose regimens including clinical remission at Week 44, maintenance of clinical response through Week 44, endoscopic healing at Week 44, corticosteroid-free remission at Week 44, and maintenance of clinical remission through Week 44 (q12w only) (all p-values <0.05). Delayed Responders:  Delayed responders were those patients who were not in clinical response to ustekinumab IV at induction Week 8 but were in clinical response at Week 16 after receiving ustekinumab 90 mg SC at Week 8; these patients received ustekinumab 90 mg SC q8w during the maintenance phase Figure 1. Proportion of patients in clinical response at Week 8 and Week 16

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 A substantial proportion (56% [n=157]) of patients who were not in clinical response at Week 8 (n=279) were in clinical response at Week 16 after receiving ustekinumab 90 mg SC 8 weeks after IV induction. Clinical benefit was also observed for ustekinumab induction delayed responders (n=157). 62.4% of patients maintained clinical response through Week 44. Delayed responder patients also achieved other measures of clinical efficacy at Week 44: Figure 2. Number of patients maintaining clinical response through Week 44 by biologic failure status; Primary efficacy analysis set

a Patients who were in clinical response to ustekinumab IV induction dosing and were randomised to maintenance placebo SC on entry into this maintenance phase. Patients who lost clinical response at any time before Week 44 were considered not to be in clinical response through Week 44.

Safety Results:  Adverse event rates in the UNIFI studies were similar in the ustekinumab and placebo arms. The overall AE profile in subjects treated with ustekinumab was generally comparable with that reported in subjects receiving placebo in both the induction and maintenance studies. Serious adverse event rates were not significantly different between treatment groups with event rates being numerically higher for placebo compared to ustekinumab arms for both induction and maintenance studies. Bayesian Network meta-analysis (NMA):  Indirect comparisons between ustekinumab and active comparators have been made based on the results of a clinical systematic literature review, for outcomes at the end of induction and end of one year (induction followed by maintenance).  As the treatment goal for patients is primarily to maintain a response or remission in the long-term, NMA results comparing efficacy after one year of treatment is considered to have the highest clinical relevance.  Comparisons of long-term clinical outcomes for ustekinumab versus other treatments in ulcerative colitis were made by using treat-through trial data, or re-calculating outcomes to reflect treat-through trial designs. o Phase III trials in ulcerative colitis are designed as either treat-through or include re- randomisation based on response to induction therapy. Long-term outcomes from the trial post-induction cannot be compared in a NMA without adjusting for study design differences. o An approach was taken to re-calculate outcomes from re-randomised response based trials to reflect treat-through data for all trials, in order to compare efficacy across active treatments at one year post initial randomisation. This approach retains the original

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randomisation of the trials and uses treat-through placebo arms to connect studies together in a network as common comparators. o Results from the head-to-head VARSITY trial corroborate with the re-calculated outcomes for the same treatments validating the approach taken.  In non-biologic failure patients, ustekinumab given as a year-long regimen (with induction therapy of 6mg/kg) was associated with a higher likelihood of clinical response, clinical remission and mucosal healing compared to all comparators (Table 1). Table 1 NMA results for clinical response and clinical remission pooled doses – non-biologic failure patients – 1-year – base case mimicking a treat-through approach Clinical response Clinical remission Treatment Median OR [CrI] Median OR [CrI] (treatment sequence for induction to Pr Pr maintenance) Ustekinumab 6mg/kg - Ustekinumab 6mg/kg - Ustekinumab 90mg pooled Ustekinumab 90mg pooled Placebo 8.70 [5.03 ; 15.40] 5.11 [2.83 ; 9.52] 100% 100% Vedolizumab 1.93 [0.75 ; 4.82] 1.47 [0.65 ; 3.33] 91.45% 82.38% Infliximab 2.62 [1.22 ; 5.60] 1.89 [0.83; 4.29] 99.31% 93.59% Golimumab 3.76 [1.90 ; 7.57] 2.40 [1.13 ; 5.22] 99.99% 98.84% Adalimumab 4.76 [2.25 ; 10.16] 2.43 [1.10 ; 5.42] 100% 98.59% Tofacitinib 2.27 [1.06 ; 4.86] 1.51 [0.64 ; 3.51] 98.21% 82.97% CrI: Credible interval; Pr: Bayesian probability of ustekinumab being better than comparator; OR: odds ratio Interpretation: OR>1: increase in likelihood of response with ustekinumab vs. comparator suggesting ustekinumab performs better Pr: Bayesian probability for ustekinumab to perform better than the comparator

 In biologic failure patients, results for ustekinumab vs. each comparator were directionally similar, but were associated with more uncertainty due to smaller sample sizes given doses could not be pooled, lower placebo rates (for remission) and differences in prior therapy across studies. Comparison of safety:  Ustekinumab demonstrated a favourable and consistent safety profile across indications  An integrated safety analysis incorporating phase II and III trials across CD, PsO, and PsA, which included approximately 6,000 patients treated with ustekinumab, reported that ustekinumab demonstrated a favourable and consistent safety profile across registrational trials in the approved indications  The results of the PSOLAR (Psoriasis Longitudinal Assessment and Registry) study which included a total of 12,093 patients accounting for 40,388 patient-years, suggested a higher risk of serious infections with adalimumab and infliximab compared with ustekinumab  A comparison between the safety profiles of ustekinumab with other advanced therapies (i.e. infliximab, adalimumab, golimumab, vedolizumab, tofacitinib) based on data in SmPC information based on evidence across all indications are provided in this submission for ease of comparison. While comparing safety profiles across products is inherently difficult and subject to qualitative interpretation and weighing of different risk profiles, the comparison of EPARs obtained after assessment of detailed data from regulators suggests ustekinumab has an acceptable safety profile.  NMA of 1-year safety outcomes was not appropriate to conduct due to heterogeneity in the placebo arms across studies, differences in eligibility criteira and lack of consistency in reporting of outcomes.

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Conclusion Ustekinumab represents an innovative treatment for moderately to severely active UC based on a mechanism of action (IL-12/23) with an established benefit/risk in other indications. Ustekinumab provides rapid improvement in disease activity and symptoms and long-term maintenance of response and remission. Ustekinumab as a one-year regimen (with induction therapy of 6mg/kg) was associated with a higher likelihood of response and remission compared to all other active treatments for patients who have not failed previously on a biologic therapy. In biological failure population, the results for ustekinumab versus each comparator were directionally similar, however these were associated with more uncertainty due to data restrictions. Compared to other treatments for UC, ustekinumab as a year-long regimen demonstrated a higher likelihood of clinical response, remission and mucosal healing in patients who had not previously failed biologic therapy. In the UNIFI study, the safety results of ustekinumab were similar to placebo. Ustekinumab has demonstrated consistent safety profile across indications (CD, PsO, and PsA). The safety comparison is based on a placebo-controlled trial in UC, and integrated analysis of clinical trials across indications, a large registry in psoriasis and the comparison of SmPC information. The safety profile is consistent with global clinical experience across PsO, PsA and CD indications. The IV infusion at induction and subcutaneous maintenance dosing (q8w or q12w) is convenient both in patients who are naïve to advanced therapies, as well as those who have failed previous biologic therapies. Ustekinumab is an innovative, safe and effective treatment for moderately to severely active UC providing rapid improvement in disease activity and symptoms and long-term maintenance of response and remission.

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1 Description and technical characteristics of the technology

Summary of the characteristics of the technology  Stelara® (ustekinumab) is a fully human immunoglobulin G1 kappa (IgG1k) monoclonal antibody to human interleukin (IL)-12/23p40 that binds with high affinity to human IL-12 and IL-23; it is the first IL 12/23 inhibitor used for the treatment of inflammatory bowel disease (IBD; i.e. Crohn’s disease [CD] and ulcerative colitis [UC])(1, 2)  It is currently licensed by the European Medicines Agency (EMA; as well as other regulatory agencies, such as Health Canada (HC), Federal Drug Administration (FDA), and SwissMedic, see Section 1.2 Question 4) as a treatment option for: paediatric and adult patients with moderate to severe plaque psoriasis (PsO) and for adult patients with active psoriasis arthritis (PsA) and Crohn’s disease (2); EMA marketing authorisation “for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies” is anticipated in August 2019 (ultimate best case; October 2019 as best case)(3)  Ustekinumab is registered as a 45 mg and 90 mg solution for injection (SC), as a 45 mg and 90 mg solution for injection in a pre-filled syringe (SC), and as a 130 mg concentrate for solution for infusion (IV); ustekinumab also provides a convenient dosing regimen- a single, high IV induction dose followed by a convenient SC injection every 8 or 12 weeks which can be administered in a home setting(1, 3)  The efficacy and safety of ustekinumab for the UC indication was demonstrated in the UNIFI clinical trial programme which comprised a phase III, double-blind, placebo-controlled, parallel-group, multicentre trial which consisted of an 8-week induction period (UNIFI induction) with responders to ustekinumab re- randomised to a 44-week maintenance period (UNIFI maintenance (see Section 5.2.1.1, 5.4, and 5.5)(1)  Based on the network meta-analysis (NMA) results, ustekinumab was associated with higher likelihoods of clinical response, clinical remission and mucosal healing at the end of a 1-year regimen (with 6mg/kg during induction) compared to all other treatments (adalimumab, golimumab, infliximab, tofacitinib and vedolizumab) for patients who had not previously failed on a biologic therapy, and especially high likelihoods compared to the anti-TNF (tumour necrosis factor)

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therapies. The results for patients who had previously failed on biologic treatment were directionally similar.  Ustekinumab has been extensively studied in clinical trials for its other indications (CD, PsA and PsO for adults and adolescents) and there is considerable experience of real world use of ustekinumab. These data provide evidence on the efficacy and safety of ustekinumab in other indications: o An integrated safety analysis incorporating phase II and III trials across CD, PsO, and PsA, which included approximately 6,000 patients treated with ustekinumab, reported that ustekinumab demonstrated a favourable and consistent safety profile across registrational trials in the approved indications o Real world evidence (RWE) supported the safety and comparative effectiveness of ustekinumab in the treatment of PsO, based on the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study: the effectiveness of ustekinumab was significantly better than all three comparators (infliximab, adalimumab, and etanercept) studied for the majority of the comparisons and no increased risk of malignancy, major adverse cardiovascular events, serious infections, and all-cause mortality was identified with use of ustekinumab (see Section 5.5.2.2)(4-6)

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1.1 Characteristics of the technology 1. In Table 2 provide an overview of the technology.

Table 2. Features of the technology Non-proprietary Ustekinumab name Proprietary name STELARA Marketing Janssen-Cilag International NV authorisation holder Class Interleukin Inhibitors Active substance(s) Ustekinumab Pharmaceutical formulation(s)  Concentrate for solution for infusion  Solution for injection

ATC code L04AC05 Mechanism of action IL-12/23 Inhibitor

Abbreviations: ATC: Anatomical therapeutic chemical; IL: Interleukin Inhibitors

2. In Table 3, summarise the information about administration and dosing of the technology.

Table 3. Administration and anticipated dosing of the technology in UC indication Method of administration Infusion followed by subcutaneous injection Doses STELARA treatment is to be initiated with a single intravenous dose based on body weight. The infusion solution is to be composed of the number of vials of STELARA 130 mg as specified below:

Body weight of Recommended Number of patient at the dose* 130 mg time of dosing STELARA Vials

≤ 55 kg 260 mg 2

> 55 kg to 390 mg 3 ≤ 85 kg

> 85 kg 520 mg 4

* Approximately 6 mg/kg

Subcutaneous dosings are available in 45 mg and 90 mg. For the dosing regime, the 90 mg will be the expected approved subcutaneous dosing.

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Dosing frequency The first subcutaneous administration of 90 mg STELARA should take place at week 8 after the intravenous dose. After this, dosing every 12 weeks is recommended. Patients who have not shown adequate response at 8 weeks after the first subcutaneous dose, may receive a second subcutaneous dose at this time. Patients who lose response on dosing every 12 weeks may benefit from an increase in dosing frequency to every 8 weeks.

Patients may subsequently be dosed every 8 weeks or every 12 weeks according to clinical judgment.

Consideration should be given to discontinuing treatment in patients who show no evidence of therapeutic benefit 16 weeks after the IV induction dose or 16 weeks after switching to the 8-weekly maintenance dose. Average length of a course of Chronic/continuous due to chronic character of Ulcerative treatment Colitis Anticipated average interval Not applicable (NA) between courses of treatments Anticipated number of repeat Not applicable (NA) courses of treatments Dose adjustments Please see dosing (above)

3. In Table 4 provide information about the different packs available.

Table 4. Pack information Pack code (if available, for example VnR code or Pack size Strength Form barcode) MA (EU) number

For treatment of Crohn’s disease, and proposed for treatment of Ulcerative Colitis

Stelara 130 mg Concentrate Concentrate for N1 = 1 vial 130 mg for solution EU/1/08/494/005 solution for infusion. for infusion.

For treatment of Crohn’s disease, Plaque Psoriasis and Psoriatic Arthritis, proposed for treatment of Ulcerative Colitis.

solution for Stelara 90 mg prefilled N1 = injection in 90 mg EU/1/08/494/004 syringe 1 syringe pre-filled syringe

Solution for Stelara 90 mg N1 = 1 vial 90 mg EU/1/08/494/002 injection

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Pack code (if available, for example VnR code or Pack size Strength Form barcode) MA (EU) number

Stelara 45 mg solution solution for N1 = 1 vial 45 mg EU/1/08/494/001 for injection injection

solution for Stelara 45 mg solution N1 = injection in for injection in pre-filled 45 mg EU/1/08/494/003 1 syringe pre-filled syringe syringe

Abbreviations: VnR: Nordic Article Number

4. State the context and level of care for the technology (for example, primary healthcare, secondary healthcare, tertiary healthcare, outside health institutions or as part of public health or other).

Moderately to severely active UC is typically diagnosed by a gastroenterologist (i.e. secondary healthcare provider. Ustekinumab induction dosing is administered intravenously (IV), which can be administered in a hospital setting or infusion clinic by a physician experienced in the diagnosis and treatment of ulcerative colitis.(3) Maintenance therapy is available as a subcutaneous (SC) injection, and can be conveniently administered in the home setting.(3)

5. State the claimed benefits of the technology, including whether the technology should be considered innovative.

Ustekinumab is the first IL 12/23 inhibitor licensed for the treatment of inflammatory bowel disease. The efficacy and safety of ustekinumab in the treatment of patients with moderately to severely active UC was demonstrated in a phase III, randomised, double- blind, placebo-controlled, multicentre UNIFI trial. The safety and efficacy of ustekinumab was also assessed in clinical trials for previously-approved indications such as CD (UNITI), PsO (PHOENIX and ACCEPT) and PsA (PSUMMIT).(7-9) The results of the NMA of efficacy outcomes showed that ustekinumab is a highly effective option in helping patients reach both short-term (6-8 weeks) response to treatment and a long-term response and remission (at the end of 1-year), in patients who did not previously fail on a biologic therapy. In the non-biologic failure population, patients having received ustekinumab 6 mg/kg in induction had consistently high likelihoods of achieving clinical response (Pr>90%), remission (Pr>80%), and mucosal healing (Pr>80%) after a year-long treatment regimen. The NMA predicts response rates after a year of treatment of 68.1% with ustekinumab versus 30.9% to 52.5% for the active comparators in non-biologic failure patients. The results of the NMA suggest that similar conclusions can be made in the biologic failure population for a year-long

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treatment regimen, but these are more uncertain partly due to smaller patient numbers for these analyses (see Section 5.4.3.2). Given the efficacy and safety profile demonstrated in the UNIFI clinical trial programme, the supporting clinical trial evidence in CD, PsO and PsA, and RWE from other indications such as PsO, the comparative efficacy and safety, as well as the convenient dosing regimen, ustekinumab provides a much needed innovative (the first IL12/23 inhibitor treatment) treatment for moderately to severely active UC patients refractory to both conventional and biologic therapies.

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1.2 Regulatory status of the technology 1. Complete Table 5 with the marketing authorisation status of the technology.

2. State any other indications not included in the assessment for which the technology has marketing authorisation.

Plaque psoriasis STELARA is indicated for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate (MTX) or psoralen and ultraviolet A (PUVA). Paediatric plaque psoriasis STELARA is indicated for the treatment of moderate to severe PsO in adolescent patients from the age of 12 years and older, who are inadequately controlled by, or are intolerant to, other systemic therapies or phototherapies Psoriatic arthritis STELARA, alone or in combination with MTX, is indicated for the treatment of PsA in adult patients when the response to previous non-biological disease-modifying anti- rheumatic drug (DMARD) therapy has been inadequate Crohn’s Disease STELARA is indicated for the treatment of adult patients with moderately to severely active CD who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a TNF-inhibitor (TNFi) or have medical contraindications to such therapies. See Summary of Product Characteristics for Stelara® for further information.(2) 3. State any contraindications or groups for whom the technology is not recommended.

Contraindications

Contraindications to ustekinumab include:  Hypersensitivity to the active substance or to any of the excipients (see Section 6.1 in the SmPC)  Clinically important, active infection (e.g. active tuberculosis; see Section 4.4 in the SmPC) See Summary of Product Characteristics for Stelara® for further information.(2, 3)

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Special populations Children and adolescents Stelara is not recommended for use in children with psoriasis under 12 years of age, or for use in children under 18 years of age with PsA, CD, or UC because it has not been studied in this age group. Other medicines, vaccines and Stelara Let a doctor or pharmacist know if the patient is taking, have recently taken or might take any other medicines. Live vaccines should not be given concurrently with Stelara. No interaction studies have been performed in humans. Pregnancy and breast-feeding  Pregnancy: There are no adequate data from the use of ustekinumab in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development. As a precautionary measure, it is preferable to avoid the use of Stelara in pregnancy.  Breast-feeding: It is unknown whether ustekinumab is excreted in human breast milk. Animal studies have shown excretion of ustekinumab at low levels in breast milk. It is not known if ustekinumab is absorbed systemically after ingestion. Because of the potential for adverse reactions in nursing infants from ustekinumab, a decision on whether to discontinue breast-feeding during treatment and up to 15 weeks after treatment or to discontinue therapy with Stelara must be made taking into account the benefit of breast-feeding to the child and the benefit of Stelara therapy to the woman.  Fertility: The effect of ustekinumab on human fertility has not been evaluated. For additional information on special populations, refer to the Stelara summary of product characteristics (SmPC).(2, 3) 4. List the other countries in which the technology has marketing authorisation.

Ustekinumab has obtained marketing authorisation for the CD, PsO, and PsA indications by various regulatory agencies, including:  European Medicines Agency (Europe)(10) o Crohn’s disease indication in 2016 o Plaque psoriasis indication in adult and adolescent patients [age of 12 years and older] in 2009 and 2015, respectively o Psoriasis arthritis indication in 2013  Health Canada (Canada)(11)  Food and Drug Administration (United States)(12)

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 Therapeutic Goods Administration (TGA; Australia)(13)  SwissMedic (Switzerland)(14, 15) o Crohn’s disease indication in June 2017 o Plaque psoriasis in October 2010 o Psoriatic arthritis in December 2012  Other countries and regions, such as: Russia, United Arab Emirates, Lebanon, South Africa, and certain northern African countries (i.e. Egypt, Libya, and Morocco).(14) The SwissMedic regulatory submission for UC was submitted in June 2019 and a final decision is expected by May 2020. Ustekinumab is anticipating the EMA marketing authorisation for the UC indication, the focus of this submission, by August 2019 (ultimate best case; October 2019 as best case).(3) It was also submitted for this indication for FDA approval.(16)

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Table 5. Regulatory status of the technology Launched (yes/no). Organisation issuing Verbatim wording of the (expected) indication(s) Date of approval If no include proposed approval date of launch

European Commission STELARA is indicated for the treatment of adult August 2019 (ultimate best case) No (after approval) patients with moderately to severely active UC who have had an inadequate response with, lost response October 2019 (best case) to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such December 2019 (base case) therapies.(3)

Abbreviations: UC: Ulcerative Colitis

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2 Health problem and current clinical practice

Summary of issues relating to the health problem and current clinical practice  Ulcerative colitis is a lifelong, progressive disease characterised by the diffuse inflammation of the rectal and colonic mucosa; the disease has a dynamic nature characterised by relapsing and remitting episodes of inflammation, which can lead to typical UC symptoms such as: rectal bleeding, bowel urgency, tenesmus, proctitis, diarrhoea and abdominal cramping, as well as fatigue and fever in patients with extensive disease(17)  Ulcerative colitis is a debilitating disease with a significant impact on patient quality of life (QoL), social and mental well-being, and patients’ day-to-day lives; the physical symptoms of UC have a broad impact on patients’ lives, which prevents them from living a ‘normal’ life in terms of their daily activities, work, and relationships when compared to people of a similar age, socioeconomic status (SES) and geographical region(18)  The anticipated target EMA indication for ustekinumab is for the treatment of adult patients with moderately to severely active UC who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies(3)  Although the management of UC has improved since the introduction of non- conventional therapies (especially biologics and therapies with innovative mechanisms of action [MOA]) over recent years, the management of disease activity and symptoms remain suboptimal; patients continue to suffer a substantial burden of disease (i.e. more than 60% of anti-TNF treated patients failing maintenance at 1 year and 50% discontinuing therapy), with high rates of dose escalation (i.e. approximately 40% of biologic naïve UC patients dose escalate within two years of anti-TNF initiation), treatment switching and finally surgery (i.e. incidence of colectomy in anti-TNF failure patients is high with nearly 20% requiring surgery despite therapy with vedolizumab), which is associated with long-term consequences (i.e. reduction of QoL)(19-24)  Ustekinumab demonstrated strong and rapid induction efficacy (i.e. 15.5% vs. 5.3% of patients achieved clinical remission on UST 6mg/kg vs. placebo at Week 8 [primary endpoint]; 61.8% vs. 31.3% of patients achieved clinical response on UST 6mg/kg vs. placebo at Week 8), clinically meaningful improvements in patient health-related quality of life (HRQoL; i.e. significantly greater proportions of subjects in the UST q8w and q12w groups had >20-point improvement in total

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inflammatory bowel disease questionnaire (IBDQ) score [69.9% and 66.3%, respectively] compared with subjects in the placebo group [42.9%] for both comparisons] at Week 44), and sustained long-term maintenance of remission in both early (i.e. 43.8% and 3.84% for UST q8w and q12w respectively, vs. 24.0% for the placebo group achieved clinical remission) and delayed responders in the UNIFI clinical trial programme for patients with UC (i.e. UNIFI induction and maintenance; see Section 5.2.1.1, 5.4, and 5.5)(1). Delayed responders are defined as patients who respond not at the end of the induction assessment but later at Week 16, in contrary of the early responders being Week 8 induction clinical responders. o The NMA of ustekinumab as a yearlong regimen (for patients who received 6mg/kg at induction) versus other active treatments showed a higher likelihood of clinical remission (Pr >80%) for patients who had not previously failed on a biologic therapy and directionally similar results for biologic failure patients.  Ustekinumab is an IL12/IL23 inhibitor which has demonstrated consistently strong efficacy and safety in the treatment of inflammatory bowel disease [IBD} (i.e. for both CD and UC), various other indications (i.e. PsA and PsO) over many years of use in clinical practice(4, 5)

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2.1 Overview of the disease or health condition 1. Define the disease or health condition in the scope of this assessment.

Ulcerative colitis (UC; ICD 10 code: K51.90) is a lifelong, progressive disease characterised by the diffuse inflammation of the rectal and colonic mucosa.(17) The disease has a dynamic nature characterised by relapsing and remitting episodes of inflammation, much like CD, which combined are referred to as inflammatory bowel disease. The aetiology of UC is not fully understood. Although it is considered idiopathic, the multifactorial pathogenesis of the disease is known to involve genetic predisposition, epithelial barrier defects, dysregulated immune responses, and environmental factors.(25). Curative medical therapies are not currently available, with the focus of treatment being on symptom management and improvement of quality of life.(26) The symptoms of UC are diverse, depending on the extent of the disease and can be severe, with a profound impact on patients’ lives.(27, 28) Patients may experience rectal bleeding, bowel urgency, tenesmus, proctitis, diarrhoea and/or abdominal cramping. In extensive disease, more general symptoms such as fatigue and fever can also be present. Nearly 70% of patients experience UC symptom flares every few months, with over 75% reporting that symptoms limit their ability to enjoy leisure activities.(29) Symptoms of UC also impact patients’ ability to work (Section 2.1, Question 3). The clinical course of UC may range from a quiescent course with prolonged periods of remission to fulminant disease and surgery.(30) Disease progression in UC takes six principal forms: proximal extension, stricturing, pseudopolyposis, dysmotility, anorectal dysfunction, and impaired permeability.(31) At disease presentation, typically 30%-60% of patients have proctitis, 16%-45% have left-sided colitis and 14%-35% have extensive pancolitis, as described in Figure 1 and Table 6.(27, 32)

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Figure 1. Ulcerative colitis phenotypes(27)

Table 6. Disease distribution definition Term Distribution Description E1 Proctitis Involvement limited to the rectum (i.e. proximal extent of inflammation is distal to the recto-sigmoid junction) E2 Left-sided Involvement limited to the proportion of the colon distal to the splenic flexure (analogous to 'distal' colitis) E3 Extensive Involvement extends proximal to the splenic flexure, including pancolitis

Several biomarkers of inflammation are commonly monitored in clinical trials and in clinical practice, including C-reactive protein (CRP). In UC, elevated CRP has been associated with severe clinical activity, an elevated sedimentation rate, and active disease as detected by colonoscopy. CRP is commonly monitored in clinical trials and routinely captured in clinical practice. Faecal lactoferrin and faecal calprotectin have been demonstrated to be sensitive and specific markers in identifying intestinal inflammation and response to treatment in patients with IBD.(33-35) Ulcerative colitis progresses in severity over time, with studies showing that within 10 years of diagnosis, up to 28% of patients diagnosed with left-sided colitis progress to extensive colitis.(36) A more extensive disease is associated with a higher clinical and economic burden, more than two times higher rate of hospitalisations and more than three times increased risk of colectomy compared to distal disease.(37, 38) Further evidence suggests that in up to 11.2% of patients disease progresses beyond the mucosal layer and leads to the formation of colonic strictures.(30) UC has a high patient burden, driven by the chronic nature of the disease, the persistency of its symptoms and the consequences of surgery and its complications:  Nearly 70% of patients experience UC symptom flare-ups every few months and more than 70% reporting inability to enjoy leisure activities(29)  High symptoms burden is an independent predictor of decreased physical and mental health-related quality of life (39, 40)

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 Typical physical symptoms of UC include, rectal bleeding, bowel urgency, tenesmus, proctitis, diarrhoea and abdominal cramping; in extensive disease more general symptoms such as fatigue and fever can also be present (see Section 2.1, Question 3 for more details)  The impact of UC extends to social encounters and family relationships, as it is often associated with feelings of embarrassment, insecurity, depression, and stress that patients experience when around other people; patients highlighted that there are many dimensions of the patient journey of UC from diagnosis to extended treatment, which contribute to the highly individualised patient experience (see Section 2.1, Question 3 for more details)  Patients undergo multiple lines of treatments in order to control their disease and up to 20% of patients eventually need surgical resection, which has life-long consequences (i.e. reduction in QoL) (41) More extensive disease is associated with a higher clinical burden, more than two times higher rate of hospitalisations and more than three times increased risk of colectomy compared to distal disease:(37, 38)  Large follow-up cohorts show that proportion of UC patients with proctitis (least extensive disease) decreases over time as the disease progresses(32)  Within 10 years of diagnosis, up to 28% of patients diagnosed with left-sided colitis progress to extensive colitis(36) Increased mortality in UC occurs both directly related to the disease, as well as additional mortality risk related to surgery. Despite improved surgical techniques, there is still an increased mortality risk in patients who undertake the procedure  Ulcerative colitis increases the risk of death with a standardised mortality ratio versus general population of 1.192. Mortality is significantly higher in patients with extensive disease who are also at an increased risk of malignancies(42, 43)  Surgery increases risk of mortality with 30-day mortality for elective and emergent surgery of 0.7% and 5.3%, respectively, and in-hospital mortality of up to 8%(44, 45) Despite the availability of alternative treatments, such as TNF inhibitors (anti-TNFs; see Section 2.3 and 2.4), lack of long-term remission is common and associated with poor clinical outcomes  In clinical practice, anti-TNF therapies account for more than 90% of biologics utilisation(46)  At 4 years, only 25% of patients who respond to adalimumab induction are in remission; Long-term response is low, with more than 60% of anti-TNF treated patients failing maintenance at 1 year and 50% of these discontinuing therapy(47, 48)  Loss of response and remission at maintenance is associated with an increased risk of colectomy(49)

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Dose escalation due to lack of efficacy is common in both non-biologic failure and biologic failure patients and is associated with poor clinical outcomes:  Approximately 40% of biologic naïve UC patients dose escalate within two years of anti-TNF initiation and this is associated with poor clinical outcomes(49-51)  A multinational chart review which examined the incidence of suboptimal therapy (i.e. dose escalation, discontinuation, switching, non-biologic therapy escalation, or surgery) in anti-TNF treated UC patients demonstrated that most UC patients who discontinued their initial anti-TNF therapy did so due to poorly controlled symptoms (45.6%), and one-in-five experienced an adverse reaction over a two- year follow-up period (23.2%)(51)  Incidence of dose escalation with vedolizumab in biologic failure patients is 39.8 per 100 person-years. However, only half of those requiring dose escalation achieve restoration of the original response(52)  Higher maintenance dose (10mg) on tofacitinib is associated with increased risk of serious infections and skin cancer(53), is no longer recommended for patients with high risk of blood clot in lungs by the EMA(54) Anti-TNF failure patients face unmet needs due to lack of efficacious alternatives  Vedolizumab is one of the few alternative treatments for an anti-TNF failure population (the other being tofacitinib), achieving response of approximately 40% at induction and less than 40% at maintenance (in induction responders) in randomised control trials (RCT) and similar outcomes observed in the real world(22, 55)  A high proportion of anti-TNF failure patients subsequently require colectomy with nearly 20% having surgery despite therapy with vedolizumab(55) Given the chronicity, progression, and highly individualised symptom burden of moderately to severely active UC, as well as the current unmet needs faced by both non-biologic failure and biologic failure patients, alternative treatments are required to help patients achieve treatment goals of remission improve their overall quality of life (see Section 2.3). 2. Present an estimate of prevalence and/or incidence for the disease or health condition including recent trends.

Ulcerative colitis is the most common form of IBD; the highest prevalence values for IBD in the world were reported in Europe, with the highest in Norway (UC, 505 per 100,000 people in Norway).(56) The most recent incidence and prevalence estimates for UC in Europe, reported in a review that included studies from 1990 to 2016, vary from 0.97 to 57.9 and 2.42 to 505.0 per 100,000 people.(56) Epidemiology data for UC categorised by European region are shown in Table 7. On a national level, there is a lack of updated epidemiology studies for many European countries, however Table 8 demonstrates the most current data available.

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Table 7. Incidence and prevalence of UC by European region(56) Incidence per 100,000 person- Prevalence per 100,000 person- year year Region Lowest Highest Highest Lowest estimate estimate estimate estimate Eastern Europe 0.97 11.9 2.42 340 Northern Europe 1.7 57.9 90.8 505.0 Southern Europe 3.3 11.47 14.5 133.9 Western Europe 1.9 17.2 43.1 412.0

Table 8. Incidence and prevalence of UC by European country

Incidence per Prevalence per Country Year Source 100,000 person-year 100,000 person-year

Germany NA 412 2010 (57) France 5 NA 2008 (58) Italy 3.4-10.5 NA 1999 (59) United Kingdom 10 243 2013 (60) (UK) Sweden NA 474 2010 (61) Finland NA 177 1993 (62) Norway NA 505 2016 (56) Denmark 18.6 NA 2013 (63) Abbreviations: NA: Not applicable; UK: United Kingdom

Ulcerative colitis may present at any age, but peak incidence is between the ages of 15 and 25 years (with a second, smaller peak between 55 and 65 years) resulting in substantial disability that impacts patients in their most productive years.(25, 64) Epidemiological data from the EpiCom cohort (2014) estimated the number of UC patients by disease distribution (i.e. proctitis, left-sided colitis, and extensive disease in both Western Europe (21% proctitis, 41% left-sided colitis, and 38% extensive disease) and in Eastern Europe (22% proctitis, 35% left-sided colitis, and 33% extensive disease).(65) More recent data for England estimated that around 52% of UC patients have moderate-to-severe disease.(66, 67) This is aligned with another study based on results from the Adelphi Inflammatory Bowel Disease Specific Programmes (IBD- DSP) database (2019), which demonstrated that gastroenterologists categorised the severity of their UC patients to be 44.7% moderate and 4.3% severe.(68) Further information regarding epidemiology and the target population for the technology of focus in this submission are included in Section 2.2. 3. Describe the symptoms and burden of the disease or health condition for patients.

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The symptoms and burden of UC affect patients in a range of ways over the course of the disease with increasing morbidity over the course of the disease. They are at risk of hospitalisation and UC-related surgery and have an increased mortality risk especially for patients with extensive disease and undergoing surgery. Ulcerative colitis has adverse effects on patients’ quality of life, mental health and social interaction. Ulcerative colitis treatment is increasingly focused on long term efficacy including histological healing and rapid induction efficacy to address these issues.

Morbidity, common symptoms, and disease course of UC patients

Ulcerative colitis symptoms are diverse, depending on the extent of the disease (see Section 2.1, Figure 1) and can be severe with profound impact on patients’ lives.(27, 28) Nearly 70% of patients experience UC symptom flares every few months, with over 75% reporting that symptoms limit their ability to enjoy leisure activities.(29) In a qualitative focus group study, adult UC patients identified and discussed the most important symptoms that they experience, which included:(69)  Cramping and abdominal pain: “I would have bouts of cramping so bad that I would roll up on the floor into [a] ball…and I didn’t know if I was going to, if anything was going to come out of me until that passed, and suddenly I would have a bowel movement. Now those were very painful.”  Stool frequency: “I average maybe two or three bowel movements on a normal day, and um, I had a flareup this fall, and it just came on…so I was just in the bathroom basically all day, and then I had to go to the hospital, it wasn’t just like once every half hour, it was like every five minutes.”  Rectal bleeding: “…I had significant passing of blood which they say, in all honesty, was it a lot at one time? No, but no matter how much they tell you not to worry, when blood is leaking [from] your body in a manner it should not be, you worry.”  Endoscopic findings and disease activity: “Testing [endoscopy] has always been pretty much a confirmation of how I’m feeling at the time.” The clinical course of UC may range from a quiescent course with prolonged periods of remission to fulminant disease and surgery.(30) While it is considered that the disease extent remains stable in most patients, some studies have shown extension of disease from initial location in 10%–19% of the patients after 5 years and from 11%–28% after 10 years post-diagnosis (see Figure 2).(32)

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Figure 2. Percentage of patients with proctitis (anatomically limited disease) over disease course by study

Abbreviations: EC-IBD: European Collaborative Study Group of Inflammatory Bowel Disease; IBSEN: Inflammatory Bowel Disease in South-Eastern Norway

The changing nature of the disease over time indicates an increasing symptomatic burden of disease over time as well as increased probability of having a surgery even in patients who started with a limited disease at diagnosis.(70) Although control of disease activity is likely to have a benefit on long-term clinical outcomes in patients, strong evidence suggests that current medical management is still lacking in disease modifying properties. Long-term data from the Inflammatory Bowel Disease in South-Eastern Norway (IBSEN) cohort has provided clarity on the natural behaviour of ulcerative colitis. The IBSEN cohort study examined newly diagnosed UC patients during the first 10 years post-diagnosis in South-Eastern Norway. Based on observations from 379 patients, Solberg et al. identified four general profiles of disease behaviour: remission to mild disease after initial high activity, increase in severity after initial low activity, chronic continuous symptoms, and chronic intermittent.(36) A visualisation of the different disease courses has been presented in Figure 3.

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Figure 3. UC disease behaviour over time in the IBSEN cohort

Abbreviations: IBSEN: Inflammatory Bowel Disease in South-Eastern Norway

As the disease progresses, UC patients might develop complications such as fulminant colitis, toxic megacolon, colorectal carcinoma, extra-intestinal manifestations (EIMs) as well as growth retardation in children. Fulminant colitis is a severe attack of colitis with bloody diarrhoea, abdominal pain and fever. Toxic megacolon is the acute dilatation of a segment of the colon with associated toxicity, which is a severe and potentially lethal complication.

Ulcerative colitis is associated with a long-term increased risk of developing colorectal carcinoma.(71) Around 30% of patients with UC will suffer from EIMs which are often related to disease activity and most frequently affect joints (i.e. peripheral and axial arthropathies), the skin (i.e. erythema nodosum, pyoderma gangrenosum), the hepatobiliary tract (i.e. primary sclerosing cholangitis), and the eye (i.e. episcleritis, uveitis). Traditionally, surgery is considered for the management of each of those complications.(72)

Burden of Hospitalisation and Surgery Most UC patients will experience a UC-related hospitalisation during their life with 1-, 5- and 10-year cumulative probabilities of 17-29%, 29-54% and 39-66%, respectively.(73) Disease activity is a known driver of costs in UC and patients with moderate-to-severe disease have significantly (p<0.0001) higher hospitalisation rates (26.5% vs 6.2%) compared to controls.(74)

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Surgery is common in patients with medically refractory UC, and in patients who experience acute episodes.(41) Given the invasive nature of the procedure and the lengthy recovery period, it is associated with an impact on QoL, economic burden, and mortality. Long term maintenance of remission is a therapeutic goal which is still not achieved by many UC patients, resulting in several lines of treatment with up to 40% of patients eventually needing surgical resection, which has life-long consequences (i.e. increased rates of infection and reduction in QoL).(41) Short and long-term complications of surgery are common and can have a profound impact on patients’ lives. Short-term complications, occurring within 30 days of a procedure include infections (20%), ileus (18%), pouch-related complications (8%), small bowel obstructions (8%), and anastomotic leakage (2%).(41, 75) Longer-term complications, occurring more than 30 days post procedure include pouchitis (29%), faecal incontinence (21%), small bowel obstruction (17%), ileus (11%), fistula (6%), and pouch failure (5%).(41) Although HRQoL in surgical patients generally increases after the procedure, studies have shown that it is still significantly lower than the general population and most importantly, patients with pouch failure have significantly lower HRQoL compared to successful ones.(76) In fact, short-term improvements in HRQoL in 80% of patients were not sustained in the long term due to depression, body image, greater eating restrictions, sexual function and reduced productivity.(77) Surgery also has an effect on mortality, with a recent review and meta-analysis of population-based studies, estimating pooled all-cause mortality in elective patients as 0.7% (95% CI: 0.6%–0.9%) and emergency patients 5.3% (95% CI: 3.8%–7.4%).(45) Increased mortality for UC patients, especially with extensive disease and undergoing surgery Patients with UC suffer from multiple co-morbidities, including cardiovascular, hepatic and mental health diseases, which are known to have significant impact on the overall disease burden to patients.(78, 79) The increased burden of disease in patients is emphasised further by the fact that presence of UC can be an independent risk factor associated with increased mortality, specifically in patients with more extensive disease.(80) Increased in mortality in UC patients has been investigated by several authors through meta-analyses.(80, 81) Although conclusions do differ between the different studies, the general consensus is that the disease does carry an increased risk of death compared to the general population with a standardised mortality ratios reported of slightly above 1-1.10 (95% CI 1.05–1.15) - 1.19 (95% CI 1.06–1.35).(80, 81) Patients with extensive colitis have been reported to have highest mortality risk with an SMR of up to 1.5.(42, 43) The effects of UC on mental health and social context The impact of UC extends to social encounters and family relationships, as it is often associated with feelings of embarrassment, insecurity, depression, and stress that patients experience when around other people.(82) A recent qualitative study in the United Kingdom (UK) assessed patients’ experiences using a series of semi-structured interviews. The authors report patients with UC often experience the fear of losing bowel control and being humiliated or socially isolated which creates difficulties in

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committing to and attending social events. It also creates difficulties for patients in terms of being intimate with their partners or taking care of their family.(83) The increased burden of disease in patients is emphasised further by the fact that the presence of UC can be an independent risk factor associated with increased mortality, specifically in patients with more extensive disease.(80) In a recent survey conducted by Janssen (2019) regarding the patient journey and unmet needs experienced by patients with moderate-to-severe UC (n=30), patients highlighted that there are many dimensions of the patient journey of UC from diagnosis to extended treatment, which contribute to the highly individualised patient experience:(84)  healthcare aspect (e.g. primary vs secondary care provider, length of time prior to diagnosis, healthcare practitioner engagement),  emotional/social aspect (e.g. anxiety levels, feelings of hope vs. hopelessness, feelings of control of their symptoms),  treatment burden (e.g. predictability of side effects),  and the aforementioned physical component (e.g. UC-related symptoms). The survey results indicate that the majority of patients focus on the emotional/social impact of UC due to the unpredictability of flares, frustration of cycling through treatment options, and feelings of anxiety, isolation and humiliation of experiencing the inability to conduct activities of daily living and work commitments. To draw from patient quotes from the survey, regarding the unpredictability and emotional burden of ulcerative colitis:  “Half the battle with UC is with your own mind, and society’s expectations of you but the most important thing you can do is be confident in yourself, and be positive.”  “I was quite worried as I had never been seriously ill before…the symptoms continued and they worsened and then you get this excoriating pain with it as well. It just gets to the point that it is unbearable. You are quite frightened as you don’t know what it is and you expect the absolute worst.”  “Ulcerative colitis completely controls your life, your career, absolutely everything, your relationships. Everything just revolves around it. You can hide it as much as possible, but it takes over even going down to Waitrose or booking a holiday. It completely controls everything.” Quality of life measures and UC A number of studies have also shown a relationship between HRQoL measures (e.g. 5- level EQ-5D (EQ-5D-5L)) and disease activity in patients with ulcerative colitis.(85) A recent observational study assessed the relationship between disease status, patient QoL and healthcare resource use in the UK.(86) According to the findings when compared with patients in remission, patients with active disease have significantly worse QoL and significantly more work impairment. Specifically, the mean EQ-5D-5L score was significantly higher in patients in remission (0.86) versus those with active disease (0.71; p<0.001). A significant difference was also observed in the mean EQ-5D-

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5L scores of patients with mild versus moderate/severe disease (0.77 vs 0.66; p<0.001). Furthermore, recent findings also suggest that the number of relapses in UC patients during the course of the disease is expected to impact their QoL significantly. According to 5-years results of the IBSEN study, UC patients with no relapses during the 5 year course of their disease, reached an average IBDQ score of 196.00 points in comparison with the 183.58 points of patients having faced relapses during the same period (p<0.001).(165) Improvements for UC treatment: a focus on histological healing, and rapid induction efficacy Endoscopy has played an important role in UC diagnosis and monitoring in both RCTs and clinical practice. Endocopic findings inform both the initial diagnosis, ongoing information about disease severity, and are also used in clinical trials to inform the outcome of mucosal healing. Mucosal healing has been associated with long-term remission of disease activity, decreased risk of surgery, and to improve HRQoL in UC patients. More recently, histologic healing of the mucosa has emerged as an important marker of treatment efficacy, allowing physicians to meaure the underlying inflammation to better manage disease activity.(25, 87, 88) This is expected to play a larger future role in ensuring patients are in true remission from inflammation beyond what is visible from endoscopy or measured through clinical tools such as the Mayo score.(89-91) The clinical course of UC varies widely between patients (Figure 1 and Figure 3). Achieving and maintaining long-term remission is an important treatment goal (see Section 2.3) for patients with moderately to severely active UC, and alternative treatments are needed for patients with high unmet need, including specific subgroups of patients: who are non-biological failure, who have previously failed biologics therapy, and those who have had delayed response to biologic therapy (i.e. responded to treatment at Week 16, instead of Week 8). It is also beneficial for patients to obtain strong and rapid efficacy in the treatment of their condition to avoid worsening of symptoms, reduce likelihood of complications and EIMs, and to ultimately improve the course of the disease. 4. Describe the aspects of the burden of disease that are targeted by the technology, that is, those that are expected to be reduced by the use of the technology.

Ustekinumab addressed many of the aspects of UC patient burden addressing the signs and symptoms of UC, reducing hospitalisation and improving patients’ quality of life. This is demonstrated in the UNIFI clinical programme by: achieving strong and rapid induction efficacy, sustained long-term maintenance efficacy, improvements in histological healing and HRQoL, as well as a consistent safety profile with other indications for ustekinumab. The results from the clinical trial programme are also applicable to specific populations of patients with UC, such as non biologic failure and biologic failure. The key efficacy and safety outcomes improved by ustekinumab, as shown in the UNIFI clinical programme, are summarised below:

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 Ustekinumab provided strong and rapid induction efficacy across a diversity of UC patients (full population, biologic failure and non-biologic failure): Full population Ustekinumab induction (~6 mg/kg IV or 130 mg [UST ~6 mg/kg is the anticipated approved induction dose]) improved the signs and symptoms of UC, the objective measures of systemic and colonic inflammation, and HRQoL in patients with moderately to severely active ulcerative colitis. At Week 8, a significantly greater proportion of patients in both the ustekinumab ~6 mg/kg (15.5%) and 130 mg (15.6%) groups achieved clinical remission compared with placebo (5.3%; p<0.001). Furthermore, at Week 8, significantly greater proportions of patients in the ~6 mg/kg and 130 mg ustekinumab groups achieved endoscopic healing (27.0% and 26.3%, respectively) compared with patients in the placebo group (13.8%; p<0.001 for both comparisons). Non biologic failure Of the patients who did not have a history of biologic failure, significantly greater proportions of patients in the ~6 mg/kg and 130 mg groups (18.6% and 19.9% respectively), achieved clinical remission at Week 8, compared with patients in the placebo group (9.5%; p=0.022 and p=0.009, respectively). Biologic failure Of the patients who had a history of biologic failure, significantly greater proportions of patients in the ~6 mg/kg and 130 mg groups (12.7% and 11.6%, respectively), achieved clinical remission at Week 8 compared with patients in the placebo group (1.2%; p<0.001 for both comparisons).  Treatment with ustekinumab results in sustained long-term maintenance of remission both in early and delayed responders Full population For clinical remission, a significantly greater proportion of patients of patients with at least clinical response post induction in the ustekinumab q8w (43.8%) and q12w (38.4%) groups were in clinical remission at Week 44 compared with placebo (24.0%; p<0.001 and p=0.002, respectively). Non Biologic Failure Patients Of the patients without a history of biologic failure, significantly greater proportions of patients in the ustekinumab q8w and q12w groups (48.2% and 49.0%, respectively) achieved clinical remission at Week 44, compared with patients in the placebo group (31.0%; p=0.024 and p=0.020, respectively). Biologic Failure Patients Of the patients with a history of biologic failure, significantly greater proportions of patients in the ustekinumab q8w and q12w groups (39.6% and 22.9%, respectively) achieved

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clinical remission at Week 44 compared with patients in the placebo group (17.0%; p<0.001 and p=0.044, respectively). Results for clinical response results for the maintenance phase of UNIFI by biologic failure status are demonstrated in Figure 4. Figure 4. Number of patients maintaining clinical response through Week 44 by biologic failure status; Primary efficacy analysis set

Delayed responders Overall, 56% (n=157) of patients who were not in clinical response at Week 8 (n=279) were in clinical response at Week 16 after receiving ustekinumab 90 mg SC 8 weeks after IV induction. In this group of delayed responders, benefit was observed with continued ustekinumab therapy (at 90 mg SC q8w) and 62.4% maintained clinical response, 30.6% achieved clinical remission, and 35.7% achieved endoscopic healing at Week 44. Figure 5 presents the proportion of patients with clinical response at week 8 (induction responders) and week 16 (delayed responders) totaling to 77.6% of the full population receiving ustekinumab.

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Figure 5 Proportion of patients in clinical response at Week 8 and Week 16

 Ustekinumab was the first biologic therapy to show statistically significant difference in histologic healing versus placebo in refractory UC patients: The proportions of patients who achieved histologic healing at Week 8 were significantly greater in both the ~6 mg/kg (35.6%) and 130 mg (37.9%) ustekinumab groups compared with the placebo group (21.9%, p<0.001 for both comparisons). At Week 44, significantly greater proportions of patients in the ustekinumab q8w and q12w groups achieved histologic healing (59.3% and 54.0%, respectively) compared with patients in the placebo group (32.9%; p<0.001 for both comparisons). Of the patients who did not have a history of biologic failure, significantly greater proportions of patients in the ustekinumab q8w and q12w groups (57.6% and 55.9%, respectively) achieved endoscopic healing at Week 44 compared with patients in the placebo group (34.5%; p=0.002 and p=0.007), respectively. Of the patients with a history of biologic failure, a significantly greater proportion of patients in the ustekinumab q8w group (45.1%) and a numerically greater proportion of patients in the q12w groups (25.7%) achieved endoscopic healing at Week 44 compared with patients in the placebo group (22.7%; p<0.001, p=0.163), respectively.  Strong medical benefit of ustekinumab was supported by clinically meaningful improvements in HRQoL of patients: Ustekinumab was efficacious in improving IBD-specific and general HRQoL outcomes as evaluated by the IBDQ, the 36-item Short Form Survery (SF-36), and the EQ-5D at Week 8, with statistically significant results for both induction doses. Through Week 44, patients in the ustekinumab q8w and q12w groups were generally able to maintain improvement in patient-reported HRQoL as assessed using the IBDQ, SF-36 and EQ-5D instruments compared with patients in the placebo group.  Ustekinumab was well-tolerated with a safety profile consistent across other indications: Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 46

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The UNIFI programme demonstrated that both IV induction and SC maintenance regimens of ustekinumab were generally well tolerated and consistent with a wealth of data from different indications both in clinical trial and real-world settings.(4, 5, 92) The proportions of subjects reporting AEs and infections in the ~6 mg/kg group in induction was generally comparable with the placebo group in induction (with the 130 mg group having a lower proportion reporting AEs or infections), while the proportions of subjects in the ustekinumab 90 mg q8w dosing regimen were generally comparable to the placebo group (with the proportions of subjects in the q12w reporting AEs). Overall, the data do not suggest that there is a meaningful difference in the safety profile of the q8w and q12w maintenance doses.

2.2 Target population 1. Describe the target population and the proposed position of the target population in the patient pathway of care.

Ustekinumab is anticipated to be approved for moderately to severely active UC adult patients who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a biologic or have medical contraindications to such therapies.(3) The EMA marketing authorisation is expected in August 2019 (ultimate best case; October 2019 as best case). 2. Provide a justification for the proposed positioning of the technology and the definition of the target population.

The targeted population for treatment with ustekinumab for this UC indication, is based on the evidence in the UNIFI clinical trial programme (UNIFI induction and UNIFI maintenance studies), which included adult patients with moderately to severely active ulcerative colitis. This patient population included patients who are both non-biologic failure and biologic failure patients, including patients who have been treated with vedolizumab.(1) The proposed positioning is also supported by the NMA which demonstrated better performance from ustekinumab versus other comparators in the non-biologic failure patients, as well as higher likelihoods for better outcomes in the biologic failure patients.

3. Estimate the size of the target population. Include a description of how the size of the target population was obtained and whether it is likely to increase or reduce over time.

The most recent incidence and prevalence estimates for UC in Europe vary from 0.97 to 57.9 and 2.42 to 505.0 per 100,000 people.(56) Epidemiology data based on European region are shown in Section 2.1 Table 7).(56) To estimate the number of UC patients by disease distribution (i.e. proctitis, left-sided colitis, and extensive disease) in Europe, epidemiological data from the EpiCom cohort (2014) demonstrated disease distribution in both Western Europe (21% proctitis, 41% left-sided colitis, and 38% extensive disease) and in Eastern Europe (22% proctitis,

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35% left-sided colitis, and 33% extensive disease).(65) More recently, it has also been estimated that around 52% have moderate-to-severe disease in England.(66, 67) This is aligned with another study based on results which analysed data from the Adelphi IBD-DSP database (2019), which demonstrated that gastroenterologists categorised the severity of their UC patients to be 44.7% moderate and 4.3% severe.(68) For the Polish population, to estimate the approximate size of the target population for ustekinumab (i.e. adult patients taking biologics for UC) the number of patients currently taking infliximab and vedolizumab were considered (adalimumab and tofacitinib are not reimbursed in Poland for UC):(93)  In 2017, 401 patients were treated with infliximab  In 2018, 618 and 142 patients were treated with infliximab and vedolizumab, respectively In Sweden, through the National Prescription Registry the number of patients currently administered with biologic therapies is available, although it is not categorized by indication (i.e. plaque psoriasis, psoriasis arthritis, Crohn’s disease):(94)  In 2018: o 12,592 patients were treated with adalimumab o 2,503 patients were treated with golimumab o 1,362 patients were treated with ustekinumab o 200 patients were treated with infliximab o 103 patients were treated with vedolizumab o 444 patients were treated with tofacitinib These patient numbers are representing the patients taking prescriptions from a retail pharmacy setting. Infliximab and vedolizumab are products available in the hospital setting and that usage is not addressed in the prescription registry (and therefore demonstrated low patients here). Hospital prescriptions and usage are not publicly available.

2.3 Clinical management of the disease or health condition 1. Describe the clinical pathway of care for different stages and /or subtypes of the disease being considered in the assessment.

In Europe, published guidelines for the management of UC described a disease management approach based on: severity of the disease and the response to previous treatments. The European Crohn’s and Colitis Organisation (ECCO) distinguish mild-to- moderate, moderate-to-severe and severe disease, with the latter requiring immediate hospital admission. Patients in the first two stages are recommended to be treated as outpatients.(95) The initial recommended treatment for mild-to-moderate UC is topical and oral 5-aminosalicylic acid (5-ASA), followed by maintenance therapy with the same treatment once remission is induced.

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For patients who did not respond to 5-ASA, the use of systematic steroids is recommended, and the treatment pathway depends on patients’ response:  Steroid-induced remission: start treatment with 5-ASA or thiopurine or anti-TNF +/- thiopurine or vedolizumab with or without thiopurine.  Steroid-refractory: start treatment with IV steroid or biologic +/- thiopurine or tacrolimus. Recommended treatments for patients who need steroids to stay in remission (steroid- dependant) are thiopurines or biologics with or without thiopurine or methotrexate, and for patients who are thiopurine-refractory only biologics with or without thiopurine are recommended. Surgery is considered based on the severity of the disease after relapses. Figure 6 synthesises the clinical pathway to induce remission, according to ECCO guidance. Figure 6. Clinical pathway to induce remission for patients with mild-to-moderate and moderate-to-severe UC from ECCO

Abbrevations: ASA: aminosalicylic acid; ECCO: European Crohn’s and Colitis Organisation; IV:intravenous, TNF:tumor necrosis factor; UC: ulcerative colitis

Patients with severe UC require immediate hospital admission. The recommended treatment path is presented in Figure 7 below. Patients are diagnosed with severe UC when they have bloody diarrhoea at least 6 times a day and any signs of systemic toxicity such as pulse > 90 min–1, temperature > 37.8°C, haemoglobin < 105 g/l,

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erythrocyte sedimentation rate > 30 mm/h, or C-reactive protein > 30 mg/l.

Figure 7. Recommended treatment for patients with severe UC from ECCO

Abbrevations: ASA: aminosalicylic acid; ECCO: European Crohn’s and Colitis Organisation; IV: intravenous, TNF: tumor necrosis factor; UC: ulcerative colitis

Most of the health technology assessment (HTA) agencies published similar guidance to the ECCO guidelines (see Table 9).(58, 60, 96, 97) The most recent guidelines were published in 2019 by societies in the UK (i.e. National Insititute for Health and Care Excellence (NICE)) and Germany, however these guidelines have overlapping clinical pathways and treatment goals as the ECCO guidelines. According to the currently available guidelines, the overarching goals of treating patients with UC are to:  avoid relapse of the disease over time (i.e. maintain remission in maintenance phase) in addition to reducing symptoms in this phase,  rapidly reduce symptoms when the disease is diagnosed as active “subacute” (defined as moderate to severely active UC) (i.e. induction phase),  improve patient quality of life,  decrease the use of corticosteroids,  and minimise complications and cancer risk.(95) The choice of treatment within the pathway is based on the severity of the disease (i.e. distinguishing patients as mild to moderate, moderate to severe, or severe), the site of Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 50

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disease, relapse frequency, response to previous medications and comprises several treatment options throughout the disease course.(95) The management of UC, as described in both the HTA and ECCO guidelines, has historically followed a step-up approach which includes conventional therapies (e.g. aminosalicylates, thiopurines, and corticosteroids), non-conventional therapies (e.g. biologics and janus kinase [JAK] inhibitors), and surgical interventions (e.g. colectomy).(95) Further details regarding current treatment options for patients with moderately to severely active UC are in Section 2.4. 2. State the technologies currently used in the clinical pathway for which the proposed technology is an alternative, or an additional treatment.

Conventional therapies are typically used as first-line management of symptoms (i.e. corticosteroids and immunosuppressants). Advanced therapies (i.e. TNFi, anti-integrin therapies, and JAK inhibitors) are approved after inadequate response, lost response, or intolerance to conventional therapies. Surgery (i.e. colectomy; inpatient procedure) is not a comparator, but used as a last resort and is required for patients with severe disease.(95) It is associated with long-term complications such as pouch failure, chronic pouchitis, and fistulas.(41) Ustekinumab will be available as a treatment in parallel to TNFi, anti-integrin therapies, and JAK inhibitors (Figure 8 and Figure 9). The comparators (adalimumab, infliximab, golimumab, vedolizumab, and tofacitinib) were aligned with EUnetHTA in the scoping document. 3. Describe the pathway of care that incorporates the new technology if the technology were to be adopted for use.

Based on the ECCO guidelines, it is anticipated that ustekinumab will enter the clinical pathway as per EMA indication (Figure 8 and Figure 9).

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Figure 8. Ustekinumab and the ECCO clinical care pathway for moderately to severely active UC

Abbrevations: ASA: aminosalicylic acid; ECCO: European Crohn’s and Colitis Organisation; IV:intravenous, TNF:tumor necrosis factor; UC: ulcerative colitis Colour code: purple text: comparator products that have not been included in the latest ECCO guidelines; green text: technology specified in submission

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Figure 9. Ustekinumab and the ECCO clinical care pathway for severe ulcerative colitis

Abbrevations: ASA: aminosalicylic acid; ECCO: European Crohn’s and Colitis Organisation; IV: intravenous, TNF: tumor necrosis factor; UC: ulcerative colitis Colour code: purple text: comparator products that have not been included in the latest ECCO guidelines; green text: technology specified in submission Note: the position of treatments listed in the boxes are not in any particular order.

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Table 9. Relevant guidelines for diagnosis and management Name of society/organisation issuing Date of issue or last Country/ies to which Summary of recommendations guidelines update guideline applies (Level of evidence/grade of recommendation for the indication under assessment) National Institute for Health and Care 2019(60) United Kingdom Excellence (NICE) German Society for Digestive and 2019(99) Germany Metabolic Diseases (DGVS) European Crohn’s and Colitis 2017(98) Europe Organisation (ECCO) Haute Autorité de Santé (HAS) 2016(58) France The main objective of existing treatments is to induce a long-lasting remission, leading to the control of the National Health Insurance Fund 2016(100) Hungary disease symptoms in order to: Spanish Group of Ulcerative Colitis Avoid relapse of the disease 2013(97) Spain and Crohn's disease (GETECCU) Improve quality of life of patients Guidelines of the working group of a Decrease the use of corticosteroids national consultant in the field of Minimise the risk of cancer. gastroenterology and the Polish Society of Gastroenterology Treatment pathway is mostly based on the severity of the disease, the site of disease, relapse frequency, regarding the management of 2013(101) and updated Poland response to previous medications and comprises several treatment options throughout the disease course. To patients with ulcerative colitis (2013); in 2015(102) optimise patients’ response and remission regarding those criteria, updated guidelines are regularly published updated by Polish Society of by gastroenterology institutions around the world, as newly approved therapies become available. The ECCO Gastroenterology document “New published the 3rd consensus on diagnosis and management of UC in 2017 and is therefore one of the most pharmaceuticals in inflammatory recent guidances, and also the most utilised in Europe.(98) Country-specific guidelines are also available are bowel disease (2015) most often older than the latest ECCO publication. Italian Society of Gastroenterology 2011(96) Italy (ISGE) Medical Products Agency Recommendation – Inflammatory 2012(103) Sweden Bowel Disease Manz et al. algorithm for treatment of 2011(104) Switzerland ulcerative colitis Include a link to relevant guidelines if publicly available Abbreviations: ECCO: European Crohn’s and Colitis Organisation (ECCO); UC: Ulcerative colitis

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2.4 Comparators in the assessment 1. On the basis of the alternatives presented, identify the technologies to be used as comparator(s) for the assessment.

Relevant comparators for ustekinumab in UC are treatments indicated in moderate to severely active UC patients who:  have failed or are intolerant to conventional therapies  have failed a previous anti-TNF or other biologic therapy Three anti-TNF therapies are currently approved in moderate to severely active UC in Europe with similar labels:  Infliximab (Remicade®)(105)  Adalimumab (Humira®)(106)  Golimumab (Simponi®)(107) Three biosimilars of infliximab are also available in Europe (Remsima®, Inflectra®, Flixabi®).(2, 108, 109) More recently, adalimumab biosimilars are also available (i.e. Kromeya®, Idacio®, Hyrimoz®).(110-112) Vedolizumab (Entyvio®; anti-integrin therapy) and tofacitinib (Xeljanz®; JAK inhibitor) are the only treatments for which the label clearly stated that they are indicated either for bio-naïve or for patients who have failed a previous anti-TNF therapy. Table 10 below presents the labels of all treatments approved by the European Medicines Agency.

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Table 10. Labels of available comparators in Europe Infliximab Adalimumab Golimumab Vedolizumab Tofacitinib EU (2, Indicated for treatment of moderately to severely active ulcerative colitis in adult patients who Entyvio is indicated for Indicated for the 105- have had an inadequate response to conventional therapy including corticosteroids and 6- the treatment of adult treatment of adult 109, MP or AZA, or who are intolerant to or have medical contraindications for such therapies. patients with moderately patients with 113) to severely active UC moderately to who have had an severely active UC inadequate response who have had an with, lost response to, or inadequate were intolerant to either response, lost conventional therapy or response, or were a TNFi antagonist. intolerant to either conventional therapy or a biologic agent. Abbreviations: 6-MP: 6-mercaptopurine; AZA: azathioprine; TNFi: tumour necrosis factor-inhibitor; UC: Ulcerative colitis

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3 Current use of the technology

Summary of issues relating to current use of the technology  Ustekinumab is not currently reimbursed globally for its UC indication, as marketing authorisation has not yet been obtained for this indication and is expected in August 2019 by the EMA (ultimate best case; October 2019 as best case)  Ustekinumab is currently reimbursed for its PsO indication in 39 countries/regions: Austria, Beligum, Bulgaria, Croatia, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Latvia, Lebanon, Libya, Lithuania, Luxembourg, Netherlands, Norway, Poland, Portugal, Qatar, Romania, Russia, Saudi Arabia, Serbia, Slovakia, Slovenia, Spain, Sweden, Switzerland, Turkey, UAE, and UK(114)  Ustekinumab is currently reimbursed for its PsA indication in 30 countries/regions: Austria, Beligum, Bulgaria, Croatia, Cyprus, Denmark, Estonia, Finland, France, Germany, Greece, Iceland, Ireland, Italy, Latvia, Lybia, Lithuania, Luxembourg, Netherlands, Norway, Portugal, Russia, Slovakia, Slovenia, South Africa, Spain, Sweden, Switzerland, Turkey and UK(114)  Ustekinumab is currently reimbursed for its CD indication in the following 34 countries/regions: Austria, Bahrain, Belgium, Croatia, Cyprus, Czech Republic, Denmark, England, Estonia, Finland, France, Germany, Greece, Hungary, Iceland, Ireland, Israel, Italy, Kuwait, Latvia, Lebanon, Luxembourg, Netherlands, Oman, Qatar, Scotland, Slovakia, Slovenia, Spain, Sweden, Switzerland, Syria, UAE and UK(114)

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3.1 Current use of the technology 1. Describe the experience of using the technology, for example the health conditions and populations, and the purposes for which the technology is currently used. Include whether the current use of the technology differs from that described in the (expected) authorisation.

The clinical efficacy and experience of patients administered with ustekinumab for the approved indications (i.e. CD, PsO, and PsA) were demonstrated in the relevant clinical trial programs summarised below:(3)

 Crohn’s disease: o The safety and efficacy of ustekinumab was assessed in three randomised, double-blind, placebo-controlled, multicentre studies in adult patients with moderately to severely active CD); the clinical development program consisted of two induction studies (UNITI-1 and UNITI-2) followed by a randomised withdrawal maintenance study (IM-UNITI) o Included in ECCO guidelines as an option for biologic treatment of CD, citing its efficacy in patient clinical response and remission(7) o As noted in Section 3.1.1 Table 13, ustekinumab is reimbursed in many countries across the world for the CD indication  Plaque psoriasis: o The safety and efficacy of ustekinumab was studied in two randomised, double-blind, placebo-controlled studies (PHOENIX 1 and 2) in patients with moderate to severe PsO; in addition, a randomised, blinded assessor, active-controlled study (ACCEPT) compared ustekinumab and etanercept in patients with moderate to severe plaque psoriasis o Included in the 2017 update of European S3‐Guideline on the systemic treatment of plaque psoriasis, with noted strong consensus of efficacy(8) o As noted in Section 3.1.2 Table 14, ustekinumab is reimbursed in many countries across the world for the PsO indication  Psoriasis arthritis: o The safety and efficacy of ustekinumab was assessed in two randomised, double-blind, placebo-controlled studies (PSUMMIT I and II) in patients with active PsA o Included in the 2015 update of the European League Against Rheumatism (EULAR) guidelines as a biologic treatment option(9) o As noted in Section 3.1.3 Table 15, ustekinumab is reimbursed in many countries across the world for the PsA indication

In addition to the clinical trial programs outlined above, the long-term safety of ustekinumab was demonstrated in the results from the PSOLAR registry, for the

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treatment of plaque psoriasis as well as from clinical trials in other indications (see Section 5.5.2.2).(4, 5) The anticipated indication for UC would expand upon the current use of ustekinumab. 2. Indicate the scale of current use of the technology, for example the number of people currently being treated with the technology, or the number of settings in which the technology is used.

For other indications covered by ustekinumab, the following data regarding the scale of use of ustekinumab are as follows:(115)

 For the PsO indication, ustekinumab treated approximately: o 38,140 patients for the full year in December 2018 in the EU-7 (France: 5,230 patients; Germany: 6,930 patients; Spain: 7,690 patients; Italy: 5,600 patients; United Kingdom: 7,890 patients; Belgium: 1,940 patients; Netherlands: 2,850 patients)  For the PsA indication, ustekinumab treated approximately: o 10,000 patients for the full year in 2018 in the EU-7 (France: 1,370 patients; Germany: 2,910 patients; Spain: 1,360 patients; Italy: 2,640 patients; United Kingdom: 1,250 patients; Belgium: 160 patients; Netherlands: 320 patients)  For the CD indication, ustekinumab treated approximately: o 14,130 patients for the full year in December 2018 in the EU-7 (France: 2,560 patients; Germany: 4,810 patients; Spain: 2,090 patients; Italy: 50 patients; United Kingdom: 2,890 patients; Belgium: 940 patients; Netherlands: 800 patients)

3.1.1 Summary of current use of ustekinumab in Crohn’s disease The real-world evidence of ustekinumab for the treatment of CD comes from a range of studies carried out in different countries:  A study by Batista et al. (2014) in the United States looked at the effects of ustekinumab in 18 CD patients (89% biologic-failure) who were followed up for a median of 9.1 months. The cumulative probability of any response was 11.1% at one month, 38.9% at three months, and 44.4% at six months. Of the 15 patients on steroids at the beginning of therapy, 4 (26.7%) were able to taper off successfully. Mucosal healing was observed in 3 of the 8 patients (37.5%) who had a repeat endoscopy. Adverse events occurred in 10 patients and the six- month survival free of events was 50%.(116) In another retrospective chart review study in the US, which included 45 patients with complicated refractory CD, showed that 17 patients attained clinical response, 13 patients achieved

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clinical remission, and 26 patients achieved endoscopic response or remission.(117)  In Spain, a study by Khorrami et al. (2016) included 116 refractory patients with CD who were followed up for a median of 10 months. Clinical response after loading ustekinumab was achieved in 97 (84%) patients. The clinical benefit at 6, 12 months, and at the end of the follow-up was 76%, 64%, and 58%, respectively. In the same population, 14 mild adverse events were reported in 11 patients with none requiring ustekinumab withdrawal.(118)  A retrospective observational open-label study examined 38 patients in Canada with anti-TNF resistant Crohn’s disease. Among the initial responders, 80% with follow-up data maintained their response for 6 months. At 12 months of follow-up, 88.9% of patients responding at 6 months maintained their response. At the last follow-up (7.9 ± 5.2 months) 71% of the patients were responding, and 73.3% were able to discontinue corticosteroids.(119)  A French/Swiss study assessing the benefit and safety of subcutaneous ustekinumab in anti-TNF refractory CD observed clinical benefit in nearly two- thirds of patients at 3 months and was maintained in the majority of these patients for up to 12 months.(120)  A study by Biemans et al. (2018) in Germany compared the use of vedolizumab versus ustekinumab for CD and demonstrated rates of 46.2% and 57.9% of clinical corticosteroid-free remission after 24 weeks in patients treated with vedolizumb and ustekinumab, respectively. In the same study, clinical remission and adverse event rates were comparable between treatments.(121)  Finally, a case report by Heron et al. (2018) observed the re-induction of ustekinumab in CD patients experiencing a partial response or secondary loss of response and found that ustekinumab re-induction can be used to safely induce clincial and endoscopic response in patients with active Crohn’s disease.(122) Ustekinumab is included/recommended for treatment of CD in the NICE, ECCO, and Italy guidelines,(123, 124). Other European guidelines (i.e. France [HAS], Spain, Germany, Poland, Hungary Sweden, Switzerland) have yet to be updated post- ustekinumab marketing authorisation/reimbursement.(104, 125-130)

3.1.2 Summary of current use of ustekinumab in plaque psoriasis In a prospective national pharmacovigilance cohort (British Association of Dermatologists Biologic Interventions Register [BADBIR]), drug survival of biologics used to treat chronic plaque psoriasis was assessed in 3,523 biologic-naïve patients. As compared with adalimumab, patients on etanercept (HR 1.63; 95% CI: 1.45-1.84) or infliximab (HR 1.56; 95% CI: 1.16-2.09) were more likely to discontinue therapy, whereas patients on ustekinumab were more likely to persist (HR 0.48; 95% CI: 0.37- 0.62). After accounting for relevant covariates, ustekinumab had the highest first-course drug survival.(131)

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In a similar study by Egeberg et al. (2017) that compared safety, efficacy and drug survival data from the DERMBIO registry (Denmark) in adalimumab, etanercept, infliximab, secukinumab and ustekinumab, found that ustekinumab was associated with the highest drug survival and secukinumab with the lowest.(132) In a prospective study by Van Reek et al. (2014), 'happy' drug survival was calculated, with data split into 'happy' (Dermatology Life Quality Index [DLQI] ≤ 5) vs. 'unhappy' (DLQI > 5) at baseline, in order to demonstrate the quality of life of plaque psoriasis patients. Ustekinumab showed a better overall drug survival than etanercept, and a trend towards a better overall drug survival than adalimumab. After 1 year, patients reported to be 'happy' in 79% of episodes and 'unhappy' in 21%.(133) Results in a study by Lunder et al. (2019) analysed drug survival and safety of the biologic drugs outlined above, in addition to apremilast and ixekizumab, and also found ustekinumab to be associated with the highest drug survival and most favourable safety profile.(134) Ustekinumab is also included/recommended for the treatment of PsO in treatment guidelines across Europe, as described in Table 11. Table 11. Inclusion of ustekinumab in European guidelines for PsO Is UST included in the Country Author Year guideline? United Kingdom NICE(135) 2017 Yes France Amatore et al.(136) 2019 Yes National Health Hungary 2010 No Insurance Fund(137) Italy Marchesoni et al.(138) 2017 Yes Spain Puig et al.(139) 2013 Yes Germany Nast et al.(140) 2017 Yes Poland Reich et al.(141) 2018 Yes Switzerland Kolios et al.(142) 2016 Yes National Board of Sweden Health and 2019 Yes Welfare(143) Pan-European Nast et al.(8) 2017 Yes medical guidelines

3.1.3 Summary of current use of ustekinumab in psoriatic arthritis In PsABio, a routine care study which collected data regarding the efficacy, tolerability, and persistence of anti-TNFs and ustekinumab in 8 European countries, demonstrated that both ustekinumab- and anti-TNF-treated PsA patients showed significant improvements in joint-related measures after 6 months, irrespective of whether it was first or further line of treatment.(144)

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Ustekinumab showed consistent clinical efficacy in two phase III clinical trials for PsA in PSUMMIT-1 and PSUMMIT-2, with data obtained up to 52 weeks and no new safety signals having occurred. PSUMMIT-1 included patients with active PsA despite conventional therapy who were all naïve to anti-TNF agents, whereas PSUMMIT-2 also included anti-TNF experienced patients.(145) In the PsA subgroup in the PSOLAR study (12,095 patients as of the 2013 data cut) that assessed survival of biologic treatments, it was demonstrated that significantly shorter times to treatment discontinuation were observed for infliximab [HR (95%CI) = 2.73 (1.48-5.04), P = 0.0014]; adalimumab [4.16 (2.80-6.20), P < 0.0001]; and etanercept [4.91 (3.28-7.35) P < 0.0001] compared with ustekinumab for first-line biologic use; results were similar for treatment effects for second/third-line therapies.(146) This can be interpreted as a proxy for both efficacy and tolerability related outcomes. Ustekinumab is included/recommended for the treatment of PsO in treatment guidelines across Europe, as described in Table 12. Many guidelines for PsA are included in PsO guidelines, as well. Table 12. Inclusion of ustekinumab in European PsA guidelines Is UST included in the Country Author Year guideline? United Kingdom NICE(135) 2015 Yes France Amatore et al.(136) 2019 Yes National Health Hungary 2010 No Insurance Fund(137) Italy Marchesoni et al.(138) 2017 Yes Spain Puig et al.(139) 2013 Yes Poland Reich et al.(141) 2018 Yes Switzerland Kolios et al.(142) 2016 Yes National Board of Sweden Health and 2019 Yes Welfare(143) Pan-European Nast et al.(8) 2017 Yes medical guidelines

3.1.4 Safety evidence from PSOLAR study for patients with plaque psoriasis Current safety results of ustekinumab in the treatment of patients with plaque psoriasis from the PSOLAR study are presented in Section 5.5.2.2 to support the safety results in the ulcerative colitis indication.

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3.1.5 Safety evidence from clinical trials of plaque psoriasis, psoriatic arthritis, and Crohn’s disease A summary of the safety results for ustekinumab in clinical trials for the Crohn’s disease, psoriatic arthritis, and plaque psoriasis indications are presented in Section 5.5.2.1 to support the safety results in the ulcerative colitis indication.

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3.2 Reimbursement and assessment status of the technology Ustekinumab has not been launched in any European country for its UC indication. However, ustekinumab has been launched in several countries globally for its indications for CD, PsO, and PsA (see Table 13, Table 14, and Table 15 respectively). 1. Complete Table 13, Table 14, and Table 15 with the reimbursement status of the technology in Europe.

Table 13. Overview of the reimbursement status of the technology for Crohn’s disease in European countries Country and issuing Status of recommendation (positive/negative/ongoing/not organisation assessed) Austria Reimbursed Per Label Belgium Reimbursed per Label Croatia Reimbursed Per Label Czech Republic Reimbursed Per Label Denmark Reimbursement Per Label Estonia Reimbursed Per Label Finland Reimbursement with Restriction France Reimbursement with Restriction Germany Reimbursed Per Label Hungary Reimbursement with Restriction Iceland Reimbursement with Restriction Ireland Reimbursed Per Label Israel Reimbursed Per Label Italy Reimbursed Per Label Latvia Reimbursement with Restriction Luxembourg Reimbursed Per Label Netherlands Reimbursed Per Label Slovakia Reimbursement with Restriction Slovenia Reimbursed Per Label Spain Reimbursement with Restriction Sweden Reimbursed Per Label Switzerland Reimbursed Per Label United Kingdom Reimbursed Per Label Include a reference to any publicly available guidance documents Abbreviations: NA: Not applicable; NHS: National Health Service; PFS: Progression Free Survival; PsA: Psoriatic Arthritis; PsO: Plaque Psoriasis; TNF: Tumour Necrosis Factor; UC: Ulcerative colitis

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Table 14. Overview of the reimbursement status of the technology for plaque psoriasis in European countries Country and issuing Status of recommendation (positive/negative/ongoing/not organisation assessed) Austria Reimbursed Per Label Belgium Reimbursed Per Label Bulgaria Reimbursed Per Label Croatia Reimbursement with Restriction Cyprus Reimbursed Per Label Czech Republic Reimbursed Per Label Denmark Reimbursed Per Label Estonia Reimbursement with Restriction Finland Reimbursement with Restriction France Reimbursed Per Label Germany Reimbursed Per Label Greece Reimbursed Per Label Hungary Reimbursed Per Label Iceland Reimbursement with Restriction Ireland Reimbursed Per Label Israel Reimbursed Per Label Italy Reimbursed Per Label Latvia Reimbursement with Restriction Lithuania Reimbursement with Restriction Luxembourg Reimbursed Per Label Netherlands Reimbursed Per Label Norway Reimbursed Per Label Poland Reimbursement with Restriction Portugal Reimbursed Per Label Romania Reimbursed Per Label Russia Reimbursed Per Label Serbia Reimbursed Per Label Slovakia Reimbursed Per Label Slovenia Reimbursed Per Label Spain Reimbursed Per Label Sweden Reimbursed Per Label Switzerland Reimbursed Per Label Turkey Reimbursed Per Label United Kingdom Reimbursed Per Label Include a reference to any publicly available guidance documents *For example full reimbursement or only partial reimbursement. If partial reimbursement give a percentage of reimbursement. Abbreviations: NA: Not applicable; NHS: National Health Service

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Table 15. Overview of the reimbursement status of the technology for psoriatic arthritis in European countries Country and issuing Status of recommendation (positive/negative/ongoing/not organisation assessed) Austria Reimbursed Per Label Beligum Reimbursed Per Label Croatia Reimbursed Per Label Cyprus Reimbursed Per Label Denmark Reimbursed Per Label Estonia Reimbursed Per Label Finland Reimbursement with Restriction France Reimbursed Per Label Germany Reimbursed Per Label Greece Reimbursed Per Label Iceland Reimbursement with Restriction Ireland Reimbursed Per Label Italy Reimbursed Per Label Latvia Reimbursed Per Label Lithuania Reimbursement with Restriction Luxembourg Reimbursed Per Label Netherlands Reimbursed Per Label Norway Reimbursed Per Label Portugal Reimbursed Per Label Russia Reimbursed Per Label Slovakia Reimbursed Per Label Slovenia Reimbursed Per Label Spain Reimbursed Per Label Sweden Reimbursed Per Label Switzerland Reimbursed Per Label Turkey Reimbursed Per Label United Kingdom Reimbursement with Restriction Abbreviations: NA: Not applicable; NICE: National Institute of Care and Excellence; NHS: National Health Service; TNFi: Tumour Necrosis Factor-inhibitor; SMC: Scottish Medicines Consortium

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4 Investments and tools required

Summary of issues relating to the investments and tools required to introduce the technology  Moderately to severely active UC is typically diagnosed by a gastroenterologist (i.e. secondary healthcare provider); the treatment pathway of patients with UC would not differ between ustekinumab and its comparators(95)  Ustekinumab induction dosing is administered via IV infusion, which can be administered in a hospital setting or an infusion clinic; treatment is to be initiated with a single intravenous dose(3)  Maintenance therapy is available as a SC injection, and can be conveniently administered in the home setting(3)  The method of administration of comparator treatments for moderately to severely active UC vary: via IV infusion (infliximab, vedolizumab),(105, 113) SC injection (adalimumab, golimumab)(106, 107) and oral therapy (tofacitinib)(53)  No additional equipment, premises or personnel would therefore be required for the introduction of ustekinumab

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4.1 Requirements to use the technology 1. If any special conditions are attached to the regulatory authorisation more information should be provided, including reference to the appropriate sections of associated documents (for example, the European Public Assessment Report [EPAR] and SmPC). Include:

 conditions relating to settings for use, for example inpatient or outpatient, presence of resuscitation facilities

 restrictions on professionals who can use or may prescribe the technology

 conditions relating to clinical management, for example patient monitoring, diagnosis, management and concomitant treatments.

Special conditions for use of ustekinumab IV infusion for induction treatment are seating for the infusion (i.e. at infusion clinic or hospital). For maintenance treatment, ustekinumab SC injection requires proper training of patients or their caregivers in SC injection technique. Ustekinumab offers a convenient dosing schedule, with a single IV infusion induction dose followed by SC injection every 8 or 12 weeks which may be administered in a home setting. See Section 4.2 Posology and method of administration in the SmPC for more details.(3)

2. Describe the equipment required to use the technology.

No additional equipment, other than those mentioned above, are required for the use of ustekinumab.

3. Describe the supplies required to use the technology.

For the maintenance dose of ustekinumab, pre-filled syringes are utilised for SC injection.(3)

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4.2 Investments, disinvestments and changes in service organisation 1. Describe any changes to current services that are needed to introduce the technology. Include:

 any tests or investigations needed for selecting or monitoring patients that are over and above usual clinical practice

 any equipment, or organisational and technical conditions that will require investment before the technology can be introduced

 any investment in infrastructure

 any programmes and services that will have to be increased due to introduction of the technology (rehabilitation, nursing etc.).

No changes to current services are anticipated to be required in order to introduce ustekinumab.

2. Describe any tests, investigations, interventions, facilities or technologies that would no longer be needed if the technology is introduced.

No additional tests, investigations, interventions, facilities, or technologies are anticipated to be required in order to introduce ustekinumab.

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5 Clinical effectiveness and safety

Guidance on this section The clinical evidence of ustekinumab, and comparator treatments, are summarised throughout this section and can be organised into four main categories: 1. Evidence related to the technology and trials of the prospective marketing authorisation holder (pMAH): the UNIFI induction and maintenance trial results 2. Evidence related to the comparator trials: the results from the systematic literature review (SLR; which also included the trials of the pMAH) 3. Evidence related to the comparative effectiveness and safety of the pMAH and comparators trials: the results of the NMA 4. Evidence across indications for ustekinumab and comparators in CD, PsO, and PsA: safety results to support the use of ustekinumab in UC o Integrated clinical trial evidence in CD, PsO, and PsA o Comparison with anti-TNFs in plaque psoriasis from a large registry (PSOLAR) o Comparison of SmPC safety information

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Summary of the clinical effectiveness  In the UNIFI induction trial for ustekinumab versus placebo in UC, results were statistically significant for both induction doses (i.e. ~6mg/kg and 130 mg doses) of ustekinumab for all primary and major secondary efficacy endpoints including clinical remission, clinical response, endoscopic healing, and mucosal healing (i.e. a combination of endoscopic healing and histologic healing) at Week 8 (all p- values <0.001)  In the UNIFI maintenance trial for ustekinumab versus placebo in UC, results were statistically significant for both dose regimens (90mg q8w and q12w) for all primary and major secondary efficacy endpoints including clinical remission, maintenance of clinical response, endoscopic healing, corticosteroid-free remission, and maintenance of clinical remission through Week 44 (all p-values <0.05, with the exception of ustekinumab q8w for maintenance of clinical remission where p=0.69). Improvements in clinical outcomes were accompanied by reductions in inflammatory biomarkers and improvements in HRQoL measures (i.e. IBDQ, EQ-5D, SF-36)  Bayesian network meta-analyses (NMA) were conducted to compare ustekinumab to other active therapies for clinical response, remission and mucosal healing at the end of one year of continued treatment o Comparisons of active treatments are more relevant at long-term timepoints. Additionally, trials with re-randomised response-based designs primarily focus on long-term outcomes for induction responders. The NMA was conducted to assess the continued year-long treatment regimens providing a more complete picture of the long-term relative efficacy of treatments received in clinical practice.  Comparative efficacy of ustekinumab based on NMA (non-biologic failure): Patients having received UST 6 mg/kg in induction had consistently higher likelihoods of achieving clinical response, remission, and mucosal healing after a year-long treatment regimen versus other active therapies  Comparative efficacy of ustekinumab based on NMA (biologic failure): The 1-year NMA of efficacy performed in the biologic failure group also suggests higher likelihoods of reaching response, remission, and mucosal healing with ustekinumab versus other active therapies. The likelihoods associated with these clinical benefits are not as pronounced as those observed at 1 year in non- biologic failure patients, due to smaller sample sizes and more uncertainty in the data.

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Summary of safety Safety results of ustekinumab based on UNIFI trial  Adverse event rates in the UNIFI studies were similar in the ustekinumab and placebo arms.  Serious adverse event rates were not significantly different between treatment groups in the induction and maintenance studies; with event rates being numerically higher for placebo compared to ustekinumab groups in the induction phase (6.6% placebo vs 3.7% UST 130mg and 3.1% UST 6mg/kg).  AEs of special interest were similar across treatment groups, such as 1) infections: infections of any severity were more common in the placebo group than in the ustekinumab groups and the rate of serious infections was low and similar across all treatment groups; 2) malignancy: through the final safety analysis of the induction study, only two subjects reported malignancies (prostate cancer and rectal adenocarcinoma) and in the maintenance study, six subjects reported malignancies (5 ustekinumab-treated subjects and 1 placebo-only subject); and 3) cardiovascular events: through Week 8 of the induction study, there was one SAE of ischemic stroke reported in the placebo treatment group and among all treated subjects in the maintenance study, serious MACE (i.e., non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) were reported in two subjects Safety comparison for ustekinumab  Various methodological challenges limit the ability to conduct an NMA on safety after 1 year of treatment. However, RWE from large registries and regulatory safety data from SmPCs published by the EMA offer detailed assessments of safety based on data obtained across indications and may provide more meaningful insights into the comparative safety profile.  The integrated safety summary of ustekinumab demonstrated a consistent safety profile across indications (in CD, PsO, and PsA), with low incidences of major adverse cardiovascular events, malignancies and deaths through to 1 year (≤ 0.5/100 patient-years), and with a comparable safety profile to placebo across indications.  A large registry in PsO (i.e. PSOLAR study) has demonstrated that ustekinumab was not associated with an increased risk of serious infections and that the cumulative risk of serious infections for patients who received ustekinumab was lower than for patients who received etanercept, adalimumab and infliximab. The results in the subpopulation with concomitant IBD resulted in similar findings.

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 While comparing safety profiles across products is inherently difficult, and subject to qualitative interpretation and weighing of different risk profiles, the comparison of the SmPCs obtained after assessment of detailed data from regulators suggests ustekinumab has an acceptable safety profile.

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5.1 Identification and selection of relevant studies

1. State the databases and trial registries searched and, when relevant, the platforms used to do this.

The search strategy was run in four databases including: MEDLINE, MEDLINE-IN- PROCESS, EMBASE, and Cochrane library. MEDLINE and MEDLINE-IN-PROCESS were searched through the PubMed platform, while EMBASE was searched through the Embase.com platform. These databases include both published studies as well as conference abstracts. In addition to the database searches, manual searches were undertaken to identify relevant publications and posters not captured in the electronic searches. Clinical trial websites reporting information on interventions for non-naïve patients with moderate to severe active UC were also searched. Congresses and conferences of interest such as the ECCO, the United European Gastroenterology Week (UEGW) and the Digestive Disease Week (DDW) were not searched manually since they are indexed in Embase.(147) Table 16. Hand searches Hand Searches URLs Search terms HTA websites National Institute for Health and Care https://www.nice.org.uk/ Excellence Haute Autorité de Santé https://www.has-sante.fr/portail/ Gemeinsamer Bundesausschuss and Institut für Qualität und Wirtschaftlichkeit im https://www.g-ba.de/ Gesundheitswesenis Canadian Agency for Drugs and Technologies in Health; pan-Canadian Oncology Drug https://www.cadth.ca/ Ulcerative Review colitis Comisión Interministerial de Precios de los Medicamento and Subdirección General de https://www.msssi.gob.es/profesionales Calidad de Medicamentos y Productos /farmacia/CIPMyPS.htm Sanitarios http://www.agenziafarmaco.gov.it/cont Agenzia Italiana del Farmaco ent/lagenzia-italiana-del-farmaco Pharmaceutical Benefits Advisory http://www.pbs.gov.au/info/industry/lis Committee ting/participants/pbac

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International Network of Agencies for Health www.inahta.org Technology Assessment Clinical trial registers

ClinicalTrials.gov https://clinicaltrials.gov/ Ulcerative EU Clinical trial register https://www.clinicaltrialsregister.eu/ colitis

Regulatory websites

Food and Drug Administration https://www.fda.gov/Drugs/default.htm Ulcerative European Medicines Agency http://www.ema.europa.eu/ema/ colitis

Abbreviations: EU: European Union; HTA: Health technology Assessment

2. State the date the searches were done and any limits (for example date, language) placed on the searches.

The searches were firstly run on 14th August 2018 and updated on 22nd January and 28th March 2019 according to the pre-specified protocol approved by Janssen to identify relevant publications.(114) No time restriction was applied to the first search conducted on 14th August, the second and third update searches restricted publication dates to reduce the number of overlapping articles with the first search (see Appendix 1 for more details). In all searches, the language limit was set to English.

3. Include as an appendix the search terms and strategies used to interrogate each database or registry.

The search strategies and terms utilised for the clinical effectiveness SLR are provided in Appendix 1.

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4. In table 17, state the inclusion and exclusion criteria used to select studies and justify these.

Table 17: Inclusion and exclusion criteria Inclusion criteria Population: Patients with moderate to severe active UC, that failed conventional therapy, as well as patients who failed prior biologic(s) Intervention(s):  Ustekinumab  Infliximab  Adalimumab  Golimumab  Vedolizumab  Tofacitinib Comparator(s): Same as mentioned in Intervention(s) Outcomes: Efficacy:  Clinical response  Durable clinical response  Clinical remission  Durable clinical remission  IBDQ response  Steroid-free (SF) remission  Mucosal healing  Durable mucosal healing Safety:  Surgery required  Hospitalisations  Overall AEs  Serious AEs  Discontinuations due to AEs  Severe AEs and fatal AEs  Infections and severe infections Settings (if applicable):  Peer reviewed published in journals or retrieved via hand searches  Abstracts and posters Study design: Randomised control trials (RCT) Language restrictions: Full text version available in English Other search limits or restrictions applied: NA Exclusion criteria Population: Naïve patients, mild active UC only

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Intervention(s): All other treatments Comparator(s): All other treatments Outcomes: Not efficacy, safety or QoL related to IBDQ response Settings (if applicable): Letters and editorials Study design:  Single arm trials  Observational studies  Case-control studies  Cohort studies  Cross-sectional studies  Case series/reports  Systematic literature reviews  Economic evaluations  Background information/expert opinion Language restrictions: Not available in English Other search limits or restrictions applied: NA

Abbreviations: AE: Adverse event; IBDQ: Inflammatory Bowel Disease Questionnaire; QoL: Quality of life; NA: Not applicable; UC: Ulcerative colitis

5. Provide a flow chart showing the number of studies identified and excluded. The preferred reporting items for systemic reviews and meta-analyses (PRISMA) statement can be used; the PRISMA flow chart is included below, as an example.

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Figure 10. PRISMA diagram (Search conducted on 14th August 2018)

Abbreviations: N: Number of studies

Figure 11. PRISMA diagram (updated search results conducted on 22nd January 2019; publication date from 01/01/2018-22/01/2019)

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Abbreviations: N: Number of studies

Figure 12. PRISMA diagram (updated search results conducted on 28th March 2019; publication date from 01/01/2019-28/03/2019)

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5.2 Relevant studies

1. Table 18 below provide a list of the relevant studies identified.

A total of 48 publications (see PRISMA diagrams in Section 5.1 Figure 10, Figure 11, and Figure 12) were identified in the SLR (including 31 full articles, 15 abstracts and 2 posters) for six drugs: ustekinumab, infliximab, tofacitinib, adalimumab, golimumab, and vedolizumab. For ustekinumab, 6 abstracts were identified through electronic search, though the clinical results of ustekinumab were primarily extracted from the clinical study reports provided by Janssen. A total of 21 trials were identified for which the data extraction was conducted (see Table 18).

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Table 18. List of all relevant studies Status Study Available documentation* (ongoing**/ reference/ID complete) Randomised controlled trials ULTRA 1 Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for Complete induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780-787.(148)

Reinisch W, Sandborn WJ, Panaccione R, et al. 52-week efficacy of adalimumab in patients with moderately to severely active ulcerative colitis who failed corticosteroids and/or immunosuppressants. Inflamm Bowel Dis. 2013;19(8):1700-1709. ULTRA 2 Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces Complete and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257-265 e251- 253.(149) NCT00853099 Suzuki Y, Motoya S, Hanai H, et al. Efficacy and safety of adalimumab Complete in Japanese patients with moderately to severely active ulcerative colitis. J Gastroenterol. 2014;49(2):283-294.(149) Silva 2017 Silva R BG, et al. Infliximab versus adalimumab: clinical and Complete endoscopy response in ulcerative colitis patients. A prospective study [Abstract]. Conference: 12th congress of the european crohn's and colitis organisation, ECCO 2017 Spain. 2017.(149) Jiang 2015 Jiang X CH, et al. Low-dose Infliximab for Induction and Maintenance Complete Treatment in Chinese Patients With Moderate to Severe Active Ulcerative Colitis. J Clin Gastroenterol. 2015;49(582-588).(150) Probert 2003 Probert C HS, Schreiber S, et al. Infliximab in moderately severe Complete glucocorticoid resistant ulcerative colitis: a randomised controlled trial. Inflammatory Bowel Disease. 2003;59:998-1002.(151) Japic Kobayashi T, Suzuki Y, Motoya S, et al. First trough level of infliximab Complete CTI060298 at week 2 predicts future outcomes of induction therapy in ulcerative colitis-results from a multicenter prospective randomized controlled trial and its post hoc analysis. J Gastroenterol. 2016;51(3):241-251.(152) ACT 1 Rutgeerts P. SW, Feagan b., et al. Infliximab for Induction and Complete Maintenance Therapy for Ulcerative Colitis. N Engl J Med. ACT 2 2005;353:2462-2476.(153) Complete PURSUIT-M Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab Complete maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):96-109 e101.(154) PURSUIT-J Hibi T, Imai Y, Senoo A, Ohta K, Ukyo Y. Efficacy and safety of Complete golimumab 52-week maintenance therapy in Japanese patients with moderate to severely active ulcerative colitis: a phase 3, double-blind, randomized, placebo-controlled study-(PURSUIT-J study). J Gastroenterol. 2017;52(10):1101-1111.(155) PURSUIT-SC Sandborn WJ, Feagan BG, Marano C, et al. Subcutaneous golimumab Complete maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2014;146(1):96-109 e101.

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NCT00787202 Sandborn WJ, Ghosh S, Panes J, et al. Tofacitinib, an oral Janus Complete kinase inhibitor, in active ulcerative colitis. N Engl J Med. 2012;367(7):616-624.(156) OCTAVE - Sandborn WJ, Su C, Sands BE, et al. Tofacitinib as Induction and Complete Induction 1 Maintenance Therapy for Ulcerative Colitis. N Engl J Med. (OCTAVE-I1) 2017;376(18):1723-1736.(156, 157) OCTAVE - Complete Induction 2 (OCTAVE-I2) OCTAVE – Complete Sustain

GEMINI 1 Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction Complete and maintenance therapy for ulcerative colitis. N Engl J Med. 2013;369(8):699-710.(158) Kobayashi Kobayashi et al. A Phase 1, Multiple-Dose Study of Vedolizumab in Complete 2018 Japanese Patients With Ulcerative Colitis. Journal of Clinical Pharmacology. 2019;59(2):271-279.(159) NCT02039505 Motoya S., Watanabe K., Ogata H., Kanai T., Matsui T., Suzuki Y., et Complete al. Vedolizumab in Japanese patients with ulcerative colitis: A Phase 3, randomized, double-blind, placebo-controlled study. PLoS ONE. 2019;14(2).(160) VARSITY Schreiber LP-B, Edward. V. Loftus J, et al. VARSITY: A double-blind, Complete double-dummy, randomised, controlled trial of vedolizumab versus adalimumab in patients with active ulcerative colitis. ECCO Conference Abstract 2019.(161)

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UNIFI Janssen. A Phase 3, Randomized, Double-blind, Placebo-controlled, On-going Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of (LTE trial) Ustekinumab Induction and Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis. Clinical Study Report CNTO1275UCO3001 Induction. 2018.(1) Janssen. A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Subjects with Moderately to Severely Active Ulcerative Colitis. Clinical Study Report CNTO1275UCO3001 Maintenance. 2018.(1)

Sands B. E., et al. Safety and efficacy of ustekinumab induction therapy in patients with moderate to severe ulcerative colitis: Results from the phase 3 UNIFI study [Abstract]. Paper presented at: American College of Gastroenterology (ACG) Annual Scientific Meeting. 2019.(162) Sands B. E., Han C., Zhang H., et al. ,Ustekinumab therapy induced clinically meaningful improvement and remission as measured by the Inflammatory Bowel Disease Questionnaire: Results from the phase 3 UNIFI induction and maintenance studies [Abstract]. Poster presentations: Clinical: Therapy and observation. 2019.(163) Sands B. E., Sands Peyrin-Biroulet L., Marano C. et al. Efficacy in biologic failure and non-biologic-failure populations in a Phase 3 study of ustekinumab in moderate–severe ulcerative colitis: UNIFI [Abstract]. Poster presentations: Clinical: Therapy and observation. 2019.(164) Sandborn W. J., et al. Efficacy and safety of ustekinumab as maintenance therapy in ulcerative colitis: Week 44 results from UNIFI [Abstract]. Poster presentations: Clinical: Therapy and observation. 2019.(165) Van Assche, S. R., et al. Sustained remission in patients with moderate to severe ulcerative colitis: Results from the Phase 3 UNIFI maintenance study. Poster presentations: Clinical: Therapy and observation. 2019.(166) Danese S., Sands B., O’Brien C. et al. Efficacy and safety of ustekinumab through Week 16 in patients with moderate-to-severe ulcerative colitis randomised to ustekinumab: results from the UNIFI induction trial. Poster presentations: Clinical: Therapy and observation. 2019.(167) *Include references to all linked documents and indicate the expected date of publication for any unpublished clinical studies **Include expected date of completion

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5.2.1 Studies identified from the SLR of RCTs

5.2.1.1 Evidence related to the technology and trials of the pMAH: UNIFI clinical trial programme The submission for ustekinumab for the treatment of moderately to severely active UC in patients who have demonstrated an inadequate response or failure to tolerate non- biologic therapy (i.e. corticosteroids, immunomodulators) or biologic therapy is based on the results of the phase III, multicentre, randomised, double-blind, placebo-controlled, parallel group trial which compared the efficacy and safety of ustekinumab to placebo, entitled the UNIFI clinical trial programme. The UNIFI clinical trial programme consisted of an 8-week induction period (UNIFI induction) with responders re-randomised to a 44-week maintenance period (UNIFI maintenance), and included a long-term extension phase which eligible subjects were followed for an additional three years in a LTE trial under the same prior protocol. A visual overview of the UNIFI trial is shown in Figure 13. The induction study included subjects with moderately to severely active UC who had demonstrated an inadequate response or failure to tolerate non-biologic or biologic therapy. The maintenance study was a randomised withdrawal study targeting subjects with moderately to severely active UC who had demonstrated a clinical response to induction treatment with IV ustekinumab. Subjects who were randomised to ustekinumab and were not in clinical response at Week 8 received a single SC injection of 90 mg ustekinumab, while those randomised to placebo received a single IV infusion of ustekinumab (~6 mg/kg) to identify if a delayed response could be achieved in some subjects. These “delayed responders” were assessed for response at Week 16 with responders eligible to enter the study and received 90 mg ustekinumab SC q8w. Overall, the programme evaluated ustekinumab treatment in subjects with moderately to severely active UC through at least one year of induction and maintenance therapy; after completion of the maintenance study through Week 44 (i.e. 52 weeks post initial baseline for the induction period), an LTE will follow eligible subjects for an additional three years. A brief summary of the study details for the induction, maintenance and long-term extension studies are presented in Table 19. More details regarding the characteristics of the UNIFI trial programme are outlined in Section 5.2.1.1.

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Figure 13. UNIFI phase III trial overview

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Table 19. Summary of studies related to the technology and the pMAH Study Population Design Dose Regimen Key Endpoints Primary Clinical remission at Week 8 (Mayo Phase III, randomised, score ≤2 with no individual subscore double-blind, placebo- 1:1:1 ratio of >1), based on centrally read controlled, parallel-group, placebo IV endoscopic subscores UNIFI multicentre study (n=319), induction Adult patients aged 18 years or ustekinumab 130 study older with moderately to severely Secondary (Major) mg IV (n=320), (CNTO1275U active ulcerative colitis (N= 961) Patients in response to Clinical response at week 8 and ustekinumab CO3001) ustekinumab at end of 8- week induction phase were ~6 mg/kg IV Endoscopic healing at Week 8 eligible to be re-randomised (n=322) Mucosal healing at week 8 in 44-week maintenance Change from induction baseline in phase total score of the IBDQ at Week 8

Subjects who completed the Primary safety and efficacy  Clinical remission at Week 44 evaluations at Week 44 and (Mayo score ≤2 with no who may have benefited individual subscore >1), based from continued treatment, in on centrally read endoscopic the opinion of the subscores 1:1:1 ratio of Adult patients aged 18 years or investigator, had the placebo IV older with moderately to severely opportunity to participate in Secondary (Major) UNIFI (n=175), active ulcerative colitis the LTE. The LTE began  Maintenance of clinical maintenance ustekinumab 90  Patients who responded to after the assessments listed response through Week 44 study mg SC q12w ustekinumab treatment at for the maintenance phase  Endoscopic healing at Week (CNTO1275U (n=172), and Week 8 of the induction Week 44 visit were 44 CO3001) ustekinumab 90 study (n=523) completed and continued mg SC q8w  Corticosteroid free clinical through Week 220 or until (n=176) remissionat Week 44 the sponsor decided not to  Maintenance of clinical pursue an indication in UC, remission through Week 44 whichever occurs first. among the subjects who had achieved clinical remission at maintenance baseline

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Subjects will continue to receive the same treatment regimen Efficacy evaluations during the LTE during the LTE will generally be based on the partial that they were Mayo score, markers of inflammation, Subjects who completed the UNIFI long- receiving at the and corticosteroid use. The full Mayo safety and efficacy evaluations at term end of the score (including an endoscopy) were Week 44 and who may have extension maintenance assessed at the final efficacy visit. benefited from continued (LTE) study study (either treatment, in the opinion of the (CNTO1275U placebo or investigator, had the opportunity to Selected patient-reported outcomes CO3001) ustekinumab 90 participate in the LTE. (PRO) and health economics data mg SC q8w or were also collected. Safety q12w), with the evaluations include an assessment of first dose in the AEs and routine laboratory analyses. LTE being administered at Week 48. Abbreviations: IBDQ = Inflammatory Bowel Disease Questionnaire, IV = intravenous, LTE= Long-Term Extension, q8w= every 8 weeks, q12w= every 12 weeks, SC = Subcutaneous, UC = ulcerative colitis

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5.2.1.2 Evidence related to the comparator studies included in the SLR A clinical SLR identified and extracted a total of 21 trials for six drugs: ustekinumab, infliximab, tofacitinib, adalimumab, golimumab, and vedolizumab. Table 19 demonstrates an overview of the trials organised by treatment. Further information regarding study characteristics of these trials is included in Section 5.2.1.

Table 20. Overview of the number of relevant studies, by treatment Number of Treatment Abbreviation Trials Names Trials* Jiang 2015(150), Probert 2003(151), Japic Infliximab IFX 6* CTI060298(152), ACT 1(153), ACT 2(153), Silva 2017(149)* OCTAVE Induction 1 (OCTAVE-I1)(157), OCTAVE Tofacitinib TOC 4 Induction 2 (OCTAVE-I2)(156), OCTAVE Sustain (OCTAVE-S)(157), NCT00787202(156) ULTRA 1(148), ULTRA 2(149), NCT00853099(149), Adalimumab ADA 5* Silva 2017(149)**, VARSITY(161)*** Golimumab GOL 3 PURSUIT-SC, PURSUIT-J(155), PURSUIT-M(154) GEMINI 1(158), Kobayashi 2018(159), Vedolizumab VDZ 4* NCT02039505(160), VARSITY*** Ustekinumab UST 1 UNIFI(1) *There are a total of 21 trials, the table adds up to 23 due to the two head-to-head trials that were assigned to IFX and ADA, and VDZ and ADA, respectively (please also see below) **Silva 2017 conducted head-to-head comparison between IFX and ADA ***VARSITY conducted head-to-head comparison between VDZ and ADA

5.2.2 Indirect comparison of ustekinumab versus other active treatments in UC To assess the comparative efficacy of ustekinumab against relevant comparators in moderately to severely active UC patients, a network meta-analysis (NMA) was performed. In the absence of head-to-head comparison between active therapies, an NMA can be used to indirectly compare outcomes between treatments, connected via common comparators between trials (in our case mostly placebo). The results of the different RCTs in a network are synthesized to obtain relative effect estimates for all possible pairwise comparisons while preserving randomisation within the trials and minimising bias due to lack of randomisation across trials.(168) A detailed explanation of the methodology can be found in the guidelines from the ISPOR Task Force on indirect treatment comparisons: Jansen et al. and Hoaglin et al.(168, 169) The main assumption behind an NMA is that of no difference between the trials in the distribution of treatment effect-modifying variables. A patient baseline characteristic is considered a treatment effect modifier if the relative treatment effect varies across different levels of the variable.

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An NMA can be conducted using a fixed effect or a random effect model. The later allows to take into account the between-trial variability. For the induction networks, both fixed and random effects models were fitted and the model with the lower DIC value was selected provided this converged. However, for the 1-year networks, as all comparisons in the available evidence networks are based on a single trial, no information is available to inform the estimate of the between study variability, which makes the results from a random effects model difficult to interpret. If such a model is fit, the estimation of the between study variability is solely driven by the prior used for this parameter. Therefore, the fixed effects models was used for the 1-year networks. A Bayesian NMA was performed using WinBUGS, with non-informative priors specified in line with guidelines from NICE DSU.(170) The Bayesian approach has clear advantages in the context of decision making compared to a conventional frequentist approach, which dichotomizes results to be either significant or non-significant, based on the chosen significance level. Such frequentist approach is less suited for decision making, as it does not indicate the probability the hypothesis will be true or false. Given that all treatments included in the network are available to patients without a formal head-to-head comparison, more relevant is the question how likely it is that, provided the available evidence, a specific treatment is more beneficial than the others. This question is addressed by the Bayesian statistical approach and is thus more relevant for clinical and reimbursement decision making than the classical frequentist approach. Additionally, the Bayesian NMA provides a framework which can easily incorporate additional direct evidence between active treatments and does not have any restriction to the number of study arms per trial. Outputs generated by WinBUGS are posterior distributions for each parameter of interest. Summary statistics of these distributions are provided as results in this report: median odds ratio (OR), 95% credible interval (171) and probabilities for the treatment of interest to perform better than the comparator. An interpretation of each of these statistics is provided below.  Odds ratios (OR): Relative treatment effects for ustekinumab versus each comparator (OR>1 suggests ustekinumab performs better for efficacy endpoints, OR<1 suggests ustekinumab performs better for safety endpoints).  95% credible intervals: Given the data and model specified, there is a 95% chance that the true value lies between the interval  Bayesian pairwise probability: Probability for ustekinumab to perform better than the comparators to achieve the endpoints. A study by Cope et al. (2013) (172) suggested that a probability ≥ 0.85 indicates a treatment is likely to be more effective than the comparator. For efficacy endpoints reflecting a positive outcome, it means that a high probability reflects a better performance of ustekinumab compared to the other treatments. Whereas for safety endpoints reflecting negative outcomes, lower probabilities of ustekinumab versus comparators are in favour of ustekinumab.

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5.2.3 Studies included in the NMA The NMA was conducted based on a selection of a specific set of studies identified as part of the systematic literature review. Only trials assessing the efficacy of at least one intervention of interest (biologics or conventional therapy for UC) were included in the NMA. Separate NMAs were conducted to assess the relative efficacy of ustekinumab versus active comparators for the following regimens and timepoints:  Induction regimen: ustekinumab 6mg/kg and 130mg (8 weeks)  1-year regimen: ustekinumab 6mg/kg induction (8 weeks) followed by 90mg q8w and q12w maintenance (44 weeks) For the analysis of 1-year outcomes, the 6mg/kg induction regimen was assessed in the base case analyses as this reflects the expected license for ustekinumab. As a sensitivity analysis on request from EUnetHTA, the 130mg induction regimen was assessed for 1-year outcomes. Selection criteria Based on the results of an SLR of randomised controlled trials, studies were included in the NMA if they met the following inclusion criteria:  Outcomes - reported one of the following efficacy outcomes: o clinical response, o clinical remission, o mucosal healing  Timepoints - reported the efficacy outcome for one of the timepoints of assessment: o end of induction: 6-8 weeks o end of maintenance: 44-54 weeks of maintenance treatment (corresponding to approximately a yearlong treatment regimen: induction followed by maintenance)  Comparators – included any of the following comparators (with doses and regimens corresponding to the EMA licences): o adalimumab, o infliximab, o golimumab, o tofacitinib, o vedolizumab  Population - included subjects with moderate to severe UC who have either: o Not failed on a previous biologic therapy (non-biologic failure), or

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o Failed on a previous biologic therapy (biologic failure) Comparators Licensed doses for each comparator were included in the NMA based on the EMA guidelines. To strengthen the evidence base, the following unlicensed doses were also included:  Infliximab 10 mg/kg IV at weeks 0, week 2 and week 6 (105)  Infliximab 10mg/kg IV every 8 weeks in maintenance (105) Although these were not in-line with EMA licensing, these treatments were included to allow for induction-to-maintenance treatment strategies to be analysed. Infliximab 10mg/kg is not the recommended regimen for UC, however it is recommended for Crohn’s disease and included in the Canadian product monograph for UC. Furthermore, dose escalation with infliximab to 10mg/kg is common practice in Europe.(173) Therefore, this dose was included in the NMA of 1-year regimens. All trials compared an active treatment to a placebo arm, with the exception of the VARSITY trial which was a head-to-head study of vedolizumab versus adalimumab. Summary of studies in the NMA A summary of studies included in the NMAs by timepoint is provided in Table 21. All studies were conducted in subjects with moderate to severe active UC who failed non- biologic therapy and/or subjects who failed prior biological treatment(s) and results were reported separately for both sub-populations.

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Table 21. Summary of studies included in the NMAs by timepoint Included in NMAs Trial Comparators Induction 1-year NMA NMA OCTAVE Induction 1 (157) Induction: OCTAVE Induction 2 (157) PBO ✓ ✓ OCTAVE I and II – Combined (157) TOF 10mg BID Maintenance: PBO OCTAVE Sustain (157) ✓ TOF 5mg BID TOF 10mg BID Induction: PURSUIT-SC (Phase 2) (154) PBO ✓ ✓ PURSUIT-SC (Phase 3) (154) GOL 200/100mg Maintenance: PBO-PBO PURSUIT–M (154) ✓ GOL 100mg Q4W GOL 50mg Q4W Induction: PBO ULTRA I (174) ADA 160/80mg ✓ Maintenance: ADA 160/80mg Induction: PBO ADA 160/80/40mg ULTRA II (175) ✓ ✓ Maintenance: PBO ADA 40mg EOW Induction: PBO VDZ 300mg GEMINI I (158) Maintenance: ✓ ✓ PBO VDZ 300mg Q8W VDZ 300mg Q4W Induction: NTC00787202 (176) PBO ✓ TOF 10mg BID Induction: PBO IFX 5mg ACT I (153) ✓ ✓ IFX 10mg Maintenance: PBO

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Included in NMAs Trial Comparators Induction 1-year NMA NMA IFX 5mg Q8W IFX 10mg Q8W

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Included in NMAs Trial Comparators Induction 1-year NMA NMA Induction: PBO IFX 5mg IFX 10mg ACT II (153) ✓ Maintenance: PBO IFX 5mg Q8W IFX 10mg Q8W Induction: Probert 2003 (151) PBO ✓ IFX 5mg Induction: PBO UST 130mg UST 6mg/kg UNIFI ✓ ✓ Maintenance: PBO UST 90mg SC Q8W UST 90mg SC Q12W Induction: PBO ADA 160/80mg Suzuki 2014 (149) ADA 80/40mg ✓ (SA) ✓ (SA) Maintenance: PBO ADA 40mg EOW Induction: Japis CTI060297 (152) PBO ✓ (SA) IFX 5mg Induction: Jiang 2015 (150) PBO ✓ (SA) IFX 5mg Induction: ADA 160/80/40mg VDZ 300mg VARSITY (161) ✓ Maintenance: ADA 40mg EOW VDZ 300mg Q8W

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Included in NMAs Trial Comparators Induction 1-year NMA NMA Induction: NCT02039505 PBO ✓ (SA) VDZ 300mg

Abbreviations: ADA: adalimumab; BID: twice a week; EOW: every other week, GOL: golimumab; IFX: infliximab; PBO: placebo; QXW: every X weeks; TOF: tofacitinib; UST: ustekinumab; VDZ: vedolizumab SA: included in the sensitivity analysis with Asian populations only

5.2.4 Outcomes assessed in the NMA The outcomes of interest analysed in the NMAs were based on a feasibility assessment and a review of outcomes assessed as part of recent publications and HTA submissions. Both efficacy and safety outcomes were considered. 1) Efficacy Among the extracted endpoint data from the SLR, the following efficacy outcomes were consistently reported across trials:  clinical response  clinical remission  mucosal healing Inclusion of these outcomes was aligned with recently conducted NMAs identified in the literature (such as Singh et al. 2018 (177)) and HTA submissions to NICE for tofacitinib [TA547] (178) and vedolizumab [TA 342] (179) in ulcerative colitis. Each of these outcomes could be assessed at the end of induction and end of maintenance (corresponding to a year of treatment). 2) Safety The variability in length of the various placebo arms of the re-randomised trials limits the assessment of safety versus placebo. Typically, safety comparisons of the active arms with the withdrawal (placebo after active induction) arm during the maintenance phase, were reported. However, there are limitations with this approach and withdrawal may result in additional (gastro-intestinal) adverse events. Given the limitations of conducting NMA on long-term safety outcomes, no NMA of safety was considered to be feasible for the 1-year timepoint. Further justification for why a NMA of 1-year outcomes is not appropriate is provided in Appendix 4. NMA of safety endpoints in maintenance phase. Instead, as described in Section 5.5, the long-term safety profile for ustekinumab has been evaluated through an integrated publication of safety across indications, assessment of regulatory submission documents, a comparison of the SmPCs for treatments and consideration of the PSOLAR study. These assessments allow for a robust qualitative assessment to be conducted for safety.

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The induction phases of RCTs in UC include standard treat-through designs from which it is possible to compare treatments in terms of safety endpoints. Given the request from EUnetHTA to compare safety outcomes across studies, a NMA of the following safety outcomes in induction were conducted:  Overall adverse events  Serious adverse events  Overall infections  Serious infections However, the findings of the safety NMA in induction are considered to be limited due to the short follow-up in the induction phases of trials (6-8 weeks), low event counts for AEs such as serious infections leading to uncertainty in the results and potential heterogeneity between the populations of the trials due to the inclusion of both non- biologic failure and biologic failure patients. Outcome definitions The definitions for each efficacy endpoint reported across studies are provided below: Clinical response  Decrease in the total Mayo score of at least 3 points and at least 30% from baseline values, with an accompanying decrease in the rectal bleeding subscore of at least 1 point or an absolute rectal bleeding subscore of 0 or 1 Clinical remission  Most studies used the following definition: total Mayo score of 0 to 2, with no individual subscore exceeding 1 point o Probert 2003 (151) used the following definition: UC symptom score (UCSS) of 2 points or less. . This study was only included in the induction NMAs as no maintenance data were available, however, the impact of adding this trial with a slightly different definition, is expected to be minimal. o OCTAVE trials (28) used remission instead of clinical remission defined as a total Mayo score of 0 to 2, with no subscore exceeding 1 point and a rectal bleeding subscore of 0. . Based on the NICE submission for tofacitinib (49) only one patient in the tofacitinib 10mg BID group was classed differently based on the endpoint definitions (results are not available from the submission for both definitions). In UNIFI, this also corresponded to a difference for one patient only. This slight difference in definition has a minimal impact and the endpoints can be considered to be comparable. Mucosal healing  An endoscopic Mayo subscore of 0 or 1 Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 96

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o For the UNIFI trial, the definition of endoscopic healing corresponded to the definition of mucosal healing across all of the other studies. Data for endoscopic healing has been considered from UNIFI instead of mucosal healing (defined as a combination of endoscopic healing and histologic healing). The data corresponding to endoscopic healing has been termed as ‘mucosal healing’ for the purpose of the network meta-analysis. A summary of the endoscopic score assessment method is provided in Table 32.

5.2.5 Comparison in design of the relevant studies

1. In the table below (Table 22), describe the main characteristics of the studies.

2. For each study provide a flow diagram of the numbers of patients moving through the trial.

See Appendix 8. Flow diagrams of the trials of the technology and comparators for the flow diagrams of the trials for the technology and the comparator treatments. Overall, trials evaluating treatments in UC have certain important features in common. Most studies that continued to evaluate the maintenance of drug effect after the induction phase, re-randomised the patients who responded to active arms at the beginning of the maintenance phase (e.g. UNIFI, PURSUIT, OCTAVE and GEMINI I); other trials did not re-randomise the patients for the maintenance phase and patients continued to receive the same treatment as in the induction phase i.e. patients were treated-through (e.g. ACT I, ULTRA II and VARSITY). The main reason for the change in clinical trial design was that it was not considered ethical to expose patients to ineffective placebo treatments. The definition of efficacy endpoints assessed and their corresponding time of assessment slightly change across trials (for further details on study endpoints see Section 5.4). The most commonly reported primary efficacy endpoint was remission (defined as a Mayo score of ≤2 with no subscore >1) but the time of assessment varied across studies from week 6 to week 8 in induction trials and from week 30 to week 54 after the end of induction in the maintenance trials. Sample size varied across trials: from 20 patients per arm to more than 400 per arm in induction trials, and from 30 patients per arm to more than 300 per arm in maintenance trials.

5.2.6 Comparison of patient characteristics across studies 3. For each study provide a comparison of patients (including demographic, clinical and social information [if applicable]) in treatment arms at baseline.

At the trial outset, there were no major discrepancies in the baseline demographic characteristics (including age, weight and the proportion of males at baseline) and the baseline disease characteristics (including duration of disease, CRP level and Mayo score across studies.

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1. Disease duration A general trend of shorter disease duration was observed for non-biologic failure patients group than that in the full patients group (Figure 14). At the start of the induction phase, 15 studies reported a mean disease duration varying from 4 to 8 years in the non-biologic failure patients, and from 6 to 11 years for the full patients.

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Figure 14. Mean and median disease duration of patients at start of induction

Key: orange bars – mean value; brown bars – median value

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2. C-reactive protein level at baseline

The mean CRP level at baseline reported by 15 studies for the induction phase ranged from 4 to 17mg/L in non-biologics failure patients and 5 to 19mg/L in full patients (Figure 15).

Figure 15. Mean and median CRP level of patients at start of induction

Key: orange bars – mean value; brown bars – median value

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3. Mayo score at baseline

All studies included patients of moderate-to-severe UC defined as a Mayo score between 6 and 12 for the induction phase (Figure 16). The mean Mayo score at baseline reported for subgroups of patients ranged from 8 to 9 across all induction phase studies and the differences are limited across trials. Figure 16. Mean and median Mayo score of patients at start of induction

Key: orange bars – mean value; brown bars – median value

Further descriptions and comparisons of characteristics of the relevant trials are described in Table 22.

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Table 22. Characteristics of the studies Study Objective Study design Eligibility criteria Intervention and Primary Secondary reference/ID Comparator outcome outcome (N enrolled) measure and measures and follow-up follow-up time time point points To assess the Phase III/IV, Inclusion: Induction: Induction: Induction: efficacy and safety multi-national, Adult patients with  Adalimumab Clinical Proportion of of adalimumab for double-blind moderately to 80/40mg remission at patients with severely active UC week 8 clinical response the induction and (induction) and (n=130) (Mayo score: 6-12;  Adalimumab per Mayo score; maintenance of open-label endoscopy score: 2- 160/80mg Maintenance: proportion of clinical remission in (maintenance) 3); patients; patients (n=130) Clinical patients with anti-TNF naive trial may be concurrently  Placebo (n=130) remission, mucosal healing; patients with treated with oral response, and proportion of moderately to corticosteroids were Maintenance: mucosal patients with severely active receiving a stable  Adalimumab healing at subscores dose prior to baseline. week 52 indicative of mild ulcerative colitis 40mg (n=390) Patients treated with disease at week immunomodulators 8 received at least a consecutive 90-day Maintenance: ULTRA 1 course prior to Proportion of (NCT00385736) baseline of patients who azathioprine (or 6- increased to MP). weekly dosing and their rate of Exclusion: clinical remission Previous receipt of at week 52, any anti-TNF agent or steroid tapering any biological agent, and SF remission at week 52, and including adalimumab; remission per receipt of intravenous partial Mayo corticosteroids within score (partial 14 days prior to Mayo score ≤2 screening and during with no screening; receipt of subscore >1) cyclosporine, over time

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tacrolimus, mycophenolate mofetil, or MTX within 60 days or cyclosporine, tacrolimus, or mycophenolate mofetil within 30 days prior to baseline

See ULTRA 1 trial for more details

To assess the Phase II, Inclusion: Induction: Clinical  Proportion of efficacy and safety multinational, Adult patients with  Adalimumab remission at patients who of adalimumab for double-blind moderately to 160mg/80mg week 8 and achieved severely active UC the induction and trial (n=258) 52 clinical (Mayo score: 6-12; remission at maintenance of  Placebo (n=260) endoscopy score: ≥2); both weeks clinical remission in patients may be Maintenance: 8 and 52 anti-TNF naive treated concurrently  Adalimumab (sustained) with corticosteroids patients with 40mg (n=258)  Clinical and/or azathioprine or moderately to  Placebo (n=260) response at severely active 6-mercaptopurine week 8,

ULTRA 2 ulcerative colitis week 52, Exclusion: and both (NCT00408629) Previous receipt of weeks 8 and any anti-TNF agent or 52 any biological agent, (sustained) including adalimumab  Mucosal healing at week 8, See ULTRA 2 trial for week 52, more details and both weeks 8 and 52 (sustained)

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See ULTRA 2 for more details To evaluate Phase II/III, Inclusion: Induction: Clinical Rectal bleeding adalimumab for double-blind, Patients with  Adalimumab response, subscore, induction and trial in Japan moderately to 80/40mg (n=87) clinical physicians global maintenance severely active UC  Adalimumab remission, assessment, and treatment in anti- (Mayo score: 6-12; 160/80mg and mucosal stool frequency (n=90) TNF–naive endoscopy score: ≥2) healing at indicative of mild  Placebo (n=96) Japanese patients who are ≥15 years; weeks 8, 32, disease (score with UC who were patients may have Maintenance: and 52 ≤1) and IBDQ refractory to received  Adalimumab response (C16- corticosteroids, corticosteroids or 40mg (n=177) point increase immunomodulators, immunomodulators  Placebo (n=96) from baseline in or both concurrently at IBDQ score) at baseline; patients may weeks 8, 32, and be refractory to 52 corticosteroids, immunomodulators, or See NCT00853099 both NCT00853099 for more details Exclusion: Patients who have received anti-TNF therapies or other biologic agents, discontinued oral corticosteroids within 2 weeks before baseline, received corticosteroid injection, cyclosporine, tacrolimus, or mycophenolate mofetil

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within 4 weeks before baseline

See NCT00853099 for more details

To compare the Head-to-head NA  Adalimumab Clinical Endoscopic efficacy of infliximab trial in Brazil (n=10) response and response versus adalimumab  Infliximab (n=21) clinical Silva 2017 in clinical response remission See trial for more and endoscopic details response in UC patients To study efficacy, Double-blind Inclusion: Induction and Clinical Clinical response safety, or dosage of trial in China Adult patients with Maintenance: response or clinical infliximab in Chinese moderately to  Infliximab 3.5mg remission with patients with severely active UC (n=41) discontinuation of (Mayo score: 6-12; moderate to severe  Infliximab 5mg corticosteroids at endoscopy score: ≥2); ulcerative colitis (n=41) week 30; clinical patients may be  Placebo (n=41) treated concurrently remission and with corticosteroids mucosal healing only or in combination at weeks 8 and with azathioprine and 30; clinical Jiang 2015 drugs containing 5- response at week aminosalicylates 8 in patients with

Exclusion: a medical history Patients who received of disease corticosteroids or refractory to drugs containing 5- corticosteroids aminosalicylates rectally within 2 weeks See trial for more before screening; details patients who were previously exposed to infliximab or any other

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anti–tumour necrosis factor

See trial for more details To conduct a double Double-blind Inclusion: Induction: Clinical Changes in blind, randomised, trial in United Adult patients with  Infliximab 5mg remission UCSS, Baron placebo controlled Kingdom and moderately to (n=23) score, quality of trial of infliximab in Germany severely active UC  Placebo (n=20) life, and serum C the treatment of (Mayo score: 6-12; reactive protein moderately severe endoscopy score: ≥2); levels, and glucocorticoid patients may be change in daily resistant ulcerative treated concurrently glucocorticoid colitis with dose a stable dose of 6- mercaptopurine or See trial for azathioprine for more further details than three months prior to trial; patients may have failed to Probert 2003 respond to conventional treatment with glucocorticoids

Exclusion: Patients who had received cyclosporin, any therapeutic agent used to directly reduce TNF, or any investigational drug within three months of enrolment, as well as those who had

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recently commenced treatment (within the last three months) with 6- MP or AZA

See trial for further details As part of a phase 3 Double-blind Inclusion: Induction and Clinical Clinical remission randomised trial in Japan Patients with Maintenance: response and mucosal controlled trial of moderately to  Infliximab 5mg healing infliximab in UC, to severely active UC (n=104)  Placebo (n=104) assess the predictive (Mayo score: 6-12; See trial for more value of the first TL endoscopy score: ≥2); details at week 2 for short- patients may be and long-term treated concurrently response with corticosteroids, oral aminosalicylates, AZA Japic and 6-MP CTI060298

Exclusion: Patients treated with other biologics, MTX, calcineurin inhibitors, or cytapheresis within the previous 18 months

See trial for more details To conduct 54-week Phase III, Inclusion: Induction and Clinical Clinical response and 30-week studies multi-national, Patients with Maintenance: response at or clinical ACT 1 of infliximab in double-blind moderately to  Infliximab week 8 remission with (NCT00036439) patients with trial severely active UC 5mg/kg (n=121) discontinuation of (Mayo score: 6-12; corticosteroids at

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moderate-to-severe endoscopy score: ≥2);  Infliximab weeks 30 and 54, ulcerative colitis patients may be 10mg/kg clinical remission treated concurrently (n=122) and mucosal with  Placebo (n=121) healing at weeks corticosteroids alone 8, 30 and 54, or in combination with clinical response AZA or at week 8 in mercaptopurine patients with a history of disease Exclusion: refractory to Patients treated with corticosteroids infliximab or any other anti-TNF agent; See ACT 1 trial rectally administered for more details corticosteroids or medications containing 5-ASA two weeks before screening

See ACT 1 trial for more details

To conduct 54-week Phase III, Inclusion: Induction and Clinical Clinical response and 30-week studies multi-national, Patients with Maintenance: response at or clinical of infliximab in double-blind moderately to  Infliximab week 8 remission with patients with trial severely active UC 5mg/kg (n=121) discontinuation of moderate-to-severe (Mayo score: 6-12;  Infliximab corticosteroids at ACT 2 ulcerative colitis endoscopy score: ≥2); 10mg/kg weeks 30, clinical (NCT00096655) (n=120) patients may be remission and  Placebo (n=123) treated concurrently mucosal healing with at weeks 8 and corticosteroids alone 30, clinical or in combination with response at week

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AZA or MP and 8 in patients with medications a history of containing 5- ASA disease refractory to Exclusion: corticosteroids Patients treated with infliximab or any other anti-TNF agent, rectally administered corticosteroids or medications containing 5-ASA two weeks before screening

See ACT 2 trial for more details

To evaluate the Phase III, Inclusion: Induction: Clinical Clinical remission efficacy and safety open-label Adult patients with  Golimumab response at and mucosal of golimumab as (induction) and moderately to 200mg (n=144) week 54 healing at week maintenance therapy double-blind severely active UC 30 and week 54; in the Japanese (maintenance) (Mayo score: 6-12; Maintenance: proportion of  Golimumab population trial in Japan endoscopy score: ≥2); patients who 100mg (n=32) patients may have  Golimumab maintained had inadequate clinical remission PURSUIT-J 100mg (n=60) response to or had at both week 30 (NCT01863771)  Placebo (n=31) failed to tolerate one and week 54 or more conventional among patients therapies (oral 5-ASA, induced into oral corticosteroids, clinical remission AZA and/or MP) or with SC had demonstrated golimumab corticosteroid dependence

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See PURSUIT-J Exclusion: trial for more Patients previously details treated with TNFi therapy

See PURSUIT-J trial for more details To evaluate the Phase II/III, Inclusion: Induction: Clinical Clinical remission safety and efficacy multi-national, Adult patients with  Golimumab response at at week 6, of the selected SC double-blind moderately to 100/50mg week 6 mucosal healing, golimumab induction trial severely active UC (n=42) IBDQ score regimens (Mayo score: 6-12;  Golimumab change 200/100mg endoscopy score: ≥2); (n=42) patients concurrently  Golimumab See PURSUIT- treated with oral 5- 400/200mg SC trial for more aminosalicylates or (n=43) details corticosteroids were to  Placebo (n=42) receive a stable dose for at least 2 weeks Maintenance: before baseline, and  Golimumab PURSUIT-SC patients receiving AZA 200/100mg (NCT00487539) (n=258) and/or 6-MP were to  Golimumab receive a stable dose 400/200mg for at least 4 weeks (n=258) before baseline.  Placebo (n=258)

Exclusion: Patients previously treated with biologic anti-TNF agent(s) natalizumab or other agents targeting the α- 4 integrin, B-cell depleting agents

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(rituximab), or T-cell depleting agents (alemtuzumab, visilizumab) within 12 months of the first study-agent injection (or continued B- or T- cell depletion >12

See PURSUIT-SC trial for more details

To evaluate SC Phase III, NA Maintenance: Maintenance Clinical remission golimumab multi-national,  Golimumab of clinical at both weeks 30 maintenance therapy double-blind 50mg (n=154) response and 54, mucosal administered every 4 trial  Golimumab through week healing at both 100mg (n=154) weeks through week 54 weeks 30 and 54, Placebo (n=156) 52 clinical remission PURSUIT-M at both weeks 30 (NCT00488631) and 54, corticosteroid- free clinical remission at week 54

NA Phase II, multi- Inclusion: Induction: Clinical Clinical remission national, Adult patients with  Tofacitinib response at 8 at, endoscopic double-blind moderately to 0.5mg (n=31) weeks response, and trial severely active UC  Tofacitinib 3mg endoscopic (n=33) (Mayo score: 6-12; remission at 8 NCT00787202  Tofacitinib 10mg endoscopy score: ≥2) (n=33) weeks  Tofacitinib 15mg Exclusion: (n=49) See trial for more Patients receiving  Placebo (n=48) details AZA or 6-MP or MTX

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within 7 days, or cyclosporine, mycophenolate, or tacrolimus within 4 weeks, or anti-TNF agents within 8 weeks

See trial for more details To further evaluate Phase III, Inclusion: Induction: Clinical Mucosal healing the efficacy of multi-national, Adult patients with  Tofacitinib 10mg remission at at week 8 tofacitinib as double-blind moderately to (n=476) week 8 induction and trial severely active UC  Placebo (n=122) See OCTAVE-1 maintenance therapy (Mayo score: 6-12; trial for more endoscopy score: 2- details 3); patients may concurrently be treated with oral aminosalicylates and oral glucocorticoids OCTAVE - Induction 1 Exclusion: (OCTAVE-I1; Patients who had NCT01465763) inadequate washout for the following medications prior to baseline: AZA, 6-MP, or MTX within 2 weeks, TNF antagonist or interferon therapy within 8 weeks

See OCTAVE-1 trial for more details

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To further evaluated Phase III, See inclusion and Induction: Clinical Mucosal healing OCTAVE - the efficacy of multi-national, exclusion criteria for  Tofacitinib 10mg remission at at week 8 Induction 2 tofacitinib as double-blind OCTAVE-1 trial (n=429) week 8 (OCTAVE-I2; induction and trial  Placebo (n=112) See OCTAVE-1 NCT01458951) maintenance therapy trial for more details To further evaluated Phase III, NA Maintenance: Clinical Mucosal healing the efficacy of multi-national,  Tofacitinib 5mg remission at at week 52, tofacitinib as double-blind (n=198) week 52 remission that induction and trial  Tofacitinib 10mg was sustained at maintenance therapy (n=197) weeks 24 and 52,  Placebo (n=198) and glucocorticoid- OCTAVE – free among Sustain patients who (NCT01458574) were in remission at maintenance- trial entry

See OCTAVE- Sustain trial for more details To evaluate the Phase III, Inclusion: Induction: Induction: Induction: efficacy and safety multi-national, Adult patients with  Placebo (n=149) Proportion of Proportion of of vedolizumab in double-blind moderately to (cohort 1) patients with patients in clinical clinical remission at patients with and open-label severely active UC  Vedolizumab response at Week 6; ulcerative colitis (induction) and (Mayo score: 6-12; 300mg (n=225) (cohort 1) Week 6 proportion of double-blind endoscopy score: ≥2); GEMINI 1  Vedolizumab patients with (maintenance) patients may have Maintenance: mucosal healing (NCT00783718) 300mg (n=521) trial been treated with one (cohort 2) Proportion of at Week 6 or more patients in glucocorticoids, Maintenance: clinical Maintenance: remission at Proportion of immunosuppressive  Vedolizumab Week 52 patients with 300mg (n=122) medications (i.e., AZA durable clinical response;

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and 6-MP), or TNF  Vedolizumab proportion of antagonists 300mg (n=125) patients with  Placebo (n=126) mucosal healing at Week 52; Exclusion: proportion of Patients previously patients with treated with TNF durable clinical antagonists within 60 remission days before enrolment or cyclosporine, See GEMINI 1 thalidomide, or trial for more details investigational drugs within 30 days before enrolment, or if they had been treated previously with vedolizumab, natalizumab, efalizumab, or rituximab

See GEMINI 1 for more details As part of a phase 3 Phase I, open- Inclusion: Induction and Clinical Clinical remission randomised label trial in Patients with Maintenance: response at at weeks 8 and controlled trial of IFX Japan moderately to  Vedolizumab week 8 30, mucosal in UC, to assess the severely active UC 150mg (n=3) healing at week predictive value of (Mayo score: 6-12;  Vedolizumab 8, clinical Kobayashi 2018 the first TL at week 2 endoscopy score: ≥2); 300mg (n=6) response at week (Japic for short- and long- patients may have  Placebo (n=9) 30 term response concurrently treated CTI060298) with corticosteroids, See trial for more oral aminosalicylates, details AZA and 6- mercaptopurine

Exclusion:

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Patients treated with other biologics, MTX, calcineurin inhibitors, or cytapheresis within the previous 18 months

See trial for further details Phase III, Induction: double-blind  Vedolizumab and open-label 300mg (n=246) (induction) and  Placebo (n=83) NCT02039505 double-blind Maintenance: (maintenance)  Vedolizumab trial in Japan 300mg (n=246)  Placebo (n=83) Phase III, Maintenance: multi-national,  Vedolizumab VARSITY double-blind 300mg (n=111) trial  Adalimumab 160/80/40 mg (n=120) To evaluate the Phase III, Inclusion: Induction: Induction: Induction: safety and efficacy multi-national, Patients with  Ustekinumab Clinical Endoscopic of ustekinumab double-blind moderately to 130mg remission at healing; clinical week 8 response, induction and trial severely active UC (n=320) change from maintenance therapy (Mayo score: 6-12;  Ustekinumab 6mg/kg Maintenance: baseline in IBDQ in participants With endoscopy score: ≥2) UNIFI (n=322) Clinical at week 8 moderately to remission (NCT02407236)  Placebo severely active Exclusion: (n=319) Among Maintenance: ulcerative colitis Presence of a stoma; participants in Clinical severe extensive Maintenance: clinical response, colitis and is at  Ustekinumab response to maintenance of 90mg q12w IV clinical remission, (n=172) ustekinumab induction

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imminent risk of  Ustekinumab treatment at endoscopic colectomy 90mg q8w Week 44 healing at Week (n=176) 44  Placebo See UNIFI trial for (n=175) See UNIFI trial more details for more details

Abbreviations: 5-ASA: 5-aminosalicylic acid; 6-MP: 6-mercaptopurine; IBDQ: inflammatory bowel disease questionnaire; MTX: Methotrexate; SF: steroid-free; TNF: tumour necrosis factor; UC: ulcerative colitis

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5.3 Methods for the indirect comparison

5.3.1 Approach for the Bayesian NMA In the UNIFI trial, patients were stratified into biologic failure and non-biologic failure groups based on their history of biologics treatment. Biologic failure was defined as patients who were treated with one or more anti-TNF treatment or vedolizumab. Non- biologic failure patients were defined as subjects who may be biologic naïve or may have been exposed to biologic therapy but did not demonstrate an inadequate response or intolerance to treatment with a biologic agent. The exclusion criteria for prior exposure or failure to biologic therapy varied across studies, and prior anti-TNF therapy exposure was found to be a potential source of heterogeneity. Table 23 provides information on the populations and definition associated with this stratification. To adjust for prior therapy as a potential treatment effect modifier and to be consistent with the population stratification used in the UNIFI trial, separate NMAs were conducted in patients who had failed biologic therapy (biologic failures) and patients who had not failed biologic therapy (non-biologic failures). This was possible for the efficacy endpoints but not for the safety endpoints as only endpoint data for the full population (non-biologic failure and biologic failure) were available for most studies. Therefore, for the safety NMAs, the full population was analysed. The comparability of studies by induction and maintenance phases are described in detail in Section 5.2.6.

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Table 23. Subgroup definitions across trials for prior therapy with the population corresponding to UNIFI Population corresponding to Trial Regimens Design Population Definition UNIFI Patients who have received treatment with 1 or more TNF antagonists and/or Placebo vedolizumab Ustekinumab 130mg IV at Parallel, Biologic failure Subjects who may be biologic- UNIFI week 0 double-blind Non-biologic naive or may have been N/A Ustekinumab 6mg/kg IV at failure exposed to biologic therapy but week 0 not demonstrated an inadequate response or intolerance to treatment with a biologic agent Placebo Infliximab 5mg/kg at week 0, Patients previously exposed to ACT I & II Parallel, Corresponds to non-biologic 2 and 6 Bio-naïve infliximab or any other anti-TNF (153) double-blind failure patients from UNIFI Infliximab 10mg/kg at week agent were excluded. 0, 2 and 6 TNF-naïve Prior anti-TNF failure Cohort 1: Placebo No prior anti-TNF therapy Parallel, Prior TNF corresponds to biologic failure Cohort 1: Vedolizumab double-blind antagonist Prior failure of anti-TNF GEMINI I patients from UNIFI 300mg at days 1 and 15 for cohort 1, failure therapy (158) No prior anti-TNF failure Cohort 2: Vedolizumab open-label No prior TNF No prior failure of anti-TNF for cohort 2 corresponds to non-biologic 300mg at days 1 and 15 antagonist therapy failure patients from UNIFI failure Probert Infliximab 5mg/kg at week 0 Parallel, No prior therapeutic agent Corresponds to non-biologic Bio-naïve 2003 (151) and 2 double-blind used to directly reduce TNF failure patients from UNIFI  Placebo  Golimumab 100/50mg at week 0 and 2 Parallel, PURSUIT No prior biologic anti-TNF Corresponds to non-biologic double-blind Bio-naïve (154)  Golimumab 200/100mg agent(s) failure patients from UNIFI at week 0 and 2  Golimumab 400/200mg at week 0 and 2

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No prior TNF antagonist No previous treatment with Prior anti-TNF failure treatment TNF antagonists corresponds to biologic failure Placebo Parallel, Prior TNF OCTAVE I Treatment failure from TNF- patients from UNIFI Tofacitinib 10mg daily for 8 double-blind antagonist & II (157) antagonist No prior anti-TNF failure weeks failure Previous treatment with TNF- corresponds to non-biologic No prior TNF antagonist and no failure failure patients from UNIFI antagonist failure ULTRA I: Placebo Adalimumab 80mg and placebo at week 0, ADA 40mg and placebo at weeks 2, ADA 40mg at weeks 4 Anti-TNF naïve Anti-TNF naïve corresponds to No previous receipt of any anti- and 6 patients non-biologic failure patients Parallel, TNF agent or any biologic ULTRA I & from UNIFI Adalimumab 160mg at week double-blind ULTRA II: anti- agent II (174, 175) 0, ADA 80mg at week 2, TNF Anti-TNF experienced ULTRA II: previous receipt of ADA 40mg at weeks 4 and 6 experienced corresponds to biologic failure any anti-TNF agent ULTRA II: patients patients from UNIFI Placebo Adalimumab 160 mg at week 0, 80mg at week 2 and then 40 mg every other week beginning at week 4 Vedolizumab IV 300mg at Anti-TNF naïve corresponds to weeks 0,2,6 and every 8 Anti-TNF naïve non-biologic failure patients VARSITY weeks after until week 46 Parallel, from UNIFI Anti-TNF NR (161) Adalimumab 160mg at week double-blind exposure/failur Anti-TNF experienced/failure 0, 80mg at week 2 and e corresponds to biologic failure 40mg Q2W until week 50 patients from UNIFI Abbreviations: ADA: IV: intravenous; TNF: tumour necrosis factor

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Induction phase In terms of study design and patient characteristics, induction phase trials in UC were similar enough for their findings to be pooled together. Treatment effect modifiers were not widely discussed in other SLRs and NMAs but potential heterogeneity sources in the induction phase were determined based on the literature.(180) The following baseline demographic and clinical characteristics were assessed and were comparable across trials: duration of disease, age and weight at baseline, proportion of males/females, C-reactive protein level and Mayo score at baseline. Graphs of the baseline characteristics for the studies are included in Section 5.2.6. Full details on baseline characteristics across studies included in the NMAs are provided in Appendix 3. Comparison of baseline characteristics of studies of the technology and comparator treatments.

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Table 24. Induction studies and time points of assessment Clinical response Clinical remission Mucosal healing Included in Timepoint Trial Non-biologic Non-biologic Non-biologic Biologic Biologic failure Biologic failure BCA? failure failure failure failure OCTAVE O (no prior O (no prior O (prior TNF O (prior TNF 8 weeks Induction I O O TNF TNF Yes failure) failure) (157) treatment) treatment) OCTAVE O (no prior O (no prior O (prior TNF O (prior TNF 8 weeks Induction II O O TNF TNF Yes failure) failure) (157) treatment) treatment) PURSUIT-SC 6 weeks (Phase 2) O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X Yes (154) PURSUIT-SC 6 weeks (Phase 3) O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X Yes (154) 8 weeks ULTRA I (174) O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X Yes O (no prior O (prior anti- O (no prior O (prior anti- O (no prior O (prior anti- 8 weeks ULTRA II (175) Yes anti-TNF) TNF) anti-TNF) TNF) anti-TNF) TNF) GEMINI I * O (TNF- O (TNF- O (TNF- 6 weeks O (TNF-naïve) O (TNF-naïve) O (TNF-naïve) Yes (158) failure) failure) failure) NCT00787202 O (no previous O (previous 8 weeks X X X X Yes (176) anti-TNF) anti-TNF) 8 weeks ACT I (153) O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X Yes 8 weeks ACT II (153) O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X Yes Probert 2003 O (bio-naïve) 6 weeks X X X X X Yes (151) ** 8 weeks UNIFI O O O O O O Yes Suzuki 2014*** 8 weeks X X X X X X No (149) PURSUIT- 6 weeks O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X No J***a(155)

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Japis 8 weeks CTI060297*** O (bio-naïve) X O (bio-naïve) X O (bio-naïve) X No (152) Jiang 2015*** 8 weeks O (TNF-naïve) X O (TNF-naïve) X O (TNF-naïve) X No (150) Silva 2017***b NR X X X X X X No (181) NR VARSITY(161) X X X X X X No Note: time points correspond to time spent on induction therapy in the studies. X indicated the data are not available, O indicates the data are available * Results on Cohort 1 for GEMINI I consists of a double-blind group with randomised patients receiving placebo or vedolizumab at weeks 0 and 2 ** Definition of clinical remission different for Probert: Ulcerative Colitis Symptom Score (USCC) ≤2 *** Trials excluded from the base case analysis (BCA) a PURSUIT-J was excluded from the analysis: all patients received golimumab in the induction period. b Silvia 2017 was excluded from the sensitivity analysis: no time of assessment was reported.

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Various time points of assessment were found across induction trials (as shown in Table 24) and similar times of assessment were selected for each intervention. Endpoints reported at 6 weeks were used as inputs for golimumab and vedolizumab, and endpoints reported at 8 weeks were used as inputs for ustekinumab, tofacitinib, adalimumab and infliximab. Results were considered comparable between 6 weeks and 8 weeks which is supported by data from all trials (except ULTRA II) reporting either the change in partial mayo score from baseline at week 4 and week 6/week 8, or the partial mayo scores at these timepoints (Table 25). Table 25. Partial mayo score at weeks 4, 6 and 8 across trials

Baseline Change in partial mayo score from Partial mayo score partial mayo baseline Trial Treatment score, mean At 4 weeks, At 6 weeks, At 8 weeks, At 4 weeks At 6 weeks At 8 weeks (SD) mean (SD) mean (SD) mean (SD)

Placebo 6.2 (1.46) -1.4 (1.86) NR -1.5 (2.07) NR NR NR

Ustekinumab 6.2 (1.33) -2.5 (1.93) NR -2.9 (2.20) NR NR NR UNIFI 6mg/kg Ustekinumab 6.2 (1.42) -2.1 (1.86) NR -2.6 (2.31) NR NR NR 130mg

Placebo 5.9 (1.37) -1.2 (1.83) -1.2 (2.04) NR NR NR NR

Golimumab 5.8 (1.15) -2.0 (1.96) -1.8 (2.21) PURSUIT- NR NR NR NR SC (all 100/50mg randomize Golimumab 6.1 (1.35) -2.3 (2.07) -2.3 (2.21) NR NR NR NR d patients) 200/100mg Golimumab 6.1 (1.29) -2.3 (2.13) -2.3 (2.37) NR NR NR NR 400/200mg

Placebo 6.5 (1.2) -1.6 (0.2) NR -1.6 (0.2) NR NR NR OCTAVE I Tofacitinib 6.3 (1.2) -2.8 (0.1) -3.1 (0.1) NR NR NR NR 10mg

Placebo 6.4 (1.2) -1.5 (0.2) NR -1.7 (0.2) NR NR NR OCTAVE II Tofacitinib 6.4 (1.3) -2.7 (0.1) -3.0 (0.1) NR NR NR NR 10mg

Placebo 6.0 (5.0-7.0) NR NR NR NR 5.0 (3.0-6.0) 5.0 (3.0-6.0)

6.0 (5.0-7.0) 3.0 (2.0-5.0) 2.0 (1.0-4.0) ACT I* Infliximab 5mg NR NR NR NR

Infliximab 6.0 (5.0-7.0) 3.0 (2.0-5.0) 3.0 (1.0-5.0) NR NR NR NR 10mg

Placebo 6.12 (0.45) NR NR NR 5.20 (0.67) 5.19 (0.76) NR GEMINI** Vedolizumab 6.01 (0.44) 4.39 (0.61) 4.09 (0.60) NR NR NR NR 300mg *For ACT I, values were reported as median (IQR). ** For GEMINI, values were reported as mean (SD) and were digitalized from a graph.

Maintenance phase Trial designs conducted in UC have evolved over time from standard treat-through designs, for anti-TNF therapies (including infliximab and adalimumab), to designs that re-randomised patients based on response to treatment, for the newer therapies. Essentially all trials in UC can be classified as being in either one of these two broad categories of designs. The response-based trial design rather focuses on another question of benefit in continued treatment for induction responders to be answered. These trial designs are considered to be more ethical as they limit patients’ exposure to ineffective treatment. The key features of each trial design are described below.

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Treat-through trial design Trials evaluating the current standard of care therapies of infliximab (ULTRA II) and adalimumab (ACT I) are based on treat-through designs as depicted in Figure 17 below. Figure 17. Treat-through trial design schematic

 Active and placebo arms at induction: The patients randomised to induction phase continue with the same treatment to the maintenance phase.  This design is conventional and allows for a straightforward interpretation of the effectiveness of a continued 1-year regimen versus placebo. Response-based re-randomised trial design All trials evaluating newer treatments, including vedolizumab (GEMINI I), tofacitinib (OCTAVE), golimumab (PURSUIT) and ustekinumab (UNIFI) trials, are based on re- randomised response designs as depicted in Figure 18 below. Although the primary analyses of maintenance data may be reported based on the induction responders who enter the maintenance phase, the studies still capture maintenance outcomes for both induction responders and non-responders for the active arms at least. One-year outcomes are captured from these trials and results from these trials can be re-calculated to correspond closely to one-year outcomes from treat-through trial arms. Figure 18. Response-based re-randomised trial design schematic

 Active arm at induction: Responders to active treatment during the induction phase are re-randomised to the treatment or placebo arm for the maintenance phase; non-responders are treated-through for the maintenance phase up to 1 year.  Placebo arm at induction: Patients either remain on placebo from induction to maintenance regardless of response (as depicted above for GEMINI I) or continued to receive placebo maintenance treatment based on response at the end of induction (PURSUIT and UNIFI).

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 In the OCTAVE, PURSUIT and UNIFI trial designs, exposure to long-term ineffective placebo is minimised as only responders continue in the trial. Non- responders cross over to active treatment or are included in an open-label extension phase of the study.  This design complicates the interpretation of continued one-year treatment regimens, as typically the efficacy of a regimen over the course of a full year is not directly reported (though these can be re-calculated as further discussed) As NMA is based on comparison of relative treatment effects versus common treatment arms, common comparators are needed to indirectly connect treatments together. The majority of trials in UC are placebo-controlled trials, with placebo being the common comparator arm in most trials. However, differences in study designs suggest that the placebo arms used across studies are not comparable and cannot be used as a common comparator in a network meta analysis. The approach used for deriving input data for the NMA to deal with differences in reporting of maintenance outcomes are described in section 5.3.2. As for induction, the time point corresponding to the end of maintenance and prior therapy exposure differed across the trials. The time of assessment for the maintenance phase (defined as the time from the end of induction to the end of the maintenance) varied from week 44 (UNIFI and ULTRA II) to week 54 (PURSUIT-M). Partial mayo scores within the trials are fairly consistent around the one-year time frame, indicating that clinical outcomes stay stable between week 44 and 54. For example, the graphs of partial mayo score over time for the maintenance phase of UNIFI, PURSUIT and GEMINI I all show similarity in the scores between weeks 40 and 54 for the active arms (Figure 49, Figure 50 and Figure 51, Appendix 5. Carry- over effects). In addition, the induction data from GEMINI I includes both a blind active treatment and an open-label active treatment, in the other trials all patients are blinded to induction treatment.

5.3.2 Approach to combine induction and maintenance trial results to enable 1-year comparisons across all active treatments

5.3.2.1 Methods for the 1-year comparisons Bayesian NMA was conducted for the 1-year outcomes. However, an alternative approach was taken to construct the data inputs for the efficacy outcomes. Details on the approach taken including the justification are provided in the following sections. Comparison of 1-year treatment regimens There are two main challenges in conducting an NMA of maintenance data in ulcerative colitis: 1) consistent definitions of active maintenance arms across trials, and most importantly, 2) a common placebo arm between studies to “connect”.

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Trials with treat-through designs provide information on the full 1-year effectiveness of treatments. Trials with response-based re-randomised designs are more complicated to interpret as the effectiveness of a continued 1-year regimen is not typically reported directly. A standard NMA of maintenance data alone is flawed for the following reasons:  The placebo arms reported from re-randomised response-based trials for the maintenance period are not true placebo arms. These are based on re- randomised responders from active induction therapy and therefore are subject to carry-over effects of induction therapy which differ between studies violating the assumptions required for NMAs (further discussed below and in Appendix 5. Carry-over effects)  This is subject to selection bias as maintenance data reported from these trials only included patients that responded to induction therapy. Therefore, response to induction needs to be accounted for in the interpretation of maintenance outcomes.  The efficacy of treatment for patients who respond later than a pre-specified induction period should be accounted for. An NMA of maintenance data alone would only include patients who responded at the end of induction and ignores delayed responders. In the UNIFI trial, there is evidence of a carry-over effect of induction therapy with ustekinumab affecting maintenance outcomes for patients who receive placebo. Evidence of carry-over effects are also found in the trials for other biologic treatments for UC however the magnitude of the carry-over effects differ across studies. This is illustrated in Figure 19 showing the evolution of the partial mayo score in the maintenance phase of UNIFI, with partial mayo scores in patients on placebo post-active ustekinumab induction therapy being notably lower (i.e. showing a better response) compared to the partial mayo scores for patients on placebo post- active golimumab induction therapy in PURSUIT. A similar difference is observed in Crohn’s Disease between ustekinumab and adalimumab in terms of clinical remission (see Figure 19). This is further illustrated by substantial differences (p<0.001) in response rates at the end of maintenance for the re-randomised placebo arms of UNIFI, PURSUIT, OCTAVE and GEMINI I, where patients received active induction therapy (see Figure 20 and Figure 21 for non-biologic and biologic failure patients respectively). The response rates across the placebo arms ranged between 26.6% to 50.6% in the non-biologic failure group and 15.8% to 38.6% in the biologic failure. For both patient groups the highest response rate was observed in the UNIFI trial for patients who received ustekinumab induction therapy. For further details on the carry-over effect differences, see Appendix 5. Carry-over effects.

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Figure 19 Evidence of carry-over of the induction with ustekinumab vs. anti-TNFs in UC and Crohn’s Disease

CD: Crohn’s disease; UC: Ulcerative Colitis; * Adalimumab trial patients all received active treatment in induction

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Figure 20 Clinical response at the end of maintenance for the re-randomised response-based trial arms – Non-biologic failure population

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Figure 21 Clinical response at the end of maintenance for the re-randomised response-based trial arms – biologic failure population

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The maintenance placebo arms are thus heterogeneous and not appropriate common comparators for a standard network meta analysis.

Approaches for comparisons at 1-year and choice of base case Based on the study designs and data available, there are two approaches that can be taken to assess 1-year treatment effects: 1) Intention-to-treat (ITT) approach mimicking a treat-through trial design

 NMA of treat-through arms (induction to maintenance)  Includes treat-through trial data directly  Involves re-calculating data from response-based trials to correspond to a treat-through design, maintaining the initial randomisation:

2) ITT approach conditional on induction response

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 NMA using an ITT approach with induction to maintenance conditional on responding to induction therapy  Delayed responders are considered as non-responders post-induction  Includes response-based trial data directly (responders to induction therapy)  Involves re-calculating data from treat-through trials to correspond to a response-based design:

Both approaches required re-calculating the data from trials to correspond to a common set of inputs for the network meta analysis. The second approach was considered to be limited as assumes that patients who do not respond at the end of induction also do not respond at the end of maintenance (i.e. ignoring delayed responders). The approach to mimic an ITT treat-through design was considered to be the most appropriate and hence chosen as the base case. This approach more closely reflected clinical practice, allows for a clearer interpretation of the treatment effects and enables including of head-to-head trial data. The approach mimicking the response-based trial design was conducted as a sensitivity analysis. The second approach was assessed in a sensitivity analysis. Full details on the advantages and disadvantages of each approach can be found in the NMA report (Section 2.3.3).

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Implementation of the approaches A summary of the trial designs of studies included in the NMA with maintenance data is provided in Table 26. Of the 7 trials included, three had treat-through designs and four had re-randomised response-based designs. Table 26. Study design - included maintenance trials Treatments Maintenance study Study design Ustekinumab vs. placebo UNIFI Re-randomised response-based Golimumab vs. placebo PURSUIT-M Re-randomised response-based Adalimumab vs. placebo ULTRA II Treat-through Infliximab vs. placebo ACT I Treat-through Tofacitinib vs. placebo OCTAVE sustain Re-randomised response-based Vedolizumab vs. placebo GEMINI I Re-randomised response-based Vedolizumab vs. VARSITY Treat-through adalimumab Notes: ULTRA I was included in the induction NMA but excluded in the maintenance NMA as the maintenance data was based on a single open-label arm of adalimumab 40mg SC; ACT II was included in the induction NMA but excluded in the maintenance NMA as the end of study time point was 30 weeks.

One-year outcome data for the base case approach to mimic a treat-through design are directly available from the ACT I, ULTRA II and VARSITY trials. Induction data are available from the re-randomised response-based trials corresponding to the base case approach. Therefore, only maintenance data from the re-randomised response-based trials needed to be re-calculated to correspond to a treat-through design. Individual patient data from ACT, PURSUIT and UNIFI were available and used in the base case analysis (for ACT I this data corresponded exactly to the published results since the trial is a treat-through trial). For the remaining studies, published data from the SLR, or identified from publicly accessible documents were included. The data required for maintenance are divided into induction responders and induction non-responders, as both are required for the base case approach. For the re-randomised response-based trials, the calculations required to attain the inputs for the 1-year NMA are as follows (Table 27):

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Table 27 Calculations to mimic a treat-through approach Period Endpoint data Calculatio n Induction % Response end of induction of the ITT population A

% No response end of induction of the ITT population B

Maintenance % Response end of maintenance of the induction responders C

% Response end of maintenance of the induction non-responders D

1-year % Response end of 1-year of the induction responders A X C

% Response end of 1-year of the induction non-responders B X D

% Response end of 1-year of the ITT population (A X C) + (B X D)

For the two approaches assessed, this leads to the following estimates for the % at the end of each sequence:  Base case approach mimicking a treat-through design: Induction responders and induction non-responders = (A X C) + (B X D)  Sensitivity analysis mimicking a response-based design: induction responders = A X C Where trials only report short-term induction data for patients remaining on the same treatment, imputation was required to estimate the long-term (end of maintenance i.e. 1-year) sequences for both the base case and sensitivity approaches. The methods for including data for both active and placebo arms are described in the following sections. Additionally, the approach requires re-calculation of the total number of patients in the re-randomised response-based trials, further described in the NMA report Section 2.3.3.3.4. Full details of the calculations undertaken for each study are provided in the NMA report Section 2.3.3. for the example of clinical response in non-biologic failure patients.

Data availability As ACT I, ULTRA II and VARSITY were all treat through trials, data were directly available from the trials so no imputation were required for these studies. Data for all active arms to inform the base case NMA were available. There were only a few cases of missing long-term placebo data. The availability of placebo and active treatment data for each trial is detailed Table 28 for the base case approach (mimicking a treat-through design).

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Table 28: Maintenance placebo and active treatment data available for approach including induction responders and induction non- responders (treat-through based approach) Time point (weeks) data available

Treatment Period ACT-I ULTRA-II VARSITY UNIFI PURSUIT-SC GEMINI-I OCTAVE (infliximab) (adalimumab) (vedolizumab, (ustekinumab) (golimumab) (vedolizumab) (tofacitinib) adalimumab) Placebo arm Induction 8wks 8wks - 8wks 6wks 6wks 8wks

Maintenance 54wks 52wks 52wks (induction 52wks (induction 52wks (induction - responders only) responders only) non-responders only for full population) Active arm Induction 8wks 8wks 52wks* 8wks 6wks 6wks 8wks (remission and mucosal healing only) Maintenance 54wks 52wks 52wks 52wks 52wks (induction 60wks** responders; (induction non- induction non- responders) responders only for full population) Imputations required

Imputation Induction None None None None None None None required

Maintenance None None Placebo non- Placebo non- 1) Placebo 1) Placebo responders at end responders at responders at end of responders at of induction end of induction induction end of induction 2) Population 2) Placebo non- specific induction responders at non-responder data end of induction for active and placebo arms Notes: for VARSITY results are only reported for the end of 52 weeks which can be used directly in the NMA. Wks, weeks; *in VARSITY trial both arms are active arms; **open-label for induction non-responders

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1) Outcome data for active treatment arms As described previously, 1-year efficacy data were available for all treat-through studies (ACT 1, ULTRA II and VARSITY) for the base case approach. For all active arms of the response-based studies (GEMINI, OCTAVE, PURSUIT and UNIFI), induction and maintenance data for both induction responders and induction non-responders were available for clinical response, clinical remission and mucosal healing, with the following exceptions:  OCTAVE – the trial re-randomised induction responders from both tofacitinib and placebo. The other trials only re-randomised induction responders from active therapy. Maintenance results were not reported by induction therapy received (placebo or tofacitinib 10 mg BID) for the non-biologic failure and biologic failure subgroups separately. o An assumption was required that placebo and tofacitinib induction responders were comparable. This assumption was considered conservative versus ustekinumab as patients who responded to placebo at induction in OCTAVE were then given active therapy (tofacitinib) in maintenance. Reported subgroup analyses assessing the impact on clinical remission by induction therapy showed minimal differences between the rates for the tofacitinib + placebo induction arms and tofacitinib induction arms [tofacitinib 5mg BID 34.3% vs. 32.4% and tofacitinib 10mg BID 40.6% vs. 41.0%, respectively] (157). Moreover, as can be expected, there were fewer placebo-responders re-randomised to maintenance as compared to tofacitinib responders (placebo: 31% [72/234]; tofacitinib: 58% [521/905] across OCTAVE induction 1 and 2).(157)  GEMINI – maintenance data for induction non-responders were found to be available from a Gemeinsamer Bundesausschuss (G-BA) document (86) for the pooled population (biologic-failure and non-biologic failure patients), for both clinical response and remission. However, these data were not available for mucosal healing. o Clinical response and clinical remission: Estimation of the proportion of patients who responded at the end of maintenance, of the induction non- responders, by population, was required for vedolizumab. The calculation of this data is further described in Appendix 4 of the NMA report. o Mucosal healing: No data were available for induction non-responders therefore GEMINI I could not be included in the base case for this endpoint. However, data for vedolizumab can still be based on VARSITY in the base case.

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Separate imputations were required for induction responders and induction non- responders as described below.

2) Outcome data for placebo arms Placebo rates for maintenance phase in induction responders Imputation for induction responders was required for OCTAVE and GEMINI trials as previously described. Placebo-placebo endpoint data at the end of maintenance were imputed using individual patient level data (IPD) from the following trials for each population assessed:  Non-biologic failure patients: UNIFI, ACT I and PURSUIT  Biologic failure patients: UNIFI Specifically, the conditional response, remission or mucosal healing maintenance probabilities for induction responders were used directly as the data input alongside the probability of response at the end of induction for the trials requiring imputation (OCTAVE and GEMINI I). For the non-biologic failure population, a weighted average of the UNIFI, ACT I and PURSUIT data was estimated and used as the imputed placebo value. A summary of the imputation data used for maintenance from the trials for each population is provided in Table 29. As can be observed, the data from the three trials are similar. Table 29 Efficacy outcomes with placebo at the end of maintenance in UNIFI, ACT I and PURSUIT for induction responders to placebo N End of End of End of maintenance maintenance maintenance placebo clinical placebo clinical placebo mucosal response (%) remission (%) healing (%) Trial Non- Biologic Non- Biologic Non- Biologic Non- Biologic biologic failure biologic failure biologic failure biologic failure failure failure failure failure UNIFI 57 46 47.4% 43.5% 26.3% 13.0% 31.6% 17.4% (IPD) ACT 45 - 40.0% - 35.6% - 35.6% - (IPD) PURSUIT 103 - 35.9% - 25.2% - 34.0% - (IPD) IPD, individual patient data *Within each population, endpoints are not mutually exclusive, so rates will not add up to 100%

Placebo rates for maintenance phase in induction non-responders Imputation for placebo induction non-responders were only required for PURSUIT, OCTAVE and UNIFI trials as previously described. For the placebo-placebo imputation for induction non-responders, this was based on the following available data:

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 Non-biologic failure patients: ACT I IPD  Biologic failure patients: GEMINI I published data from the G-BA document These sources allowed for imputation of the missing placebo data for induction non- responded by population for clinical response and remission. However, mucosal healing data were not available from GEMINI I therefore for the biologic failure population only, it was not possible to attain these estimates. For GEMINI I, data for clinical response and clinical remission were only provided for the full population (including biologic failure and non-biologic failure patients). Therefore, it was necessary to estimate the population specific effects as described in Appendix 4 of the NMA report. This resulted in the following imputed values being used for the NMA for both populations based on GEMINI I and ACT (Table 30). The rates are all low as expected and therefore have a small impact on the overall proportion responding in 1-year. Table 30. Imputation maintenance data from ACT I and GEMINI I for placebo induction non-responders used in the NMA Treatment Population Clinical Clinical sequence response remission Placebo Non-biologic failure patients (ACT I) 7.89% 5.26% induction – placebo Biologic failure patients (GEMINI I) 8.15% 3.17% maintenance

The statistical methodology used for the NMAs are described in detail in the NMA report Section 2.3.5 alongside the direct ‘pairwise’ meta-analyses that were conducted to detect heterogeneity.

5.3.2.2 Pooling of doses For the maintenance treatment arms, where no potential dose response relationship was identified for the treatments included in an analysis, it was considered to be appropriate to pool the doses for the same treatment. This increased the statistical power in the analyses as pooling the doses for a treatment would increase the sample size. Evidence for a dose response relationship was defined as follows:  Dose response relationship: higher dose/shorter interval between doses led to higher clinical rates vs. a lower dose/longer interval between doses (as expected) o In this case doses were not pooled  No dose response relationship: lower dose/longer interval between doses led to higher clinical rates vs. a higher dose/shorter interval between doses (opposite to what is expected) o In this case doses were pooled

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In the base case NMAs, doses were pooled or not based on these criteria. In the cases where it was considered appropriate to pool the doses, additional analyses were conducted where the doses were un-pooled to assess the impact of pooling (full details on the results are provided in the NMA report Section 3.3).

5.3.3 Sensitivity analyses (induction and 1-year timepoints) Sensitivity analyses were conducted to test the robustness of the results obtained in the base case analysis for both induction and 1-year timepoints. Sensitivity analyses at induction Sensitivity analyses including trials focusing on Japanese and Chinese population were conducted to test whether including a broader population provided similar results to the base case. The studies included were: Jiang 2015 (150), Japis CTI060297 (152), NCT02039505 (160) and Suzuki 2014 (149). Detailed results for these sensitivity analyses are reported in the NMA report (Appendix 6). Sensitivity analyses at one-year Sensitivity analyses including trials focusing on Japanese and Chinese population were conducted to test whether including a broader population provided similar results to the base case. The Suzuki 2014 (149) trial was included in this analysis. Details on the results for these sensitivity analyses are reported the NMA report (Appendix 6). Additional sensitivity analyses were conducted using the 130mg induction ustekinumab dose (as provided in Appendix 6 NMA sensitivity analyses). An additional sensitivity analysis was conducted to assess the impact of using fixed values for the imputation of missing placebo data. A multiple imputation approach was taken using the following steps: 1) Sampling values for the imputations from the underlying distributions of the data 2) Including the sampled values for the imputations in the re-calculated input data for the NMA to generate multiple datasets 3) Re-running the NMA multiple times for each set of the datasets corresponding to the sampled imputation values 4) Combining the posterior distributions for the treatment effects from each NMA to provide summaries of the treatment effect accounting for the variance in the imputed values. Details on the methodology and results of the multiple imputation analysis are provided in Appendix 7. Multiple imputation sensitivity analysis.

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5.4 Individual study results (clinical outcomes and NMA results)

5.4.1 Description of relevant efficacy endpoints 1. Describe the relevant endpoints, including the definition of the endpoint, and method of analysis.

5.4.1.1 Clinical endpoints captured in trials of the pMAH

In the UNIFI clinical trial programme for ustekinumab in UC, outcomes were measured for disease activity, health-related quality of life and health utility using different instruments and scoring systems (Table 31). A key component of efficacy outcomes of clinical remission, clinical response, endoscopic and mucosal healing is the Mayo score. The Mayo score is calculated as the sum of 4 subscores (stool frequency, rectal bleeding, PGA, and endoscopy findings) and ranges from 0 to 12 points. Scores of 3 to 5 points indicates mildly active disease, a score of 6 to 10 indicates moderately active disease, and a score of 11 to 12 points indicates severe disease. The partial Mayo score is the Mayo score without the endoscopy subscore and ranges from 0 to 9 points. Adverse events were also recorded as safety endpoints. A quantitative study showed that the 6-points PRO symptomatic score was highly correlated with 9-points partial Mayo score (rho=0.96, p<0.0001) and the 12-points total Mayo score (rho=0.88, p<0.0001),(182) reflecting good internal consistency in assessing disease activity.(182) More information regarding the relevance of the Mayo score is found in the EUnetHTA action point guide in Section 6. Endoscopy subscores were assessed by both the local endoscopists and central review of a video of the endoscopy. The use of central review is a relatively new process in UC studies since most of the previous phase 3 studies assessed efficacy using the endoscopy subscores provided by the local endoscopists. Therefore, to provide a bridge to the earlier studies, clinical endpoints (clinical remission, endoscopic healing, clinical response, mucosal healing, and normal or inactive mucosal disease at Week 8 were also analysed based on the local endoscopy subscores. Outcome definitions in the UNIFI maintenance phase were identical to those in the induction study. There were additional outcomes in the UNIFI maintenance study (i.e. regarding corticosteroid use), however all technical outcome definitions are identical to those in the induction study. Table 31. Clinical outcome measures in the UNIFI clinical trial programme Outcome Definition Efficacy Clinical remission Mayo score ≤2 points, with no individual subscore >1. A decrease from induction baseline in the Mayo score by ≥30% and Clinical response ≥3 points, with either a decrease in the rectal bleeding subscore ≥1 or a rectal bleeding subscore of 0 or 1.

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Endoscopic healing Mayo endoscopy subscore of 0 or 1. Based on features of the Geboes score, defined as neutrophil Histologic healing infiltrations in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue. Both endoscopic healing (Mayo endoscopy subscore of 0) and Mucosal healing histologic healing (neutrophil infiltration in <5% of crypts, no crypt destruction, and no erosions, ulcerations, or granulation tissue). Patient reported outcomes IBDQ is a 32-item questionnaire for subjects with IBD that will be used to evaluate the disease-specific health-related quality of life across 4 dimensional scores: bowel (loose stools, abdominal pain), systemic (fatigue, altered sleep pattern), social (work attendance, IBDQ need to cancel social events), and emotional (anger, depression, irritability) Scores range from 32 to 224, with higher scores indicating better HRQoL. The short form 36 questionnaire (SF-36) consists of 8 multi-item scales: limitations in physical functioning due to health problems; limitations in usual role activities due to physical health problems; bodily pain; general mental health (psychological distress and well- being); limitations in usual role activities due to personal or emotional SF-36 problems; limitations in social functioning due to physical or mental health problems; vitality (energy and fatigue); and general health perception. Scales are scored from 0 to 100, with higher scores indicating better health. The EQ-5D is a self-administered, non-disease-specific measure of health status that provides a simple descriptive profile and a single index value that can be used in the clinical and economic evaluation EQ-5D of health care and in population health surveys. Specifically, the EQ- 5D assesses health outcomes from a wide variety of interventions on a common scale for purposes of economic evaluation, resource allocation, and monitoring. The Work Productivity and Activity Impairment Questionnaire- General Health (WAPI-GH) questionnaire is a validated instrument designed to measure the ability to work and perform regular activities, specifically as a results of the target health problem WPAI-GH (ulcerative colitis). The WPAI-GH yields four scores: percent of time missed due to health, percent impairment while working due to health, percent overall work impairment due to health, and percent activity impairment due to health

5.4.1.2 Clinical endpoints used in the SLR and NMA The efficacy endpoints used in the SLR and NMA across the included studies were clinical response, clinical remission and mucosal healing at week 6, 8 and 10 for the induction phase, and from week 30 to week 60 for the maintenance phase. The definitions of the outcomes are shown below:

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 Clinical response was defined as a reduction in the Mayo score of ≥3 points and ≥30% from the baseline score, with a decrease of ≥1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1.

 Clinical remission was most commonly defined by a Mayo score ≤2 points, with no individual subscore >1 at the time point of assessment. Some discrepancies occurred in the definition used in the following trials:

o OCTAVE-I1, OCTAVE-I2 and OCTAVE-S defined remission as a full Mayo score of ≤2 with no subscore>1 and a rectal bleeding subscore of 0.

o Probert 2003 used a different scoring system, namely the Ulcerative Colitis Symptom Score (USCC) ≤2, for defining the clinical remission.

 Mucosal healing was defined as achieving a Mayo Endoscopic Score of 0 or 1 across the studies.

o A discrepancy occurred in the definition of ‘mucosal healing’ in UNIFI compared with the other studies. UNIFI defined mucosal healing as: ‘having both endoscopic healing and histologic healing’, where endoscopic healing was defined as a Mayo endoscopy subscore of 0 or 1; and histologic healing was defined as 0 to <5% neutrophils in epithelium, no crypt destruction, and no erosions or ulcerations or granulations. Since the ‘endoscopic healing’ definition in UNIFI was the same as the ‘mucosal healing’ definition in the other studies, to maintain consistency for comparisons, the endoscopic healing results from UNIFI are reported in this study for mucosal healing. The term ‘mucosal healing’ is used throughout the rest of the report.

o As shown in Table 32, the endoscopic score was assessed in most of the studies by a local endoscopist, except for OCTAVE, in which the endoscopic reading for both eligibility screening and efficacy analyses were based on centrally assessed Mayo sub-scores. In UNIFI, both a local reading and a central reading (performed by a readier who reviewed the video of endoscopy) were conducted; the efficacy analyses were based on the local reading data in UNIFI.

 Central vs. local endoscopic readings

A summary of the methods of central versus local endoscopic readings where reported is summarised in Table 32.

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Table 32. Central vs. local endoscopic reading Endoscopic Data Used for Efficacy Trial name Treatment Measurement Analysis OCTAVE (I1, I2 and Tofacitinib Local and central Central Sustain)(157) ACT (1 and 2)* Infliximab Local Local

PURSUIT-SC(154) Golimumab Local Local

PURSUIT-M* Golimumab Local Local

ULTRA (1 and 2)* Adalimumab Local Local

GEMINI 1* Vedolizumab Local Local

UNIFI(155) Ustekinumab Local and central Local *Reference used: NICE tofacitinib submission(178); since information regarding the local vs. central reading was not discussed in the publication papers for these trials.

An additional comparison of the description and measurement of main study outcomes are described in Table 33, Table 34 and Table 35.

5.4.2 Results of the technology and comparator trials 2. Provide a summary of the study results for each relevant comparison and outcome.

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Table 33. Methods of data collection and analysis of clinical remission Study Endpoint definition Method of analysis reference/ID All trials Clinical remission A Mayo score ≤2 points, with no individual subscore >1 at the time point of (except those assessment below) OCTAVE Clinical remission A Mayo score of ≤2 with no subscore>1 and a rectal bleeding subscore of 0 trials UNIFI trial Clinical remission A Mayo score ≤2 Points, with no Individual Subscore >1 Probert 2003 Clinical remission Ulcerative Colitis Symptom Score (USCC) ≤2

Table 34. Methods of data collection and analysis of clinical response Study Endpoint definition Method of analysis reference/ID All trials Clinical response A reduction in the Mayo score of ≥3 points and ≥30% from the baseline score, with a decrease of ≥1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1

Table 35. Methods of data collection and analysis of mucosal healing Study Endpoint definition Method of analysis reference/ID All trials Mucosal healing A Mayo Endoscopic Score of 0 or 1 (except UNIFI trial below) UNIFI trial Mucosal healing Having both endoscopic healing and histologic healing: where endoscopic healing was defined as a Mayo endoscopy subscore of 0 or 1; and histologic healing was defined as 0 to <5% neutrophils in epithelium, no crypt destruction, and no erosions or ulcerations or granulations

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5.4.2.1 Efficacy results based on full patient population Table 36. Results summary for clinical remission in the full patient population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg 57/320 (17.8) PBO 22/319 (6.9) Induction UST 6mg/kg 61/322 (18.9) PBO 22/319 (6.9) UNIFI Maintenance UST 90mg Q12W 66/172 (38.4) PBO 42/175 (24.0) UST 6mg/kg Q8W 77/176 Maintenance PBO 42/175 (24.0) (43.8) Infliximab trials Induction IFX 5mg/kg 47/121 (38.8) PBO 18/121 (14.9) Induction IFX 10mg/kg 39/122 (32.0) PBO 18/121 (14.9) ACT 1 Maintenance IFX 5mg/kg 42/121 (34.7) PBO 20/121 (16.5) Maintenance IFX 10mg/kg 42/122 (34.4) PBO 20/121 16.5 Induction IFX 5mg/kg 41/121 (33.9) PBO 7/123 (5.7) ACT 2 Induction IFX 10mg/kg 33/120 (27.5) PBO 7/123 (5.7) Japic CTI060298 Induction IFX 5mg 21/104 (20.2) PBO 11/104 (10.6) Induction IFX 3.5mg/kg 21/41 (51.2) PBO 9/41 (21.9) Jiang 2015 Induction IFX 5mg/kg 22/41 (53.7) PBO 9/41 (21.9) Adalimumab trials Induction ADA 80/40mg NA/130 (10.0) PBO NA/130 (9.2) Induction ADA 160/80mg NA/130 (18.5) PBO NA/130 (9.2) ULTRA 1 ADA 80/40mg, 160/80mg, Maintenance NA placebo pooled 115/390 (29.5)

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Induction ADA 40mg EOW NA/248 (16.5) PBO NA/246 (9.3) ULTRA 2 Maintenance ADA 40mg EOW NA (17.3) PBO NA (8.5) Induction ADA 80/40mg NA/87 (14) PBO NA/96 (11) NCT00853099 Induction ADA 160/80mg NA/90 (10) PBO NA/96 (11) Maintenance ADA 40mg EOW NA/96 (23) PBO NA/177 (7) VARSITY Maintenance VDZ 300 mg 120/383 (31.3) ADA 160/80/40mg 87/386 (22.5) Golimumab trials Maintenance GOL 50mg (NA/151); (23.2) PBO (NA/154); (15.6) PURSUIT-M Maintenance GOL 100mg (NA/151); (27.8) PBO (NA/154); (15.6) Induction GOL 200 mg (27/144); (18.8) NA PURSUIT-J Maintenance GOL 100mg (16/32); (50.0) PBO (2/31); (6.5) GOL 200/100mg (45/253); Induction PBO (16/251); (6.4) (17.8) PURSUIT-SC GOL 400/200mg (46/257); Induction PBO (16/251); (6.4) (17.9) Vedolizumab trials Induction VDZ 300 mg 38/225 (16.9) PBO 8/149 (5.4) GEMINI Maintenance VDZ 300 mg q4w 56/125 (44.8) PBO 20/126 (15.9) Maintenance VDZ 300 mg q8w 51/122 (41.8) PBO 20/126 (15.9) NCT02039505 Induction VDZ 300 mg 30/164 (18.3) PBO 10/82 (12.2) Induction TOC 10mg 16/33 (48) PBO 5/48 (10) NCT00787202 Induction TOC 15mg 20/49 (41) PBO 5/48 (10) VARSITY Maintenance VDZ 300 mg 120/383 (31.3) ADA 160/80/40mg 87/386 (22.5) Tofacitinib trials OCTAVE-I1 Induction TOC 10mg 88/476 (18.5) PBO 10/122 (8.2) OCTAVE-I2 Induction TOC 10mg 71/429 (16.6) PBO 4/112 (3.6) Maintenance TOC 5mg 68/198 (34.3) PBO 22/198 (11.1) OCTAVE – Sustain Maintenance TOC 10mg 80/197 (40.6) PBO 22/198 (11.1)

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Table 37. Results summary for clinical response in the full patient population Study reference/ID Induction/ Maintenance Outcome intervention n/N (%) Outcome comparator n/N (%) Ustekinumab trials (technology) Induction UST 130mg 164/320 (51.3) PBO 100/319 (31.3) Induction UST 6mg/kg 199/322 (61.8) PBO 100/319 (31.3) UST 90mg SC q12w 117/172 UNIFI Maintenance PBO 78/175 (44.6) (68.0) UST 90mg SC q8w 125/176 Maintenance PBO 78/175 (44.6) (71.0) Infliximab trials Silva 2017 NR IFX 12/21 (57.14) ADA 6/10 (60) Induction IFX 3.5mg/kg 30/41 (73.1) PBO 15/41 (36.6) Jiang 2015 Induction IFX 5mg/kg 32/41 (78.1) PBO 15/41 (36.6) Japic CTI060298 Induction IFX 5mg/kg 57/104 (54.8) PBO 37/104 (35.6) Induction IFX 5mg/kg 84/121 (69.4) PBO 45/121 (61.5) Induction IFX 10mg/kg 75/122 (61.5) PBO 45/121 (61.5) ACT 1 Maintenance IFX 5mg/kg 55/121 (45.5) PBO 24/121 (19.8) Maintenance IFX 10mg/kg 54/121 (44.3) PBO 24/121 (19.8) Induction IFX 5mg/kg 78/121 (64.5) PBO 36/123 (29.3) ACT 2 Induction IFX 10mg/kg 83/120 (69.2) PBO 36/123 (29.3) Tofacitinib trials OCTAVE-I1 Induction TOC 10mg 285/476 (59.9) PBO 40/122 (32.8) OCTAVE-I2 Induction TOC 10mg 236/429 (55.0) PBO 32/112 (28.6)

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Maintenance TOC 5mg 102/198 (51.5) PBO 40/198 (20.2) OCTAVE-Sustain Maintenance TOC 10mg 122/197 (61.9) PBO 40/198 (20.2) Induction TOC 0.5mg 10/31 (32) PBO 20/48 (42) Induction TOC 3mg 16/33 (48) PBO 20/48 (42) NCT00787202 Induction TOC 10mg 20/33 (61) PBO 20/48 (42) Induction TOC 15mg 38/49 (78) PBO 20/48 (42) Vedolizumab trials Induction VDZ 300mg 106/225 (47.1) PBO 38/149 (25.5) GEMINI 1 Maintenance VDZ 300mg q8w 69/122 (56.6) PBO 30/126 (23.8) Maintenance VDZ 300mg q4w 65/125 (52.0) PBO 30/126 (23.8) Induction VDZ 300mg 65/164 (39.6) PBO 27/82 (32.9) NCT02039505 Maintenance VDZ 300mg 27/41 (65.9) PBO 15/42 (35.7) Adalimumab trials Induction ADA 80/40mg NA (51.5) PBO NA (44.6) ULTRA 1 Induction ADA 160/80mg NA (54.6) PBO NA (44.6) Maintenance ADA 166/390 (42.6) NA Induction ADA NA (50.4) PBO NA (34.6) ULTRA 2 Maintenance ADA NA (30.2) PBO NA (18.3) Induction ADA 80/40mg NA (43) PBO NA (35) NCT00853099 Induction ADA 160/80mg NA (50) PBO NA (35) Maintenance ADA 40mg EOW NA (31) PBO NA (18) Golimumab trials Induction GOL 200/100mg NA (51.0) PBO NA (30.3) PURSUIT-SC Induction GOL 400/200mg NA (54.9) PBO NA (30.3) Maintenance GOL 50mg NA (47.0) PBO NA (31.2) PURSUIT-M Maintenance GOL 100mg NA (49.7) PBO NA (31.2) PURSUIT-J Maintenance GOL 100mg NA (56.3) PBO NA (19.4)

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Table 38. Results summary for mucosal healing in the full patient population Study reference/ID Induction/ Maintenance Outcome intervention n/N (%) Outcome comparator n/N (%) Ustekinumab trials (technology) Induction UST 130mg 84/320 (26.3) PBO 44/319 (13.8) Induction UST 6mg/kg 87/322 (27.0) PBO 44/319 (13.8) UNIFI UST 90mg SC q12w 75/172 Maintenance PBO 50/175 (28.6) (43.6) Maintenance UST 90mg SC q8w 90/176 (51.1) PBO 50/175 (28.6) Infliximab trials Induction IFX 3.5mg/kg 23/41 (56.1) PBO 10/41 (24.4) Jiang 2015 IFX 5 mg/kg Induction PBO 10/41 (24.4) 24/41 (58.5) Japic CTI060298 Induction IFX 5 mg/kg 48/104 (46.2) PBO 29/104 (27.9) Induction IFX 5 mg/kg 75/121 (62.0) PBO 41/121 (33.9) Induction IFX 10 mg/kg 72/122 (59.0) PBO 41/121 (33.9) ACT 1 Maintenance IFX 5mg/kg 55/121 (45.5) PBO 22/121 (18.2) Maintenance IFX 10 mg/kg 57/122 (46.7) PBO 22/121 (18.2) Induction IFX 5mg/kg 73/121 (60.3) PBO 38/123 (30.9) ACT 2 Induction IFX 10 mg/kg 74/120 (61.7) PBO 38/123 (30.9) Tofacitinib trials OCTAVE-I1 Induction TOC 10mg 149/476 (31.3) PBO 19/122 (15.6) OCTAVE-I2 Induction TOC 10mg 122/429 (28.4) PBO 13/112 (11.6) Maintenance TOC 5mg 74/198 (37.4) PBO 26/198 (13.1) OCTAVE-Sustain Maintenance TOC 10mg 90/197 (45.7) PBO 26/198 (13.1) Vedolizumab trials Induction VDZ 300mg 92/225 (40.9) PBO 37/149 (24.8) GEMINI 1 Maintenance VDZ 300mg q8w 63/122 (51.6) PBO 25/126 (19.8) Maintenance VDZ 300mg q4w 70/125 (56.0) PBO 25/126 (19.8) Induction VDZ 300mg 60/164 (36.6) PBO 25/82 (30.5) NCT02039505 Maintenance VDZ 300mg 26/41 (63.4) PBO 14/42 (33.3)

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VARSITY Maintenance VDZ 152/383 (39.7) ADA 107/386 (27.7) Adalimumab trials Induction ADA 80/40mg NA (37.7) PBO NA (41.5) ULTRA 1 Induction ADA 160/80mg NA (46.9) PBO NA (41.5) Maintenance ADA 148/390 (37.9) NA Induction ADA NA (41.1) PBO NA (31.7) ULTRA 2 Maintenance ADA NA (31.7) PBO NA (15.4) Induction ADA 80/40mg NA (39) PBO NA (30) NCT00853099 Induction ADA 160/80 NA (44) PBO NA (30) Maintenance ADA 40mg EOW NA (29) PBO NA (16)

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Golimumab trials Induction GOL 200/100mg 107/253 (42.3) PBO 72/251 (28.7) PURSUIT-SC Induction GOL 400/200mg 116/257 (45.1) PBO 72/251 (28.7) Maintenance GOL 50mg NA (41.7) PBO NA (26.6) PURSUIT-M Maintenance GOL 100mg NA (42.4) PBO NA (26.6) PURSUIT-J Maintenance GOL 100mg NA (59.4) PBO NA (16.1)

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5.4.2.2 Subgroup analyses based on biologic failure status Table 39. Results summary for clinical response in the non-biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=90/156); 57.7 PBO (n=158); 35.4 Induction UST 6mg/kg (n=104/156); 66.7 PBO (n=158); 35.4 UNIFI Maintenance UST 90mg Q12W (n=102); 76.5 PBO (n=87); 50.6 Maintenance UST 6mg/kg Q8W (n=85); 77.6 PBO (n=87); 50.6 Infliximab trials Induction IFX 5mg/kg (n=84/121); 69.4 PBO (n=45/121); 37.2 Induction IFX 10mg/kg (n=/75122); 61.5 PBO (n=45/121); 37.2 ACT 1 Maintenance IFX 5mg/kg (n=55/121); 45.5 PBO (n=24/121); 19.8 Maintenance IFX 10mg/kg (n=54/122); 44.3 PBO (n=24/121); 19.8 Induction IFX 5mg/kg (n=78/121); 64.5 PBO (n=36/123); 29.3 ACT 2 Induction IFX 10mg/kg (n=83/120); 69.2 PBO (n=36/123); 29.3 Japic CTI060298 Induction IFX 5mg (n=57/104); 54.8 PBO (n=37/104); 35.6 Induction IFX 3.5mg/kg (n=30/41); 73.1 PBO (n=15/41); 36.6 Jiang 2015 Induction IFX 5mg/kg (n=32/41); 78.1 PBO (n=15/41); 36.6 Adalimumab trials Induction ADA 80/40mg (n=130); 51.5 PBO (n=130); 44.6 ULTRA 1 Induction ADA 160/80mg (n=130); 54.6 PBO (n=130); 44.6 Maintenance ADA 40mg EOW (n=390); 42.6 NA ULTRA 2 Maintenance ADA 40mg EOW (n=150); 36.7 PBO (n=145); 24.1 NCT00853099 Maintenance ADA 40mg EOW (n=NR); 31.0 PBO (n=NR); 18.0 Golimumab trials Maintenance GOL 50mg (n=151); 47.0 PBO (n=154); 31.2 PURSUIT-M Maintenance GOL 100mg (n=151); 49.7 PBO (n=154); 31.2

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Induction GOL 200 mg (n=63/144); 43.8 NA PURSUIT-J Maintenance GOL 100mg (n=18/32); 56.3 PBO (n=6/31); 19.4 Induction GOL 200/100mg (n=253); 51.0 PBO (n=251); 30.3 PURSUIT-SC Induction GOL 400/200mg (n=257); 54.9 PBO (n=251); 30.3 Vedolizumab trials Induction VDZ 300 mg (n=69/130); 53.1 PBO (n=20/76); 26.3 GEMINI Maintenance VDZ 300 mg (n=88/145); 60.7 PBO (n=21/79); 26.6 NCT02039505 Induction VDZ 300 mg (n=79); 53.2 PBO (n=41); 36.6 Tofacitinib trials Induction TOC 10mg (n=23); 60.9 PBO (n=33); 45.5 NCT00787202 Induction TOC 15mg (n=34); 82.4 PBO (n=33); 45.5 OCTAVE I1+I2 Induction TOC 10mg (n=440); 64.5 PBO (n=110); 39.1 Maintenance TOC 5mg (n=115); 56.5 PBO (n=109); 24.8 OCTAVE – Sustain Maintenance TOC 10mg (n=104); 64.4 PBO (n=109); 24.8

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Table 40. Results summary for clinical response in the biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=74/164); 45.1 PBO (n=44/161); 27.3 Induction UST 6mg/kg (n=95/166); 57.2 PBO (n=44/161); 27.3 UNIFI Maintenance UST 90mg Q12W (n=70); 55.7 PBO (n=88); 38.6 Maintenance UST 6mg/kg Q8W (n=91); 64.8 PBO (n=88); 38.6 Adalimumab trials Induction ADA 160/80/40mg (n=98); 36.7 PBO (n=101); 28.7 ULTRA 2 Maintenance ADA 40mg EOW (n=98); 20.4 PBO (n=101); 9.9 Vedolizumab trials Induction VDZ 300 mg (n=32/82); 39.0 PBO (n=13/63); 20.6 GEMINI Maintenance VDZ 300 mg (n=37/83); 44.6 PBO (n=6/38); 15.8 Tofacitinib trials Induction TOC 10mg (n=10); 60.9 PBO (n=15); 33.3 NCT00787202 Induction TOC 15mg (n=15); 66.7 PBO (n=15); 33.3 OCTAVE I1+I2 Induction TOC 10mg (n=465); 51.0 PBO (n=124); 23.4 Maintenance TOC 5mg (n=83); 44.6 PBO (n=89); 14.6 OCTAVE – Sustain Maintenance TOC 10mg (n=93); 59.1 PBO (n=89); 14.6

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Table 41. Results summary for clinical remission for the non-biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=31/156); 19.9 PBO (n=15/159); 9.4 UNIFI Induction UST 6mg/kg (n=29/156); 18.6 PBO (n=15/159); 9.4

UST 90mg sc Q12W (n=102); Maintenance PBO (n=87); 31.0 49.0

Maintenance UST 90mg sc Q8W (n=85); 48.2 PBO (n=87); 31.0 Infliximab trials Induction IFX 5mg/kg (n=47/121); 38.8 PBO (n=18/121); 14.9 Induction IFX 10mg/kg (n=39/122); 32.0 PBO (n=18/121); 14.9 ACT 1 Maintenance IFX 5mg/kg (n=42/121); 34.7 PBO (n=20/121); 16.5 Maintenance IFX 10mg/kg (n=42/122); 34.4 PBO (n=20/121); 16.5 Induction IFX 5mg/kg (n=41/121); 33.9 PBO (n=7/123); 5.7 ACT 2 Induction IFX 10mg/kg (n=33/120); 27.5 PBO (n=7/123); 5.7 Japic CTI060298 Induction IFX 5mg (n=21/104); 20.2 PBO (n=11/104); 10.6 Induction IFX 3.5mg/kg (n=21/41); 51.2 PBO (n=9/41); 21.9 Jiang 2015 Induction IFX 5mg/kg (n=22/41); 53.7 PBO (n=9/41); 21.9 Probert 2003 Induction IFX 5mg (n=9/23); 39.0 PBO (n=6/20); 30.0 Adalimumab trials Induction ADA 80/40mg (n=130); 10.0 PBO (n=130); 9.2 ULTRA 1 Induction ADA 160/80mg (n=130); 18.5 PBO (n=130); 9.2 Maintenance ADA 40mg EOW (n=390); 25.6 NA Induction ADA 160/80/40mg (n=150); 21.3 PBO (n=145); 11.0 ULTRA 2 Maintenance ADA 40mg EOW (n=150); 22.0 PBO (n=145); 12.4

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Induction ADA 80/40mg (n=87); 14.0 PBO (n=96); 11.0 NCT00853099 Induction ADA 160/80mg (n=90); 10.0 PBO (n=96); 11.0 Maintenance ADA 40mg EOW (n=177); 23.0 PBO (n=96); 7.0 Maintenance VDZ 300mg (n=304); 34.2 NA VARSITY Maintenance ADA 160/80/40mg (n=305); 24.3 NA Golimumab trials Maintenance GOL 50mg (n=151); 33.1 PBO (n=154); 22.1 PURSUIT-M Maintenance GOL 100mg (n=151); 33.8 PBO (n=154); 22.1 Induction GOL 200 mg (n=27/144); 18.8 NA PURSUIT-J Maintenance GOL 100mg (n=16(32); 50.0 PBO (n=2/31); 6.5 Induction GOL 200/100mg (n=45/253); 17.8 PBO (n=16/251); 6.4 Induction GOL 400/200mg (n=46/257); 17.9 PBO (n=16/251); 6.4 PURSUIT-SC Maintenance GOL 200/100mg (n=) PBO (n=) Maintenance GOL 400/200mg (n=) PBO (n=) Vedolizumab trials Induction VDZ 300 mg (n=30/130); 23.1 PBO (n=5/76); 6.6 GEMINI Maintenance VDZ 300 mg (n=68/145); 46.9 PBO (n=15/79); 19.0 Induction VDZ 300 mg (n=79); 27.8 PBO (n=41); 14.6 NCT02039505 Maintenance VDZ 300 mg (n=24); 54.2 PBO (n=28); 35.7 Induction VDZ 150mg (n=) PBO (n=) Kobayashi 2018 Induction VDZ 300mg (n=) PBO (n=) Maintenance VDZ 300mg (n=304); 34.2 NA VARSITY Maintenance ADA 160/80/40mg (n=305); 24.3 NA Tofacitinib trials NCT00787202 Induction TOC 10mg (n=); PBO (n=); Induction TOC 15mg (n= PBO (n=);

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OCTAVE I1+I2 Induction TOC 10mg (n=440); 24.1 PBO (n=110); 11.8 OCTAVE I1 Induction TOC 10mg (n=222); 25.2 PBO (n=57); 15.8 OCTAVE I2 Induction TOC 10mg (n=195); 22.1 PBO (n=47); 8.5 Maintenance TOC 5mg (n=115); 41.7 PBO (n=79); 11.0 OCTAVE – Sustain Maintenance TOC 10mg (n=104); 44.2 PBO (n=79); 11.0

Table 42. Results summary for clinical remission for the biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=19/164); 11.6 PBO (n=2/161); 1.2 Induction UST 6mg/kg (n=22/166); 12.7 PBO (n=2/161); 1.2 UNIFI Maintenance UST 90mg sc Q12W (n=70); 22.9 PBO (n=88); 17.0 Maintenance UST 90mg sc Q8W (n=91); 39.6 PBO (n=88); 17.0 Adalimumab trials Induction ADA 160/80/40mg (n=98); 9.2 PBO (n=101); 6.9 ULTRA 2 Maintenance ADA 40mg EOW (n=98); 10.2 PBO (n=101); 3.0 Maintenance VDZ 300mg (n=79); 20.3 VARSITY Maintenance ADA 160/80/40mg (n=81); 16.0 Vedolizumab trials Induction VDZ 300 mg (n=28/82); 9.8 PBO (n=2/63); 3.2 GEMINI Maintenance VDZ 300 mg (n=30/83); 36.1 PBO (n=2/38); 5.3

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Induction VDZ 300 mg (n=85); 9.4 PBO (n=41); 9.8 NCT02039505 Maintenance VDZ 300 mg (n=17); 58.8 PBO (n=14); 21.4 Maintenance VDZ 300mg (n=79); 20.3 NA VARSITY Maintenance ADA 160/80/40mg (n=81); 16.0 NA Tofacitinib trials OCTAVE I1+I2 Induction TOC 10mg (n=465); 11.4 PBO (n=124); 0.8 Maintenance TOC 5mg (n=83); 24.1 PBO (n=89); 11.2 OCTAVE – Sustain Maintenance TOC 10mg (n=93); 36.6 PBO (n=89); 11.2

Table 43. Results summary for mucosal healing for the non-biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=156); 34.6 PBO (n=158); 20.8 Induction UST 6mg/kg (n=156); 33.3 PBO (n=158); 20.8 UNIFI Maintenance UST 90mg Q12W (n=102); 55.9 PBO (n=87); 34.5 Maintenance UST 6mg/kg Q8W (n=85); 57.6 PBO (n=87); 34.5 Infliximab trials

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Induction IFX 5mg/kg (n=75/121); 62.0 PBO (n=41/123); 33.9 Induction IFX 10mg/kg (n=120); 59.0 PBO (n=41/123); 33.9 ACT 1 Maintenance IFX 5mg/kg (n=55/121); 45.5 PBO (n=22/121); 18.2 Maintenance IFX 10mg/kg (n=57/122); 46.7 PBO (n=22/121); 18.2 Induction IFX 5mg/kg (n=73/121); 60.3 PBO (n=38/123); 30.9 ACT 2 Induction IFX 10mg/kg (n=74/120); 61.7 PBO (n=38/123); 30.9 Japic CTI060298 Induction IFX 5mg (n=48/104); 46.2 PBO (n=29/104); 27.9 Induction IFX 3.5mg/kg (n=23/41); 56.1 PBO (n=10/41); 24.4 Jiang 2015 Induction IFX 5mg/kg (n=24/41); 58.5 PBO (n=10/41); 24.4 Adalimumab trials Induction ADA 80/40mg (n=130); 37.7 PBO (n=130); 41.5 ULTRA 1 Induction ADA 160/80mg (n=130); 46.9 PBO (n=130); 41.5 Maintenance ADA 40mg EOW (n=309); 54.0 NA Induction ADA 160/80/40mg (n=150); 49.3 PBO (n=145); 35.2 ULTRA 2 Maintenance ADA 40mg EOW (n=150); 31.3 PBO (n=145); 19.3 Induction ADA 80/40mg (n=87); 39.0 PBO (n=96); 30.0 NCT00853099 Induction ADA 160/80mg (n=90); 44.0 PBO (n=96); 30.0 Maintenance ADA 40mg EOW (n=177); 29.0 PBO (n=96); 16.0 Maintenance VDZ 300mg (n=304); 43.1 NA VARSITY Maintenance ADA 160/80/40mg (n=305); 29.5 NA Golimumab trials Maintenance GOL 50mg (n=151); 41.7 PBO (n=154); 53.2 PURSUIT-M Maintenance GOL 100mg (n=151); 42.4 PBO (n=154); 53.2 Induction GOL 200 mg (n=53/144); 36.8 NA PURSUIT-J Maintenance GOL 100mg (n=19/32); 59.4 PBO (n=5/31); 16.1 GOL 200/100mg (n=107/253); Induction PBO (n=72/251); 28.7 42.3 PURSUIT-SC GOL 400/200mg (n=116/257); Induction PBO (n=16/251); 28.7 45.1

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Vedolizumab Induction VDZ 300 mg (n=64/130); 49.2 PBO (n=19/76); 25.0 GEMINI Maintenance VDZ 300 mg (n=87/145); 60.0 PBO (n=19/79); 24.1 Induction VDZ 300 mg (n=79); 48.1 PBO (n=41); 31.7 NCT02039505 Maintenance VDZ 300 mg (n=24); 62.5 PBO (n=28); 35.7 Maintenance VDZ 300mg (n=304); 43.1 NA VARSITY Maintenance ADA 160/80/40mg (n=305); 29.5 NA Tofacitinib trials OCTAVE I1+I2 Induction TOC 10mg (n=440); 38.2 PBO (n=110); 21.8 OCTAVE I1 Induction TOC 10mg (n=222); 39.6 PBO (n=57); 25.3 OCTAVE I2 Induction TOC 10mg (n=195); 36.4 PBO (n=47); 19.1 Maintenance TOC 5mg (n=115); 42.6 PBO (n=109); 13.8 OCTAVE – Sustain Maintenance TOC 10mg (n=104); 51.0 PBO (n=109); 13.8

Table 44. Results summary for mucosal healing in the biologic failure population Outcome Induction/ Outcome intervention Study reference/ID Comparator Maintenance n/N (%) n/N (%) Ustekinumab trials (technology) Induction UST 130mg (n=164); 18.3 PBO (n=160); 6.9 Induction UST 6mg/kg (n=166); 21.1 PBO (n=160); 6.9 UNIFI Maintenance UST 90mg Q12W (n=70); 25.7 PBO (n=88); 22.7 Maintenance UST 6mg/kg Q8W (n=91); 45.1 PBO (n=88); 22.7 Adalimumab trials Induction ADA 160/80/40mg (n=98); 28.6 PBO (n=101); 26.7 ULTRA 2 Maintenance ADA 40mg EOW (n=98); 15.3 PBO (n=101); 9.9 Maintenance VDZ 300mg (n=79); 26.6 NA VARSITY Maintenance ADA 160/80/40mg (n=81); 21.0 NA

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Vedolizumab trials Induction VDZ 300 mg (n=25/82); 30.6 PBO (n=13/63); 20.6 GEMINI Maintenance VDZ 300 mg (n=37/83); 44.6 PBO (n=3/38); 7.9 Induction VDZ 300 mg (n=85); 27.1 PBO (n=41); 29.3 NCT02039505 Maintenance VDZ 300 mg (n=17); 64.7 PBO (n=14); 28.6 Maintenance VDZ 300mg (n=79); 26.6 NA VARSITY Maintenance ADA 160/80/40mg (n=81); 21.0 NA Tofacitinib trials OCTAVE I1+I2 Induction TOC 10mg (n=465); 22.2 PBO (n=124); 6.5 Maintenance TOC 5mg (n=83); 30.1 PBO (n=89); 12.4 OCTAVE – Sustain Maintenance TOC 10mg (n=93); 39.8 PBO (n=89); 12.4

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5.4.3 Results of the clinical efficacy NMAs The results of the efficacy NMAs are presented in the following section for the end of induction and 1-year time points. For each of these time points the results for non- biologic failure patients are presented first followed by the results for biologic failure patients for clinical response, clinical remission and mucosal healing.

5.4.3.1 Induction NMA 1a) Non-biologic failure: Clinical response

For all of the induction NMAs, the fixed effects models were preferred over the random effects models after a comparison of the DIC values and assessment of convergence for the random effects models. The DIC values are provided in Appendix 6 of the NMA report. The network of evidence for clinical response among non-biologic failure patients is shown in Figure 22. A total of 10 studies were included in the analysis. Figure 22. Network of evidence for clinical response - non-biologic failure patients (induction)

* No results for clinical response reported for OCTAVE I and OCTAVE II separately IFX: Infliximab, ADA: Adalimumab, VDZ: Vedolizumab, UST: Ustekinumab, GOL: Golimumab, TOF: Tofacitinib, IV: Intravenous, SC: Sub-cutaneous The data inputs for the 10 studies included in the network of evidence for clinical response among non-biologic failure patients is shown in Figure 23.

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The sample size of the studies ranged from 56 (NTC00787202) to 550 (OCTAVE I and II – combined). The response rates ranged from 43.9% in PURSUIT – SC Phase 2 (GOL 200/100mg, n=41) to 69.4% in ACT I (IFX 5mg, n=121). UNIFI reported response rates of 57.7% and 66.7% in the 130mg and in the 6mg/kg treatment arm, respectively. The clinical response rates in the placebo arms across all trials ranged from 26.3% in GEMINI I (n=76) to 45.5% in NTC00787202 (n=33); UNFI reported 35.4% response rate in placebo arm.

Figure 23. Data inputs for clinical response - non-biologic failure patients (induction)

The NMA results for clinical response in non-biologic failure patients are shown in Table 45. Ustekinumab was more likely to be associated with higher clinical response than adalimumab 160/80mg (probability for ustekinumab to be better, Pr=83 to 99%). Ustekinumab 6mg/kg showed higher odds of clinical response vs. vedolizumab 300 mg, tofacitinib 10mg and golimumab 200/100mg (Pr=63 to 95%) and ustekinumab 130mg showed higher odds of clinical response vs. golimumab 200/100mg and adalimumab 160/80mg (Pr=61 to 83%). Compared to the other treatments, ustekinumab appeared to be associated with lower clinical response.

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Table 45. NMA results for clinical response - non-biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Infliximab 5mg/kg 0.61 [0.33; 1.10], Pr=5% 0.89 [0.49; 1.63], Pr=36% Infliximab 10mg/kg 0.65 [0.36; 1.19], Pr=8% 0.96 [0.53; 1.76], Pr=45% Ustekinumab 6mg/kg 0.68 [0.43; 1.08], Pr=5% - Vedolizumab 300mg 0.78 [0.36; 1.68], Pr=26% 1.14 [0.52; 2.47], Pr=63% Tofacitinib 10 mg 0.92 [0.50; 1.71], Pr=40% 1.36 [0.74; 2.53], Pr=84% Ustekinumab 130mg - 1.47 [0.93; 2.34], Pr=95% Golimumab 200/100 mg 1.09 [0.61; 1.93], Pr=61% 1.60 [0.90; 2.84], Pr=95% Adalimumab 160/80 mg 1.32 [0.75; 2.33], Pr=83% 1.94 [1.10 ; 3.45], Pr=99% Placebo 2.49 [1.58 ; 3.96], Pr=100% 3.66 [2.31 ; 5.88], Pr=100%

1b) Non-biologic failure: Clinical remission

The network of evidence for clinical remission among non-biologic failure patients is shown in Figure 24. A total of 11 studies were included in the analysis. Figure 24. Network of evidence for clinical remission - non-biologic failure patients (induction)

Abbreviations: ADA: Adalimumab; GOL: Golimumab; IFX: Infliximab, IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs for the 11 studies included in the network of evidence for clinical response among non-biologic failure patients is shown in Figure 25.

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The sample size of the studies ranged from 43 (Probert 2003) to 254 (PURSUIT-SC Phase 3). The remission rates ranged from 17.1% in PURSUIT – SC Phase 2 (GOL 200/100mg, n=41) to 39% in Probert 2003 (IFX 5mg/kg, n=23). UNIFI reported remission rates of 19.9% and 18.6% in the 130mg and in the 6mg/kg treatment arm, respectively. The clinical remission rates in the placebo arms across all trials ranged from 5.7% in ACT II (n=123) to 30% in Probert 2003 (n=20); UNIFI reported 9.5% remission rate in placebo arm.

Figure 25. Data inputs for clinical remission - non-biologic failure patients (induction)

The NMA results for clinical remission in non-biologic failure patients are shown in Table 46. Both ustekinumab arms were associated with higher odds of clinical remission than placebo (probability for ustekinumab to be better, Pr=99 to 100%). Ustekinumab 130mg showed higher odds of clinical remission compared to adalimumab 160/80mg (Pr=57%). Compared to the other treatments, both doses for ustekinumab were associated with lower clinical remission (Pr=5 to 48%).

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Table 46. NMA results for clinical remission - non-biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Infliximab 5mg/kg 0.54 [0.24; 1.22], Pr=7% 0.489 [0.22; 1.14], Pr=5% Vedolizumab 300mg 0.52 [0.14; 1.70], Pr=14% 0.48 [0.13; 1.58], Pr=12% Infliximab 10mg/kg 0.70 [0.31; 1.62], Pr=20% 0.64 [0.28; 1.48], Pr=15% Golimumab 200/100 mg 0.80 [0.34; 1.93], Pr=31% 0.74 [0.31; 1.78], Pr=25% Tofacitinib 10 mg 0.98 [0.38; 2.42], Pr=48% 0.90 [0.35; 2.24], Pr=41% Ustekinumab 130mg - 1.47 [0.44; 4.93], Pr=39% Ustekinumab 6mg/kg 1.09 [0.62; 1.92], Pr=61% - Adalimumab 160/80 mg 1.08 [0.47; 2.49], Pr=57% 0.99 [0.43; 2.30], Pr=49% Placebo 2.38 [1.24; 4.78], Pr=100% 2.19 [1.14; 4.39] , Pr=99%

1c) Non-biologic failure: Mucosal healing

The network of evidence for mucosal healing among non-biologic failure patients is shown in Figure 26. A total of nine studies were included in the analysis. Figure 26. Network of evidence for mucosal healing - non-biologic failure patients (induction)

* No results for mucosal healing reported for OCTAVE I and OCTAVE II separately Abbreviations: ADA: Adalimumab; GOL: Golimumab; IFX: Infliximab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the nine studies included in the network of evidence for mucosal healing among non-biologic failure patients are shown in Figure 27.

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The sample size of the studies ranged from 82 (PURSUIT-SC Phase 2) to 550 (OCTAVE I and II - combined). The mucosal healing rates ranged from 33.3% in UNIFI (ustekinumab 6mg/kg, n=156) to 62% in ACT I (infliximab 5mg/kg, n=121). The mucosal healing rates in the placebo arms across all trials ranged from 20.9% in UNIFI (n=158) to 41.5% in ULTRA I (n=130). Figure 27. Data inputs for mucosal healing - non-biologic failure patients (induction)

The NMA results for mucosal healing in non-biologic failure patients are shown in Table 47. Both ustekinumab arms were associated with a higher odds of mucosal healing than placebo (probability for ustekinumab to be better, Pr=99 to 100%). Both doses of ustekinumab showed higher odds of mucosal healing vs. adalimumab 160/80mg and golimumab 200/100 mg (Pr=57 to 82%). Compared to the other treatments, ustekinumab was likely to be associated with lower mucosal healing.

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Table 47. NMA results for mucosal healing - non-biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Infliximab 5mg/kg 0.61 [0.32; 1.15], Pr=6% 0.57 [0.30; 1.10], Pr=5% Infliximab 10mg/kg 0.63 [0.33; 1.20], Pr=8% 0.59 [0.32; 1.13], Pr=6% Vedolizumab 300mg 0.68 [0.30; 1.52], Pr=17% 0.64 [0.29; 1.45], Pr=14% Tofacitinib 10 mg 0.90 [0.44; 1.81], Pr=38% 0.85 [0.41; 1.72], Pr=32% Ustekinumab 130mg - 0.94 [0.59; 1.52], Pr=41% Ustekinumab 6mg/kg 1.06 [0.66; 1.70], Pr=59% - Golimumab 200/100 mg 1.12 [0.60; 2.09], Pr=64% 1.06 [0.57; 1.98], Pr=57% Adalimumab 160/80 mg 1.33 [0.72; 2.49], Pr=82% 1.26 [0.68; 2.35], Pr=77% Placebo 2.01 [1.22; 3.40], Pr=100% 1.90 [1.15; 3.20], Pr=99%

2a) Biologic failure: Clinical response

The network of evidence for clinical response among biologic failure patients is shown in Figure 28. A total of five studies were included in the analysis. Figure 28. Network of evidence for clinical response - biologic failure patients (induction)

* No results for clinical response reported for OCTAVE I and OCTAVE II separately Abbreviations: ADA: Adalimumab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the five studies included in the network of evidence for clinical response among biologic failure patients is shown in Figure 29.

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The sample size of the studies ranged from 25 (NTC00787202) to 465 (OCTAVE I and II - combined). The response rates ranged from 36.7% in ULTRA II (ADA 160/80mg, n=98) to 60% in NTC00787202 (TOC 10mg, n=10). However, the latter study is conducted on 25 patients only, so the high response rate might have been affected. UNIFI reported response rates of 45.1% and 57.2% in the 130mg and in the 6mg/kg treatment arm, respectively. The clinical response rates in the placebo arms across all trials ranged from 20.6% in GEMINI I (n=63) to 33.3% in NTC00787202 (n=15); UNFI reported 27.3% response rate in placebo arm. Figure 29. Data inputs for clinical response - biologic failure patients (induction)

The NMA results for clinical response in biologic failure patients are shown in Table 48. Both ustekinumab arms were likely to be associated with higher clinical response than placebo and adalimumab 160/180mg (probability for ustekinumab to be better, Pr=86 to 100%). Ustekinumab 6 mg/kg showed higher odds of clinical response compared to tofacitinib 10 mg and vedolizumab 300 mg (Pr=56 to78%). Compared to the other treatments, ustekinumab 130mg was likely to be associated with lower clinical response.

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Table 48. NMA results for clinical response - biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Ustekinumab 6 mg/kg 0.61 [0.40; 0.95], Pr=1% - Tofacitinib 10 mg 0.64 [0.34; 1.21], Pr=8% 1.05 [0.55; 1.98], Pr=56% Vedolizumab 300 mg 0.87 [0.35; 2.11], Pr=38% 1.43 [0.58; 3.43], Pr=78% Ustekinumab 130 mg - 1.63 [1.06; 2.52], Pr=99% Adalimumab 160/80 mg 1.52 [0.71; 3.25], Pr=86% 2.48 [1.17; 5.31], Pr=99% Placebo 2.20 [1.39; 3.53], Pr=100% 3.58 [2.27; 5.74], Pr=100%

2b) Biologic failure: Clinical remission

The network of evidence for clinical remission among biologic failure patients is shown in Figure 30. A total of four studies were included in the analysis. Figure 30. Network of evidence for clinical remission - biologic failure patients (induction)

OCTAVE 1 showed no events in the placebo group, therefore the pooled study data was used as input. Abbreviations: ADA: Adalimumab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the four studies included in the network of evidence for clinical remission among biologic failure patients is shown in Figure 31. The sample size of the studies ranged from 145 (GEMINI I) to 589 (OCTAVE I and II - combined). The remission rates ranged from 9.2 % in ULTRA II (ADA 160/80mg, n=98) to 12.7% in UNIFI (UST 6mg/kg, n=166). The clinical remission rates in the placebo

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arms across all trials ranged from 0.8% in OCTAVE I and II combined (n=124) to 6.9% in ULTRA II (n=101); UNFI reported 1.2% remission rate in placebo arm. Figure 31. Data inputs for clinical remission - biologic failure population (induction)

The NMA results for clinical remission in biologic failure patients are shown in Table 49. Both ustekinumab arms were likely to be associated with higher clinical remission than placebo and adalimumab 160/180 mg (probability for ustekinumab to be better, Pr=99 to 100%). Ustekinumab showed higher odds of clinical remission vs. vedolizumab 300 mg (Pr=84 to 86%). Compared to the other treatments, ustekinumab was likely to be associated with lower clinical remission (Pr=32 to 35%).

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Table 49. NMA results for clinical remission - biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Tofacitinib 10 mg 0.54 [0.02; 7.18], Pr=32% 0.59 [0.02; 7.92], Pr=35% Ustekinumab 6 mg/kg 0.90 [0.46; 1.76], Pr=38% - Ustekinumab 130 mg - 1.11 [0.57; 2.17], Pr=62% Vedolizumab 300 mg 3.27 [0.29; 36.81], Pr=84% 3.60 [0.32; 40.71], Pr=86% Adalimumab 160/80 mg 9.01 [1.58; 80.08], Pr=99% 9.97 [1.77; 88.37], Pr=100% Placebo 12.12 [3.24; 86.24], Pr=100% 13.41 [3.62; 94.58], Pr=100%

2c) Biologic failure: Mucosal healing

The network of evidence for mucosal healing among biologic failure patients is shown in Figure 32. A total of four studies were included in the analysis. Figure 32. Network of evidence for mucosal healing - biologic failure patients (induction)

* No results for mucosal healing reported for OCTAVE I and OCTAVE II separately Abbreviations: ADA: Adalimumab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the four studies included in the network of evidence for mucosal healing among biologic failure patients are shown in Figure 33. The sample size of the studies ranged from 145 (GEMINI I) to 589 (OCTAVE I and II - combined). The mucosal healing rates ranged from 18.3% in UNIFI (UST 130mg, n=164) to 30.5% in GEMINI I (VDZ 300mg, n=82). The mucosal healing rates in the placebo arms across all trials ranged from 6.5% in OCTAVE I and II combined (n=124)

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to 26.7% in ULTRA II (n=101); UNFI reported 6.8% mucosal healing rate in placebo arm. Figure 33. Data inputs for mucosal healing – biologic failure patients (induction)

The NMA results for mucosal healing in biologic failure patients are shown in Table 50. Both ustekinumab arms were likely to be associated with higher mucosal healing than placebo and adalimumab 160/180 mg (probability for ustekinumab to be better, Pr=98 to 100%). Ustekinumab showed higher odds of mucosal healing vs. vedolizumab 300 mg (Pr=86 to 93%). Compared to the other treatments, ustekinumab was likely to be associated with lower mucosal healing (Pr=28 to 40%). Table 50. NMA results for mucosal healing - biologic failure patients (induction) Median OR [Crl] Treatment Ustekinumab 130 mg vs. Ustekinumab 6 mg/kg vs. Tofacitinib 10 mg 0.73 [0.24; 2.07], Pr=28% 0.87 [0.29; 2.46], Pr=40% Ustekinumab 6 mg/kg 0.84 [0.48; 1.44], Pr=26% - Ustekinumab 130 mg - 1.20 [0.69; 2.08], Pr=74% Vedolizumab 300 mg 1.83 [0.63; 5.40], Pr=86% 2.19 [0.76; 6.41], Pr=93% Adalimumab 160/80 mg 2.85 [1.10; 7.68], Pr=98% 3.42 [1.33; 9.12], Pr=99% Placebo 3.12 [1.53; 6.78], Pr=100% 3.73 [1.86; 8.04] , Pr=100%

Summary of efficacy in induction

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In the population that had not previously failed on a biologic therapy, ustekinumab 6mg/kg was associated with a higher likelihood of achieving clinical response compared to adalimumab, tofacitinib and golimumab and was associated with a lower likelihood of being better than both doses of infliximab. Ustekinumab 6mg/kg was associated with lower clinical remission and mucosal healing rates compared to the other treatments, with the exception of adalimumab 160/80mg and golimumab 200/100 mg for mucosal healing. For the biologic failure population, ustekinumab 6mg/kg was associated with a higher likelihood of achieving clinical response, remission and mucosal healing compared to adalimumab. Ustekinumab 6mg/kg was associated with similar clinical response, remission and mucosal healing results compared to tofacitinib and vedolizumab. There was more uncertainty associated with the results in the biologic failure group due to the lower sample sizes and event counts, particularly for clinical remission. Overall, one of the main goals of induction is to induce response, since this enables rapid improvement and continuation of therapy. The treatment effects for ustekinumab for clinical response are robust and similar conclusions can be seen between the non- biologic failure and biologic failure populations. The comparative assessment for mucosal healing and clinical remission is limited, given qualitatively different results versus the comparators in the non-biologic failure and biologic failure population. The length of the induction phase may not be optimal to fully assess clinical remission or mucosal healing as patients would not necessarily reach a maximal remission or mucosal healing status by this time point, also applying to clinical response. Moreover, labels of advanced treatments, and clinical practice allow for continuation of treatment despite non-response after induction. As such, while rapid improvement is important to patients, the overall ‘relevance’ of induction is relatively limited in a comparative assessment.

5.4.3.2 One-year NMA The results of the one-year NMAs are presented for the base case approach mimicking a treat-through design. Data for the end of 1-year clinical efficacy are presented below. Full details on the calculations of these data are provided in the NMA report (Section 2.3.3 and Appendix 4 for the methods and Appendix 7 for the full datasets). Only fixed effects model results for the maintenance analyses are presented. This is due to the fact that there is only one study informing each pair of treatments in the networks and therefore no data to inform the random effects parameter, without further information. Random effects models were tested. An example of one of these models is provided in Appendix 9 of the NMA report, to demonstrate the lack of convergence. 1a) Non-biologic failure: Clinical response

The network of evidence for clinical response among non-biologic failure patients is shown in Figure 34. A total of six studies were included in the analysis.

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Figure 34. Network of evidence for clinical response – non-biologic failure patients – one- year base case mimicking a treat-through approach

Abbreviations: ADA: Adalimumab; GOL: Golimumab; IFX: Infliximab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab

The data inputs from the six studies included in the network of evidence for clinical response among non-biologic failure patients are shown in Figure 35. Based on the results in the individual trials, no dose response relationship was observed for clinical response therefore it was appropriate to pool the doses for the same treatment. The pooled results are therefore presented below as the base case. Results without pooling are also provided in the NMA report (Section 3.3).

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Figure 35. Data inputs for clinical response – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach

The NMA results for clinical response in non-biologic failure patients are shown in Table 51 for the pooled doses. When pooling ustekinumab 90mg Q8W and Q12W, ustekinumab was associated with higher odds of clinical response than placebo (Pr=100%). The odds ratio of pooled doses for ustekinumab 90mg compared to pooled doses of vedolizumab, infliximab, golimumab, adalimumab and tofacitinib were high and in favour of ustekinumab with higher probabilities to be better (Pr= 91.5, 99.3, 99.9, 100 and 98.2%). Table 51. NMA results for clinical response (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach Median OR [Crl], Pr Treatment sequence Ustekinumab 6 mg/kg and 90 mg pooled vs. Placebo – Placebo 8.70 [5.03; 15.40], 100% Vedolizumab 300mg – Vedolizumab 300mg pooled 1.93 [0.75; 4.82], 91.45% Infliximab pooled – Infliximab pooled 2.62 [1.22; 5.60], 99.31% Golimumab 200/100mg – Golimumab pooled 3.76 [1.90; 7.57], 99.99% Adalimumab 160/80/40mg – Adalimumab 40mg EOW 4.76 [2.25; 10.16], 100% Tofacitinib 10mg - Tofacitinib pooled 2.27 [1.06; 4.86], 98.21%

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1b) Non-biologic failure: Clinical remission

The network of evidence for clinical remission among non-biologic failure patients is shown in Figure 36. A total of seven studies were included in the analysis. Figure 36. Network of evidence for clinical remission – non-biologic failure patients – one-year base case mimicking a treat-through approach

Abbreviations: ADA: Adalimumab; GOL: Golimumab; IFX: Infliximab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab

The data inputs from the six studies included in the network of evidence for clinical remission among non-biologic failure patients are shown in Figure 37. Importantly, the results from the VARSITY head-to-head trial of vedolizumab versus adalimumab corroborate with the results from GEMINI and ULTRA II for the same arms, validating the approach taken associated with the imputations that were necessary to include the GEMINI I trial for vedolizumab. Based on the results in the individual trials, no dose response relationship was observed for clinical remission therefore it was appropriate to pool the doses for the same treatment. The pooled results are therefore presented below as the base case.

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Figure 37. Data inputs for clinical remission – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach

The NMA results for clinical remission in non-biologic failure patients are shown in Table 52 for the pooled doses. When pooling ustekinumab 90mg received Q8W or Q12W, ustekinumab was associated with higher odds of clinical remission than placebo (Pr=100%), adalimumab (Pr=98.6%) and golimumab (Pr=98.8%). Ustekinumab 90mg was likely to be associated with higher clinical remission than other pooled treatments (Pr=82.4 to 93.6%). Table 52. NMA results for clinical remission (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach Median OR [Crl], Pr Treatment sequence Ustekinumab 6 mg/kg and 90 mg pooled vs. Placebo – Placebo 5.11 [2.83; 9.52], 100% Vedolizumab 300mg – Vedolizumab 300mg pooled 1.47 [0.65; 3.33], 82.38% Infliximab pooled – Infliximab pooled 1.89 [0.83; 4.29], 93.59% Golimumab 200/100mg – Golimumab pooled 2.40 [1.13; 5.22], 98.84% Adalimumab 160/80/40mg – Adalimumab 40mg EOW 2.43 [1.10; 5.42], 98.59% Tofacitinib 10mg - Tofacitinib pooled 1.51 [0.64; 3.51], 82.97%

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1c) Non-biologic failure: Mucosal healing

The network of evidence for mucosal healing among non-biologic failure patients is shown in Figure 38. A total of six studies were included in the analysis. Figure 38. Network of evidence for mucosal healing – non-biologic failure patients – one- year base case mimicking a treat-through approach

Abbreviations: ADA: Adalimumab; GOL: Golimumab; IFX: Infliximab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the six studies included in the network of evidence for mucosal healing among non-biologic failure patients are shown in Figure 39. Based on the results in the individual trials, no dose response relationship was observed for mucosal healing therefore it was appropriate to pool the doses for the same treatment. The pooled results are therefore presented below as the base case. Results without pooling are also provided in the NMA report in the Section 3.3

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Figure 39. Data inputs for mucosal healing – non-biologic failure patients – one-year (pooled doses) base case mimicking a treat-through approach

The NMA results for mucosal healing in non-biologic failure patients are shown in Table 53 for the pooled doses. When pooling ustekinumab 90mg received Q8W or Q12W, ustekinumab was associated with higher odds of mucosal healing than placebo (Pr=100%). The odds ratio of ustekinumab 90mg compared to pooled golimumab and adalimumab favoured ustekinumab with high probabilities to be better than each of these treatments (Pr= 99.8 and 99.6%). Finally, ustekinumab seemed to perform better than pooled doses of infliximab, tofacitinib and vedolizumab. Table 53. NMA results for mucosal healing (pooled doses) – non-biologic failure patients – one-year base case mimicking a treat-through approach Median OR [Crl], Pr Treatment sequence Ustekinumab 6 mg/kg and 90 mg pooled vs. Placebo – Placebo 5.57 [3.19 ; 9.92], 100% Infliximab pooled – Infliximab pooled 1.43 [0.66 ; 3.09], 81.59% Golimumab 200/100mg – Golimumab pooled 2.79 [1.39 ; 5.69], 99.81% Adalimumab 160/80/40mg – Adalimumab 40mg EOW 2.91 [1.33 ; 6.39], 99.62% Tofacitinib 10mg - Tofacitinib pooled 1.94 [0.88 ; 4.25], 95.11% Vedolizumab 300mg – Vedolizumab 300mg Q8W 1.60 [0.69 ; 3.77], 86.24%

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2a) Biologic failure: Clinical response

The network of evidence for clinical response among biologic failure patients is shown in Figure 40. A total of four studies were included in the analysis. Figure 40. Network of evidence for clinical response – biologic failure patients – one-year base case mimicking a treat-through approach

Abbreviations: ADA: Adalimumab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the four studies included in the network of evidence for clinical response among biologic failure patients is shown in Figure 41. Based on the results in the individual trials, a potential dose response relationship was observed for clinical response for tofacitinib therefore it was deemed inappropriate to pool the doses for the same treatment. Only the results for unpooled doses are therefore presented below.

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Figure 41. Data inputs for clinical response – biologic failure patients – one-year base case mimicking a treat-through approach

The NMA results for clinical response in biologic failure patients are shown in Table 54 for the unpooled doses. Both ustekinumab maintenance doses were associated with higher probabilities of being better than all other comparators (Pr>80%) with the exception of tofacitinib at the highest 10 mg BID maintenance dose (Pr=65%-66%).

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Table 54. NMA results for clinical response (unpooled doses) – biologic failure patients – one-year base case mimicking a treat-through approach Median OR [Crl], Pr Treatment sequence UST 6mg/kg - UST 90mg Q8W Induction UST 6mg/kg - UST 90mg Q12W induction responders and induction non- responders + UST 90mg Q8W induction responders vs. non-responders vs. Placebo – Placebo 4.83 [2.56 ; 9.25], 100% 4.82 [2.28 ; 10.30], 100% VDZ 300mg – VDZ 300mg Q8W induction responders + 1.76 [0.51 ; 6.00], 81.45% 1.75 [0.48 ; 6.35], 80.04% VDZ 300mg Q4W induction non-responders VDZ 300mg – VDZ 300mg Q4W Induction responders 1.89 [0.53 ; 6.69], 83.94% 1.88 [0.50 ; 7.06], 82.54% and induction non-responders ADA 160/80/40mg – ADA 40mg EOW 2.03 [0.70 ; 5.72], 90.52% 2.02 [0.65 ; 6.14], 88.85% TOF 10mg - TOF 5mg induction responders + TOF 10mg 1.66 [0.69 ; 3.94], 87.24% 1.65 [0.63 ; 4.28], 84.72% induction non-responders TOF 10mg - TOF 10mg Induction responders and 1.21 [0.51 ; 2.83], 66.49% 1.20 [0.46 ; 3.08], 64.70% induction non-responders UST 6mg/kg - UST 90mg Q12W induction responders + 1.00 [0.45 ; 2.25], 50.38% - UST 90mg Q8W induction non-responders UST 6mg/kg - UST 90mg Q8W Induction responders and - 1.00 [0.44 ; 2.23], 49.62% induction non-responders

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2b) Biologic failure: Clinical remission

The network of evidence for clinical remission among biologic failure patients is shown in Figure 42. A total of five studies were included in the analysis. Figure 42. Network of evidence for clinical remission – biologic failure patients – one- year base case mimicking a treat-through approach

Abbreviations: ADA: Adalimumab; IV: Intravenous; SC: Sub-cutaneous; TOF: Tofacitinib; UST: Ustekinumab; VDZ: Vedolizumab The data inputs from the five studies included in the network of evidence for clinical remission among biologic failure patients is shown in Figure 43. Based on the results in the individual trials, a dose response relationship was observed for clinical remission for tofacitinib and ustekinumab therefore it was deemed inappropriate to pool the doses for the same treatment. Only the results for unpooled doses are therefore presented below.

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Figure 43. Data inputs for clinical remission – biologic failure patients – one-year base case mimicking a treat-through approach

The NMA results for clinical remission in biologic failure patients are shown in Table 55 for the unpooled doses. The credible intervals around the estimated treatment effects are wide due to the smaller patient counts in this subgroup, lower placebo efficacy rates and no pooling of the doses. All comparisons of the high dose ustekinumab arm (Q8W) versus other comparators are associated with odds ratios greater 1. The odds ratios associated with the low dose ustekinumab arm (Q12W) versus the low doses of other comparators ranged between 0.97 (vedolizumab Q8W) to 1.32 (adalimumab EOW).

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Table 55. NMA results for clinical remission (unpooled doses) – biologic failure patients – one-year base case mimicking a treat-through approach Median OR [Crl], Pr Treatment sequence UST 6mg/kg - UST 90mg Q8W Induction UST 6mg/kg - UST 90mg Q12W induction responders and induction non- responders + UST 90mg Q8W induction responders vs. non-responders vs. Placebo – Placebo 6.89 [2.98 ; 16.90], 100% 5.34 [1.97 ; 14.62], 99.94% VDZ 300mg – VDZ 300mg Q8W induction responders + 1.26 [0.31 ; 4.91], 62.87% 0.97 [0.22 ; 4.11], 48.53% VDZ 300mg Q4W induction non-responders VDZ 300mg – VDZ 300mg Q4W Induction responders 1.32 [0.26 ; 6.63], 63.48% 1.02 [0.19 ; 5.48], 51.07% and induction non-responders ADA 160/80/40mg – ADA 40mg EOW 1.71 [0.42 ; 6.55], 77.63% 1.32 [0.29 ; 5.48], 64.31% TOF 10mg - TOF 5mg induction responders + TOF 10mg 1.57 [0.44 ; 5.36], 76.05% 1.21 [0.31 ; 4.52], 60.94% induction non-responders TOF 10mg - TOF 10mg Induction responders and 1.08 [0.31 ; 3.61], 54.80% 0.83 [0.21 ; 3.05], 39.18% induction non-responders UST 6mg/kg - UST 90mg Q12W induction responders + 1.29 [0.53 ; 3.32], 70.88% - UST 90mg Q8W induction non-responders UST 6mg/kg - UST 90mg Q8W Induction responders and - 0.77 [0.30 ; 1.90], 29.12% induction non-responders

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2c) Biologic failure: mucosal healing

Results are not available for mucosal healing in the biologic failure population, as no data from GEMINI I were available to inform the imputation of induction non-responder data (required for UNIFI, PURSUIT and OCTAVE trial).

Summary of efficacy at 1-year The NMA consistently showed ustekinumab has a high likelihood of being more effective than all comparators in achieving clinical response, clinical remission and mucosal healing for the non-biologic failure population at one year. The likelihoods were very high against each of the three anti-TNFs, both for infliximab and adalimumab which were investigated in treat-through trials as well as golimumab which was investigated in a re-randomised response-based trial. In the non-biologic failure group, ustekinumab pooled (90mg SC Q8W and Q12W) was associated with a higher likelihood of achieving clinical response compared to all treatments, and higher a higher likelihood of achieving clinical remission compared to adalimumab, infliximab and golimumab pooled treatments. The probabilities for ustekinumab pooled to be better than tofacitinib and vedolizumab were high but slightly lower for clinical remission. Ustekinumab pooled was associated with higher odds of achieving mucosal healing compared to golimumab, adalimumab and tofacitinib pooled treatments. Probabilities for ustekinumab pooled to perform better than comparators for clinical remission and mucosal healing ranged from 81.59% to 99.81%. Network meta analyses results in the biologic failure group were directionally similar for the three endpoints but more limited due to smaller sample sizes, a potential dose response relationship observed (doses could not be pooled), and the fact that placebo rates for remission are very low. Network meta analyses were also run with treatment arms including 130mg ustekinumab induction dose. For each endpoint, results are reported in Appendix A6.1 for the base case analysis and in Appendices A6.2 and A6.3 for sensitivity analyses. In summary, the results were similar to the ones with 6mg/kg ustekinumab induction dose in term of trend even so the odds ratios and likelihoods were lower. Sensitivity analyses performed showed no substantially differences in terms of results and interpretations. The sensitivity analyses conducted using a response-based approach provided results that were directionally similar to those from the ITT based approach. Moreover, the results from the VARSITY trial for vedolizumab and adalimumab corroborated with the results from the individual studies for these treatments (GEMINI I and ULTRA II), validating the base case approach taken for the NMA. Results in the non-biologic failure population are more robust than the results from the biologic failure population for the following reasons:  Placebo imputations

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o More robust imputations were conducted in the non-biologic failure population (combined UNIFI, ACT I and PURSUIT patient level data for induction responders) compared to the biologic failure population (only from UNIFI). o No imputations required for adalimumab or infliximab trials  Larger sample sizes across studies o Less uncertainty in data  Pooling of dosing arms resulting in additional power to detect differences  VARSITY trial results help to validate the NMA o Most patients in VARSITY were non-biologic failures (~80% of the population are TNF-naïve) The results of the biologic failure population therefore need to be considered in this context to understand why these are more uncertain. Overall, given the more robust analyses in the non-biologic failure population and the directionally similar results in the biologic failure population, the NMA demonstrated that treatment with ustekinumab (with 6 mg/kg at induction) is highly likely to result in greater proportions of patients with response and remission at 1 year compared to other advanced treatments. To assess the impact of using fixed values for the imputation of missing long-term placebo data, a multiple imputation sensitivity analysis was conducted for clinical response in non-biologic failure patients. This accounted for the variance in the individual study data used for the imputation. The results showed that the relative treatment effects, in terms of both the point estimates and credible intervals, remained consistent to those produced from the base case NMA. The NMAs were conducted for both induction and 1 year timepoints. However, UC is a chronic disease and the induction phase according to treatment labels and clinical practice stretches beyond the predefined timepoints in clinical trials. To illustrate this, 56% percent of patients without a response to ustekinumab at week 8 achieve a response at week 16. Therefore, the NMA results at one year are the clinically relevant results.

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5.5 Individual study results (safety outcomes and NMA results)

5.5.1 Description of the relevant safety outcomes 1. Describe the relevant endpoints, including the definition of the endpoint and methods of analysis (Table 56).

5.5.1.1 Safety endpoints used in the trials of the pMAH

The safety data of ustekinumab are number of: adverse events, serious adverse events, serious infections, malignancies, opportunistic infections, tuberculosis, and death at Week 8 (induction) and Week 44 (maintenance).(167)

5.5.1.2 Safety endpoints analysed in the SLR and NMA

2. For the technology, and the comparator, tabulate the total number of adverse events, frequency of occurrence (as a %), absolute and relative risk and 95% CI reported in each of the clinical studies. Categorise the adverse events by frequency, severity and system organ class. See Table 57 to Table 63.

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Table 56. Methods of data collection and analysis of overall adverse events Study reference/ID Endpoint definition Method of analysis All trials All safety endpoints event Adverse events were either voluntarily reported by the subject or were obtained by means of interviewing subjects in a nondirected manner at study visits.

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Table 57. Overview of adverse events: Infliximab trials (Japic CTI060298) Japic CTI060298 Japic CTI060298 Non-biologic failure Non-biologics failure Safety endpoint Induction (Week 8) Maintenance (Week 8) PBO IFX 5mg/kg PBO IFX 5mg/kg (N=104) (N=104) (N=104) (N=104) Adverse events, n (%) 86 (82.7) 85 (81.7) 94 (90.4) 100 (96.2) Serious adverse events, n (%) 13 (12.5) 9 (8.7) 19 (18.3) 18 (17.3) Any infection, n (%) 35 (33.7) 33 (31.7) 51 (49) 62 (59.6) Serious infection, n (%) 2 (1.9) 1 (1) 2 (1.9) 1 (1.1) Adverse events leading to discontinuation, n (%) 8 (7.7) 5 (4.8) 8 (7.7) 7 (6.7)

Table 58. Overview of adverse events: Infliximab trials (ACT 1, ACT 2, Jiang 2015)

ACT 1 ACT 2 Jiang 2015 Non-biologic failure Non-biologic failure Non-biologic failure Safety endpoint Maintenance (Week 54) Maintenance (Week 30) Maintenance (Week 8) PBO IFX 5mg/kg IFX 10mg/kg PBO IFX 5mg/kg IFX 10mg/kg PBO IFX 3.5mg/kg IFX 5mg/kg (N=121) (N=121) (N=122) (N=123) (N=121) (N=120) (N=41) (N=41) (N=41) Adverse events, n (%) 103 (85.1) 106 (87.6) 111 (91) 90 (73.2) 99 (81.8) 96 (80) 16 (39) 16 (39) 17 (41.5) Serious adverse events, n (%) 31 (25.8) 26 (21.5) 29 (23.8) 24 (19.5) 13 (10.7) 11 (9.2) NR NR NR Any infection, n (%) 47 (38.8) 53 (43.8) 60 (49.2) 29 (23.6) 33 (27.3) 34 (28.3) 5 (12.2) 5 (12.2) 6 (14.6) Serious infection, n (%) 5 (4.1) 3 (2.5) 8 (6.6) 1 (0.8) 2 (1.7) 3 (2.5) 0 (0) 0 (0) 1 (2.4) Adverse events leading to discontinuation, n (%) 11 (9.1) 10 (8.3) 11 (9) 12 (9.8) 2 (1.7) 5 (4.2) 2 (4.9) 0 (0) 1 (2.4)

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Table 59. Overview of adverse events: Adalimumab trials (ULTRA 1 and NCT00853099)

ULTRA 1 NCT00853099 Non-biologic failure Full patient population Safety endpoint Maintenance (Week 52) Induction (Week 8) PBO ADA 80/40mg ADA 160/80mg Any ADA (N=557) (N=96) (N=87) (N=90) Adverse events, n (%) NR NR NR NR Serious adverse events, n (%) NR NR NR NR Any infection, n (%) NR 15 (15.6) 11 (12.6) 17 (18.9) Serious infection, n (%) NR 0 (0) 0 (0) 3 (3.3) Adverse events leading to discontinuation, n (%) 78 (14.0) 2 1 3

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Table 60. Overview of adverse events: Golimumab trials (PURSUIT-SC, PURSUIT-J and PURSUIT-M)

PURSUIT-J PURSUIT-J PURSUIT-J PURSUIT-SC Non biologic Non PURSUIT-M Non biologic failure failure biologic Non-biologic failure Non biologic failure Maintenance (double- Maintenance failure Induction (Week 6) Maintenance (Week 54) blind; Week 68) (open-label ; Induction Safety endpoint Week 68) (Week 68) GOL GOL GOL GOL GOL PBO/GOL GOL PBO PBO GOL 100mg GOL 100mg GOL 200mg PBO GOL 50mg 100mg/20 100/50mg 200/100mg 400/200mg 100mg NR/100mg 50mg/100 (N=126) (N=31) (N=32) (N=60) (N=144) (N=156) (N=154) 0mg (N=71) (N=331) (N=332) (N=154) (N=76) mg (N=25) (N=14) Adverse events, n 126 (38.2) 34 (47.9) 37.5 (124) 38.9 (129) 22 (71) 31 (96.9) 47 (78.3) 65 (45.1) 103 (66) 112 (72.7) 113 (73.4) 54 (71.1) 16 (64) 9 (64.3) (%) Serious adverse 20 (6.1) 2(2.8) 9(2.7) 11(3.3) 4 (12.9) 1 (3.1) 6 (10) 5 (3.5) 12 (7.7) 13 (8.4) 22 (14.3) 8 (10.5) 5 (20) 1 (7.1) events, n (%) Any infection, n 40 (12.1) 8 (11.3) 39 (11.8) 41 (12.3) 11 (35.5) 21 (65.6) 26 (43.3) NR 44 (28.2) 60 (39) 60 (39) 26 (34.2) 10 (40) 4 (0) (%) Serious infection, 6 (1.8) 0 (0) 1 (0.3) 3 (0.9) NR NR NR NR 3 (1.9) 5 (3.2) 5 (3.2) 1 (1.3) 1 (4) 0 (0) n (%) Adverse events leading to 3 (0.9) 2 (2.8) 1 (0.3) 1 (0.3) NR NR NR 10 (6.9) 10 (6.4) 8 (5.2) 14 (9.1) 8 (10.5) 4 (16) 0 (0) discontinuation, n (%)

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Table 61. Overview of adverse events: Vedolizumab trials (GEMINI, NCT02039505)

GEMINI 1 GEMINI 1 NCT02039505 NCT02039505 Full patient population Full patient population Full patient population Full patient population Induction (Week 52) Maintenance (Week 8) Induction (Week 6) Maintenance (Week 52) Safety endpoint VDZ 300mg VDZ 300mg VDZ 300mg VDZ 300mg PBO cohort 1 cohort 2 PBO VDZ cohort VDZ cohort PBO VDZ Q8w Q4w PBO (N=82) (N=149) patients patients (N=126) 1 (N=164) 2 (N=46) (N=42) (N=41) (N=122) (N=125) (N=225) (N=521) Adverse events, n (%) NR NR NR NR NR NR NR NR NR NR NR Serious adverse events, n (%) NR NR NR NR NR NR NR NR NR NR NR Any infection, n (%) 22 (15) 31 (14) 71 (14) 89 (71) 87 (71) 90 (72) NR NR NR NR NR Serious infection, n (%) 3 (2) 1 (<1) 3 (<1) 4 (3) 3 (2) 2 (2) NR NR NR NR NR Adverse events leading to discontinuation, n (%) 4 0 7 15 7 6 8 (4.9) 2 (2.4) 6 (13.0) 2 (4.9) 6 (14.3)

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Table 61. Overview of adverse events: Vedolizumab trials (Kobayashi, 2018)

Kobayashi Full patient population Safety endpoint Maintenance (Week 34; 239 days) VDZ 150mg (n=4) VDZ 300mg (n=6) Adverse events, n (%) NR NR Serious adverse events, n (%) NR NR Any infection, n (%) 0 4 (66.7) Serious infection, n (%) NR NR Adverse events leading to discontinuation, n (%) 0 0

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Table 62. Overview of adverse events: Tofacitinib trials (OCTAVE 1, OCTAVE 2, OCTAVE Sustain)

OCTAVE-Sustain NCT00787202 OCTAVE-I1 OCTAVE-I2 Full patient population Full patient population Full patient population Induction (Week 8) Full patient population Induction (Week 8) Maintenance (Week 52) Induction (Week 12) Safety endpoint TOC TOC TOC TOC TOC TOC PBO TOC 10mg PBO TOC 10mg PBO PBO 5mg 10mg 0.5mg 3mg 10mg 15mg (N=122) (N=476) (N=112) (N=429) (N=198) (N=48) (N=198) (N=196) (n=31) (n=33) (n=33) (n=49) 149 143 156 NR NR NR NR NR Adverse events, n (%) 73 (59.8) 269 (56.5) 59 (52.7) 232 (54.1) (75.3) (72.2) (79.6) Serious adverse events, n (%) 5 (4.1) 16 (3.4) 9 (8) 18 (4.2) 13 (6.6) 10 (5.1) 11 (5.6) NR NR NR NR NR Any infection, n (%) 19 (15.6) 111 (23.3) 17 (15.2) 78 (18.2) 48 (24.2) 71 (35.9) 78 (39.8) 7 (15) 8 (26) 3 (9) 9 (27) 3 (6) Serious infection, n (%) 0 (0) 6 (13) 0 (0) 1 (0.2) 2 (1) 2 (1) 1 (0.5) NR NR NR NR NR Adverse events leading to discontinuation, n (%) 2 (1.6) 18 (3.8) 8 (7.1) 17 (4) 37 (18.7) 18 (9.1) 19 (9.7) 4 (8) 2 (6) 0 1 (3) 2 (4)

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Table 63. Summary of adverse events in UNIFI trial programme; Safety Anlaysis Set UNIFI UNIFI Full patient population Full patient population Safety endpoint Induction (Week 8) Maintenance (Week 44) PBO UST 130 mg UST ~6 mg/kg PBO SC UST 90mg q12w UST 90mg q8w (N=319) (N=321) (N=320) (N=175) (N=172) (N=175) Adverse events, n (%) 153 (48.0) 133 (41.4) 160 (50.0) 138 (78.9) 119 (69.2) 136 (77.3) Serious adverse events, n (%) 22 (6.6) 12 (3.7) 10 (3.1) 17 (9.7) 13 (7.6) 15 (8.5) Most frequent adverse events, n (%) Worsening ulcerative, n (%) 18 (5.6) 9 (2.8) 7 (2.2) 50 (28.6) 19 (11.0) 18 (10.2) Nasopharyngitis, n (%) NR NR NR 28 (16.0) 31 (18) 26 (14.8) Headache, n (%) 14 (4.4) 22 (6.9) 13 (4.1) 7 (4.0) 11 (6.4) 18 (10.2) Arthralgia, n (%) 2 (0.6) 3 (0.9) 6 (1.9) 15 (8.6) 15 (8.7) 8 (4.5) Any infection, n (%) 48 (15.0) 51 (15.9) 49 (15.3) 81 (46.3) 58 (33.7) 86 (48.9) Serious infection, n (%) 4 (1.3) 2 (0.6) 1 (0.3) 4 (2.3) 6 (3.5) 3 (1.7) Adverse events of special interest, n (%) Malignancies (excluding non-melanoma skin cancer), n (%) 0 0 0 0 1 (0.6) 1 (0.6) Possible anapyhlatic and possible delayed hypersensitivity, n (%) 1 (0.3) 0 0 0 0 0 Cardiovascular events, n (%) 1 (0.3) 0 0 0 0 0 Death, n (%) 0 0 1 (0.3) 0 0 0 Adverse events leading to discontinuation, n (%) NR NR NR 20 (11.4) 9 (5.2) 5 (2.8) Abnormal laboratory results, n (%) N/A N/A N/A 1 0 0

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5.5.2 Comparison of safety Introduction The comparison of safety is derived from a number of sources in order to give a complete picture of the comparative safety of ustekinumab versus its comparators, including data across indications. There is extensive long-term experience with Ustekinumab in clinical trials, long term registries and clinical use in other indications. Firstly, results from an integrated safety assessment for the use of ustekinumab across all its indications were considered. Data that was used to compare safety across products included:-  Safety data from large registries  A comparison of safety data from regulatory data assessed by the European Medicines Agency  An NMA for the induction phase of the trials (understanding the limitations of a safety comparison only for induction) The efficacy and safety of ustekinumab for the UC indication was demonstrated in the UNIFI clinical trial programme. Ustekinumab has also been extensively studied in clinical trials for its other indications (CD, PsA and PsO for adults and adolescents) and there is considerable experience of real-world use of ustekinumab. An integrated safety analysis incorporating phase II and III trials across CD, PsO, and PsA, which included approximately 6,000 patients treated with ustekinumab, reported that ustekinumab demonstrated a consistent and favourable safety profile across registrational trials in all the approved indications. This analysis is consistent with the safety data from the UNIFI clinical trial programme. There is robust long-term real-world evidence (RWE) that supports the safety of ustekinumab in the treatment of PsO, based on the Psoriasis Longitudinal Assessment and Registry (PSOLAR) study. This showed that the safety of ustekinumab compared with all three comparators (infliximab, adalimumab, and etanercept) studied and showed that no increased risk of malignancy, major adverse cardiovascular events, serious infections, and all-cause mortality was identified with use of ustekinumab (see Section 5.5.2.2).(4-6) To demonstrate the in-depth comparisons of safety profiles between the technology and the comparator treatments, including their clinical implications, information from the SmPCs was outlined in Appendix 2 (due to size limitations). This is supplemented by the tables provided in Section 5.5.1 which detail the safety data reviewed by the EMA in their regulatory assessments. Network meta analyses for the induction phase only were conducted, however these were considered to be limited for a number of reasons:  The length of the induction phases of studies is only 6-8 weeks which is not sufficiently long enough to assess the safety profiles of treatments for continued use.  The sample sizes are small and event counts are low for some of the endpoints increasing the uncertainty in the results.

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 The full populations of trials (non-biologic failure and biologic failure patients) were included in the NMAs as it was not possible to stratify all study outcomes by the subgroups introducing heterogeneity  The inclusion/exclusion criteria relevant to infections differed (as further discussed in Appendix 4. NMA of safety endpoints in maintenance phase) Results of the safety NMA conducted for the induction phase are provided in Appendix 9. Results of the induction safety NMA. An NMA of the one-year outcomes was not considered appropriate based on the following (further details included in Appendix 4. NMA of safety endpoints in maintenance phase):  Different definitions of the placebo safety population, comprising of non- homogeneous placebo arms with different efficacy and exposure can result in spurious conclusions about safety, both for SAEs and infections  Differences exist in inclusion criteria which may influence results on infections  There is insufficient information is available for all comparators to enable attempting to correct for these factors As described previously, other data sources based on an integrated analysis of safety data across indications for ustekinumab, large registry databases and a comparison of the regulatory data for each treatment provides more robust and relevant evidence to compare the safety profile of ustekinumab to other treatments in UC. These are described in detail in the following sections.

5.5.2.1 Safety evidence from clinical trials of plaque psoriasis, psoriatic arthritis, and Crohn’s disease The safety profile of ustekinumab demonstrated in the UNIFI (ustekinumab) clinical programme is consistent with that of other clinical studies, both in Crohn’s disease, as well as in plaque psoriasis and psoriatic arthritis.(92) The IV ustekinumab doses of 130mg and ~6mg/kg were generally well-tolerated. The proportions of patients with AEs and SAEs were comparable across treatment groups, with no evidence of an ustekinumab dose effect. Similarly, the proportions of patients who discontinued due to AEs were comparable (ustekinumab no higher than placebo) across treatment groups with no evidence of an ustekinumab dose effect. Subcutaneous ustekinumab at doses of 90mg q12w or q8w was generally well- tolerated. As was observed in induction studies, the proportions of patients with AEs and SAEs were comparable across treatment groups, with no evidence of an ustekinumab dose effect. Similarly, the proportions of patients who discontinued due to AEs were comparable (ustekinumab no higher than placebo) across treatment groups, with no evidence of an ustekinumab dose effect. In an integrated safety analysis incorporating Phase II and III trials across Crohn’s disease (two Phase II and three Phase III), plaque psoriasis (one Phase II and three Phase III), and psoriatic arthritis (one Phase II and two Phase III) studies, Ghosh et al (2016) compare the safety of ustekinumab across indications. The analysis includes 3,636 patients treated with ustekinumab (1,582 plaque psoriasis, 692 PsA and 1,362 CD). The authors report the rates of AEs, SAEs, infection/serious infections were similar between the ustekinumab group and placebo groups across

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the pooled indications. Overall, ustekinumab demonstrated a favourable safety profile in Crohn’s disease consistent with psoriatic diseases.

5.5.2.2 Safety evidence from the PSOLAR study for patients with plaque psoriasis The PSOLAR is an ongoing, disease-based, observational study in which patients eligible for, or who are receiving either non-biologic systemic or biologic agents for treatment of plaque psoriasis are followed. This registry is designed to capture AEs of special interest including serious infection data across all therapies used in the treatment of plaque psoriasis. An overview of adverse events of special interest (AEoSI) were reported by Papp et al. (2015),(5) in which cumulative rates of AEoSI were reported for ustekinumab, infliximab, other biologics (mostly adalimumab and etanercept), and non-biologic therapy. The pre-specified analyses used attribution rules biased against ustekinumab with safety events attributed to ustekinumab if patients switched to a different therapy and subsequently experienced an AE. The study included a total of 12,093 patients accounting for 40,388 patient-years. The authors reported that exposure to the combined group of biologics other than ustekinumab (i.e. mostly infliximab, etanercept, and adalimumab) on registry was associated with increased risk of serious infection. In addition, the analyses did not identify any increased risk of malignancy, major adverse cardiac event (MACE), serious infection, or mortality with ustekinumab. In a separate study focused on the risk of serious infections, Kalb et al. (2015) analysed data from 11,466 patients representing 22,311 patient years.(4) The cumulative incidence rate of serious infections was 1.45 per 100-patient years across treatment cohorts, with rates of 0.83, 1.47, 1.97, and 2.49 per 100 patient- years in the ustekinumab, etanercept, adalimumab, and infliximab cohorts, respectively. The authors conclude that results from PSOLAR suggest a higher risk of serious infections with adalimumab and infliximab compared with non- methotrexate and nonbiologic therapies, with no increased risk observed with ustekinumab.

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Figure 44. Cumulative Incidence Rates of Serious Infections of Interest per 100 Patient-years

aThe overall population includes patients who received a biologic agent before (prevalent population) or after (incident population) enrolling in the registry. bThe incident population, a subset of the overall population, includes patients who received a biologic agent at or after enrolling in the registry but may have been exposed to a different biologic previously. cThe bionaive population is a further subset of the incident population and includes patients who received their first biologic agent at or after enrolling in the registry and had never received prior biologic exposure. dThe other biologics cohort includes patients who received alefacept, efalizumab, golimumab, and other investigational biologic agents.

Another analysis of this study studied patients with concomitant IBD (at the time of analysis there was 12,093 patients and 40,388 total patient-years of follow-up), it was demonstrated that patients treated with ustekinumab had numerically lower rates of serious infections compared with patients receiving other biologic and systemic therapies for PsO in the IBD subset as well as overall.(183) Table 64. Cumulative incidence rates of serious infections per 100 patient-years within 91 days of biologic administration Non-Sponsor UST IFX Non-Biologic Total Biologic (N=4,363) (N=1,394) (N=2,083) (N=12,093) (N=4,251) Total IBD 72 (1.7%) 71 (5.1%) 81 (1.9%) 52 (2.5%) 276 (2.3%) population CD 15 (20.8%) 21 (29.6%) 18 (22.2%) 6 (11.5%) 60 (21.7%)

UC 22 (30.6%) 30 (42.3%) 28 (34.6%) 13 (25.0%) 93 (33.7%)

IC 27 (37.5%) 19 (26.8%) 28 (34.6%) 32 (61.5%) 106 (38.4%)

Pt Yrs 218 226 301 173 918 Rate of Sis/100 Pt 1.38 5.75 4.32 3.47 3.81 Yrs

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Full PSOLAR

Population Pt Yrs 7,944 3,301 12,823 16,322 40,389 Rate of Sis/100 Pt 0.93 2.91 1.91 1.43 1.60 Yrs

5.5.2.3 Comparison of safety profiles for the comparator treatments based on SmPC The safety assessments of the EMA are summarised in the SmPCs. The relative amount and content of safety information in the SmPCs of the technology and comparator treatments is an important aspect of the safety evidence for the technology and its comparator treatments. This is summarised in Appendix 2 due to size limitations, and these tables provide an overview of adverse events associated with ustekinumab and the comparators as assessed by the EMA.

The comparison of the SmPCs obtained after assessment of detailed data from regulators suggests Stelara (ustekinumab) has an acceptable safety profile.

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5.6 Conclusions 1. Provide a general interpretation of the evidence base considering the benefits associated with the technology relative to those of the comparators.

5.6.1 Conclusions of the trials of the pMAH The UNIFI clinical trial programme provided highly significant and consistent evidence that ustekinumab at both doses was effective at inducing and maintaining clinical remission, endoscopic healing, clinical response, and mucosal healing (a combination of endoscopic and histologic healing), reducing inflammatory burden, and improving health-related quality of life in a population of subjects with moderately to severely active UC who had previously failed or were intolerant of conventional and/or biologic therapy. This included a large proportion of patients who responded between Week 8 and 16. Overall, 56% (n=157) of patients who were not in clinical response at Week 8 (n=279) were in clinical response at Week 16 after receiving ustekinumab 90 mg SC 8 weeks after IV induction. For all efficacy endpoints during the induction and maintenance phases, the proportion of patients who achieved the clinical endpoint were higher in the treatment arms than in the placebo arms in all individual studies. For both the induction and the maintenance phases, the proportion of patients with improved clinical efficacy in the treatment arms were higher in the non-biologics failure group than in the biologics failure group. For the induction phase, the efficacy results of non-biologics failure patients in UNIFI were in the mid-range for all of the three clinical endpoints compared with other studies, with 58% and 67% response rates, 20% and 19% remission rate and 35% and 34% mucosal healing rates for the UST 130mg and UST 6mg/kg treatment arms, respectively. For the maintenance phase, UNIFI treatment arms showed the numerically highest rates in clinical response and remission in both the biologics failure and non- biologics failure groups compared with other studies. In terms of mucosal healing, in the non-biologics failure group, UNIFI showed the second highest mucosal healing rates in its treatment arms (56% and 58% for the UST 12mg q12w and the q8w treatment arms, respectively) after GEMINI (60% in the VDZ 300mg treatment arm). In biologics failure group, UNIFI UST q8w treatment arm showed the second highest mucosal healing rate of 40% after GEMINI (41% and 48% for VDZ 300mg E8W and VDZ 300mg E4W, respectively).

Ustekinumab was generally well-tolerated over the induction and maintenance study phases in this population of adult subjects with moderately to severely active ulcerative colitis.

5.6.2 Conclusions of the comparative efficacy (NMA) Ustekinumab as a one-year regimen (with induction therapy of 6mg/kg) was associated with a higher likelihood of response compared to all other treatments and remission compared to the anti-TNF treatments, for moderate-to-severe UC patients who have not failed previously on a biologic therapy. As the treatment goal for patients is primarily to maintain a response or remission in the long-term, NMA

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results comparing efficacy after one year of treatment is considered to have the highest clinical relevance. Additionally, in this population ustekinumab was associated with a higher likelihood of achieving mucosal healing compared to golimumab, adalimumab and tofacitinib. The results in non-biologic failure patients remained robust to a number of sensitivity analyses conducted. Additionally, where imputations were required for the maintenance placebo data, these were informed by individual patient data from multiple studies for induction responders. After imputation (where needed), the results of the individual study arms for vedolizumab and adalimumab corroborated with the results of the head-to-head VARSITY trial (vedolizumab vs. adalimumab). In biological failure population, the results for ustekinumab vs. each comparator were directionally similar to those in the non-biologic failure population, however these were associated with more uncertainty due to smaller sample sizes, lower event counts for the placebo arms, differences in prior therapy received across studies and the fact that doses could not be pooled for the one-year network meta analysis.

2. Provide a general interpretation of the evidence base considering the harms associated with the technology relative to those of the comparators.

NMA of 1-year safety outcomes was not considered to be feasible due to differences in the definitions of placebo safety populations, differences in inclusion criteria with regards to safety outcomes and the lack of information for all comparators to attempt to correct for these factors. An integrated safety analysis, incorporating phase II and III trials across CD, PsO, and PsA, which included approximately 6,000 patients treated with ustekinumab, reported that ustekinumab demonstrated a favourable and consistent safety profile across registrational trials in the approved indications. There is robust long-term RWE that supports the safety of ustekinumab in the treatment of PsO, based on the PSOLAR study. This showed that the safety of ustekinumab compared with all three comparators (infliximab, adalimumab, and etanercept) studied and showed that no increased risk of malignancy, major adverse cardiovascular events, serious infections, and all-cause mortality was identified with use of ustekinumab (see Section 5.5.2.2).(4-6) Another analysis of this study examined patients with concomitant IBD (at the time of analysis there was 12,093 patients and 40,388 total patient-years of follow-up). In-line with the overall PSOLAR analysis, it was demonstrated from this study that patients treated with ustekinumab had numerically lower rates of serious infections (22 [30.6%]) compared with patients receiving other biologic and systemic therapies (infliximab: 30 [42.3%] and non-sponsor biologics: 28 [34.6%]) for PsO in the IBD subset as well as overall. To demonstrate the in-depth comparisons of safety profiles between the technology and the comparator treatments, information from the SmPCs was outlined in Appendix 2. While a qualitative cross comparison of different safety profiles from the SmPCs is inherently difficult, and subject to weighing of different safety attributions, the comparison demonstrates that ustekinumab has an acceptable safety profile.

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NMAs were conducted for safety outcomes in the induction phases of clinical trials. These demonstrated that overall ustekinumab 6mg/kg was associated with similar likelihoods of overall adverse events, serious adverse events and infections compared to other active comparators. Due to the low event counts, the results of the NMA for serious infections were associated with a high uncertainty. The relevance of the results from these NMAs is are limited due to the short time period of assessment and inherent uncertainty given low event counts for some endpoints and small sample sizes. Results from the integrated analysis, registry databases and SmPCs provide more robust and relevant evidence to describe the safety profile of ustekinumab and comparison to other treatments in UC. This collective information demonstrated that ustekinumab is an innovative, safe and effective treatment for moderately to severely active UC providing rapid improvement in disease activity and symptoms and long- term maintenance of response and remission.

5.7 Strengths and limitations 1. Summarise the internal validity of the evidence base, taking into account the study quality, the validity of the endpoints used as well as the overall level of evidence. Include a statement about the consistency of the results in the evidence base.

5.7.1 Strengths and limitations of the clinical evidence base for ustekinumab in UC The UNIFI trial demonstrated the efficacy and safety of ustekinumab in moderately to severely active UC patients. All primary and major secondary endpoints of ustekinumab at induction and maintenance were met and results regarding remission (Mayo score ≤2 with no subcomponent >1), response (decrease in Mayo score by ≥30% and ≥3 points), endoscopic healing, mucosal healing and corticosteroid reduction were statistically significant. The UNIFI trial for ustekinumab is stratified for non-biologic therapy failure and biologic failure patients and is the only trial to date which includes patients that have been previously treated with vedolizumab, therefore representing a biologic failure treatment group which truly reflects current practice in UC treatment. Ustekinumab managed to induce strong remission and response rates at induction, which were respectively up to three and two times higher in the ustekinumab group compared to the placebo group and allowed to maintain remission and response throughout week 44 in the ustekinumab q8w and q12w groups. In addition to the usage of remission as a primary endpoint, defined as Mayo score ≤2 with no subcomponent >1, ustekinumab is the first biologic treatment in UC that demonstrates evidence of mucosal healing defined as a composite endpoint of endoscopic and histologic healing in registrational trials, which is considered an important marker of treatment efficacy. As with many other clinical trials within UC, the UNIFI studies lack a direct comparison versus active comparators (i.e., other non-conventional therapies).

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Moreover, the trial contained patients refractory (or intolerant) to both anti-TNFs and vedolizumab, for which including an active comparator is questionable. This limitation has been addressed by conducting an NMA.

5.7.2 Strengths and limitations of the NMAs Strengths of the analysis The baseline populations of the studies included in the NMAs were considered to be comparable. The endpoint definitions were consistent across all of the trials with only a minor difference for OCTAVE for clinical remission (one patient difference between definitions). The induction phase study designs were all consistent across the trials allowing for a standard NMA approach to be taken. The approach taken to mimic a treat-through trial design is associated with several strengths, including:  Clear interpretation: Treat-through trials can be clearly interpreted as continued treatment is given for around one full year. Response-based re- randomised trials complicate the interpretation of a full year of treatment given that results are not always directly reported for patients continuing treatment. Therefore, by mimicking an ITT approach and re-calculating the outcomes of response-based re-randomised trials, this provides a clear interpretation of the treatment effects for full one-year regimens. The approach also allows for estimation of the true relative treatment effect of active therapies compared to placebo for full one-year regimens.  Satisfies NMA assumptions: An NMA of maintenance phase data alone violates assumptions required for an NMA for comparable common arms to connect the studies. Including induction re-calculating treat-through placebo arms allowed for a common ‘true’ placebo arm to be used to connect the studies, thus adhering to the assumptions required for network meta analysis.  Robust data for anti-TNFs: Although a certain degree of imputations was required to attain treat-through treatment arms across the re-randomised response based studies, the comparisons to anti-TNF therapies required minimal or no imputations. No imputation of active arm efficacy was needed for the anti-TNF treatments and fewer imputations were required compared to tofacitinib and vedolizumab for placebo arms.  Maintains randomisation: By considering induction therapy, the NMA conducted maintains the initial randomisation to active or placebo. An analysis of maintenance data alone would be subject to selection bias as not all patients continued in the maintenance phases of the trials reported for the re- randomised response-based trials.  Consistency to head-to-head data: Results from the VARSITY trial, the only head-to-head study in UC, could be included in the base case approach, which strengthened the comparisons made to vedolizumab and adalimumab. Moreover, the efficacy results from the VARSITY trial were similar to those constructed from the individual studies for vedolizumab and adalimumab, validating the base case approach to combine treat-through data between the trials.

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 Sensitivity analyses show consistent results: As a sensitivity analysis, an alternative approach was taken to mimic response-based trial designs. This required fewer imputations to be conducted for the placebo arms compared to the base case approach, and no imputation on the active arms. No imputations were required for the placebo arms of UNIFI, PURSUIT, ULTRA-2 and ACT-1, as efficacy data were reported that could be included in the analysis. The conclusions made on the treatment effect for ustekinumab were directionally similar to those from the base case analysis, further validating the base case approach. Data limitations The NMAs are associated with some data limitations that apply to both the induction NMA and one-year NMA due to the low counts of events in some of the analysed trials and assumptions made for the networks. In the biologic failure subpopulation, low event counts for clinical remission in the placebo arms (especially in OCTAVE and UNIFI trials) led to wider credible intervals. The endpoints were considered to be consistently defined across the study. The one notable difference was the endoscopic measurement used for the efficacy analyses. For OCTAVE this was centrally assessed and for all other studies this was locally assessed or not reported. As described in Singh et al. (177) this can influence the absolute remission and mucosal healing rates. The time points reported for induction and maintenance assessments across slightly varied. However, on inspection of the partial mayo scores over time, these were shown to be similar around the ranges for each phase, suggesting that response is similar between 6 and 8 weeks for induction and similar around time points close to one year. Therefore, this limitation was considered to have a minor impact. The comparability of results could also be affected by the assumptions made around prior therapy groups. The UNIFI trial inclusion criteria for biologic failure corresponds anti-TNFs and/or vedolizumab whereas for other trials failure this corresponds to anti-TNFs only. An assumption was made that these patients were similar across the studies, which was considered to be conservative for ustekinumab. Additionally, the UNIFI trial grouped patients according to biologic failure and non-failure, whereas other trials grouped patients either according to anti-TNF naïve/experienced or biologic naïve/experienced. However, only a small proportion of patients in the UNIFI trial were non-biologic failures with previous exposure to a biologic therapy (27 out of 961 patients [2.8%] across the induction study arms in the primary efficacy analysis). Fixed effects models have been selected for the induction NMAs, based on model fits, and for one-year NMAs, given the lack of data to inform a random effects model. Fixed effects models assume that each study is estimating the same treatment effect. Random effects models are preferred over fixed effects models, where they can be sufficiently estimated, as these account for between-study heterogeneity. However, in the case of the one-year NMAs, there were no cases of multiple studies comparing the same pair of treatments to inform the model estimates. A number of limitations are associated with the analysis of maintenance data for the one-year NMA specifically.  GEMINI I data limitations: For GEMINI I, data published for vedolizumab arms are limited as efficacy data for induction non-responders were available

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from a G-BA document only for the overall population. This required estimation of results by populations for active and placebo arms. Also, cohort 1 patients from GEMINI I were included in the induction efficacy data, comprising of patients that had been blinded and randomised to treatment. The maintenance data were based on cohort 1 and cohort 2, whereby cohort 2 included patients that had received open-label vedolizumab induction. Data were not provided from GEMINI I stratified by cohort in the maintenance phase. Despite these limitations in the data available, the re-calculated 1-year efficacy data from GEMINI I corresponded closely to the efficacy data from VARSITY.  Placebo imputations for biologic failure group: The placebo imputations (where required) for the biologic failure populations relied on more limited data and assumptions compared to the non-biologic failure population. For the biologic failure population, induction responder data relied on a single study (UNIFI) whereas the corresponding data for the non-biologic failure population utilised data from three studies (UNIFI, PURSUIT and ACT I), to strengthen the estimates. Additionally, non-responder data used for the imputation were based on GEMINI (which itself required estimation of the population specific values).  Calculation of total number of re-randomised responders: The total number of patients in the re-randomised responder arms in maintenance were re-calculated to reflect an ITT population. This applied to active arms of GEMINI I, UNIFI and PURSUIT-M and OCTAVE. This was considered necessary to reflect the more limited sample sizes in the re-randomised arms of these studies and ensure that this is not overestimated. The re-calculation of the total number of patients resulted in smaller patient counts than the ITT population, therefore leading to a loss of power to detect treatment differences. Limitations biasing against ustekinumab Some of the limitations faced in the analysis were considered to bias results against ustekinumab, and therefore can be viewed as conservative. Despite this, the results from the NMA demonstrated a higher likelihood for ustekinumab of achieving clinical response and clinical remission versus all comparators.  OCTAVE re-randomises both placebo and tofacitinib induction responders: The published data for the maintenance phase of OCTAVE included patients who responded to induction therapy on placebo or tofacitinib, and were subsequently re-randomised. Subgroup analyses have been published for clinical remission at 52 weeks stratified by therapy received at induction, for the re-randomised responders. This showed that the clinical remission rates for the combined induction arms were similar to the tofacitinib induction arms. Use of the combined data could potentially overestimate the overall tofacitinib maintenance responses, as the placebo responders from induction in this group would be receiving tofacitinib for the first time. However, based on the data from the subgroup analysis and given the small proportion of re-randomised responders who received placebo at induction, this is not expected to have a major impact.

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 Heterogeneity in prior biologic therapy across trials: As for the induction phase, some heterogeneity lies in the inclusion criteria for prior biologic failure. Data for adalimumab in the biologic failure population do not reflect a true biologic failure population, as this population excluded patients with primary non-response to infliximab and multiple failure of anti-tumour necrosis factors. In addition, the UNIFI biologic failure population includes patients that previously failure on anti-TNFs and/or vedolizumab whereas for other trials, failure corresponds to anti-TNFs only.  Differences in delayed response assessment times: In PURSUIT and UNIFI only, delayed responders had to respond at week 14 and 16, respectively. This potentially underestimates the number of delayed responders included in the golimumab and ustekinumab trial arms.  OCTAVE included an open-label treatment for induction non- responders: Induction non-responders in the OCTAVE trial continued to receive open-label tofacitinib to 60 weeks, which may introduce bias in favour of tofacitinib.

2. Provide a brief statement of the relevance of the evidence base to the scope of the assessment.

The evidence based of ustekinumab for the treatment of UC patients is supported mainly by the UNIFI clinical trial programme and the network meta analysis. The UNIFI trials included patients which were reflective of a contemporary population of patients with moderately to severely active UC who have previously failed or were intolerant of conventional and/or biologic therapies, including TNF antagonists and/or vedolizumab (Section 5.2.1.1). Specifically, UNIFI is the first trials including vedolizumab failures into the study population. This reflects the current relevant patient population (non-biofailure, TNFi failure and vedolizumab failure) in real-world. Ustekinumab demonstrates a favourable efficacy in remission, response and mucosal healing for the whole patient population, independent if conventional therapy failure or biologic failure. The included endpoints in this report are the once that are recommended by guidelines. They are used by the gastroenterologist to make treatment decision or treatment modifications.(10) The comparators, study design, and outcomes of this trial were aligned with previous comparator trials in this disease area (Section 5.2 and 5.3). The NMA also included all relevant and contemporary comparators which are used for the treatment of ulcerative colitis (Section 5.2.2 and 5.2.3).

Given UC is a chronic disease, and induction in response according to labels and clinical practice stretches beyond the predefined timepoints in clinical trials, the NMA results at one year are the clinically relevant results.

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6. EUnetHTA action point guide In this section, action points raised by EUnetHTA during and after the scoping meeting are numbered and the answers to EUnetHTA questions and comments are provided, unless the location within the main document is provided. 1. Provide similarities and differences regarding inclusion and exclusion criteria for each study in detail. Table 65. Comparison of population stratifications between UNIFI and other key trials Trial Population* Definition Comparison with UNIFI UNIFI  Biologic  Patients who have received NA failure treatment with 1 or more TNF antagonists or vedolizumab  Non-biologic failure  Subjects who may be biologic- or patients may have been exposed to biologic therapy but not demonstrated an inadequate response or intolerance to treatment with a biologic agent (i.e. 42.9% were non-biologic failure patients: 40.5% biologic-naïve and 2.4% were biologic-experienced, but with no documented biologic failure) ACT I & II  Bio-naïve  Patients previously exposed to  Subpopulation of non- patients infliximab or any other anti-TNF biologic failure patients agent were excluded. from UNIFI GEMINI I  TNF-naïve  No prior anti-TNF therapy  The combination of TNF-naïve and no prior  Prior TNF  Prior failure of anti-TNF therapy TNF antagonist failure antagonist  No prior failure of anti-TNF therapy patients is the same as failure the non-biologic failure  No prior TNF patients population from antagonist UNIFI failure Probert  Bio-naïve  No prior therapeutic agent used to  Subpopulation of non- 2003 patients directly reduce TNF biologic failure patients from UNIFI PURSUIT  Bio-naïve  No prior biologic anti-TNF agent(s)  Subpopulation of non- patients biologic failure patients from UNIFI OCTAVE  No prior TNF  No previous treatment with TNF  The combination of no I & II antagonist antagonists prior TNF antagonist treatment treatment and no prior  Treatment failure from TNF- TNF antagonist failure  Prior TNF antagonist patients is the non- antagonist biologic failure patients failure  Previous treatment with TNF- antagonist and no failure population from UNIFI  No prior TNF antagonist failure ULTRA I  Anti-TNF  No previous receipt of any anti-TNF  Anti-TNF naïve patient & II naïve patients agent or any biological agent is a subpopulation of non-biologic failure  ULTRA II:  ULTRA II: previous receipt and patients from UNIFI anti-TNF discontinuation of any anti-TNF Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 209

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experienced agent (primary non-responders to  Anti-TNF experienced patients infliximab were excluded) patients is assumed to be comparable to non- biologic failure patients

2. Discuss how clinical response is achieved at different time points. See Section 5.2.1.1 and Section 5.4. 3. How clinical remission and response were defined in all studies. See Section 5.2.1.1 and Section 5.4. 4. Elaborate on the relevance of patient sub scores of the Mayo score. Ulcerative colitis (UC) is an idiopathic inflammatory disease that primarily affects the colonic mucosa. UC mainly affects the superficial layers of the colonic lining which translates into endoscopic findings such as mucosal oedema, erythema, granularity, friability, and ulcers. Randomized controlled trials designed to study the efficacy of therapeutic interventions require outcome measures that characterize the activity of the disease. Such measures frequently combine findings from invasive tests (sigmoidoscopy or colonoscopy) and clinical characteristics of the patient. Disease activity may be classified as mild, moderate, severe, or fulminant based on combined clinical and endoscopic assessments. The Mayo score is one of the most commonly used activity indices in placebo- controlled clinical trials for UC. It is composed of four components: patient-reported outcome assessment for stool frequency and rectal bleeding (PRO symptomatic score), physician global assessment (PGA), and endoscopic appearance. Each component is rated from 0–3 that are summed to give a total Mayo score that ranges from 0–12, a partial Mayo score (PRO plus PGA) from 0-9 and PRO symptomatic score from 0-6. A quantitative study showed that the 6-points PRO symptomatic score was highly correlated with 9-points partial Mayo score (rho=0.96, p<0.0001) and the 12-points total Mayo score (rho=0.88, p<0.0001),(182) reflecting good internal consistency in assessing disease activity. Total Mayo score, partial mayo score and PRO symptomatic score correlated well with patient-self reported assessment of UC disease activity on a 6-points Likert scale, with a correlation coefficient of 0.71, 0.70 and 0.61, respectively, indicating that each sub score in the index has added value in defining disease activity and demonstrating validity of each assessment from patients' perspectives. Additionally, each sub score was highly correlated with disease specific health related quality of life (HRQoL). A cut-off point of 4.5 in total Mayo score, 2.5 in partial Mayo core or 1.5 in PRO symptomatic score was related with patient-reported disease remission; and a change of 3.5 point in total Mayo score or partial Mayo core, or a 2.5 points change in PRO score was related with patient-perceived treatment response, indicating clinical meaningfulness of these total or individual sub scale from patient’s perspectives.(182) Specifically, for PRO symptomatic score, it was observed from qualitative study that stool frequency (reflected as increased number of bowel movement including liquid bowel movement) and rectal bleeding (blood in bowel movements) are two most important patient-reported outcomes in patient with moderate to severe UC.(184)

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High symptoms burden associated with increased disease activity pose significant impact on patients’ daily life. In clinical trial, PRO symptomatic sub scale was highly correlated with disease specific as well as general health related quality of life as measured by IBDQ and SF-36,(40, 182) and improvement in UC symptomatic score was parallel with the improved HRQoL.(185) The impact of UC on HRQoL can be direct or indirect. For example, loss of blood due to rectal bleeding can lead to anemia, a common complication of patients with UC at the disease onset and during the long-term course of disease.(186) Anemia in patients with UC was associated with extended time of hospitalization.(186) Frequent bowel movement at the night may cause sleep disturbance and fatigue, two common symptoms reported by patients with UC.(187) Additionally, PRO symptomatic scores were found to be a reliable predictor of endoscopic remission in patients with moderate to severe UC. For example, in one of our historical trial of similar study population, it was found that among patients who reported no rectal bleeding, 66.5% achieved mucosal healing based on endoscopic appearance, compared to 16.0% of patients with rectal bleeding (OR=9.9, p<0.001, PPV=0.65, LR=3.0). Similarly, among patients with normalized stool frequency, 77.1% achieved mucosal healing vs 32.8% of patients with abnormal stool frequency (OR=6.9, p<0.001, PPV=0.77, LR=5.3).(48) Similar results were observed from a systematic literature review that most UC patients with normal rectal bleeding and stool frequency sub scores have attained endoscopic remission.(188) Given the physical as well as economic burden of endoscopic examination to the patients, these analyses suggest that patient-reported outcomes of stool frequency and rectal bleeding might be used as one option in the clinic to assess for the likelihood of endoscopic healing at the patient level. This would mitigate the need for repeated endoscopic procedures following the initiation of treatment and thus reduce the burden on the patient as well as the cost of treatment. From long-term perspectives, mucosal healing or remission is associated with fewer surgeries, long-term clinical remission, and fewer hospitalizations in patient with UC. A recent systematic review and meta-analysis analyzed 13 studies comprising 2,073 patients with active UC. It is found that patients with active UC wo had mucosal healing at the first endoscopic evaluation after initiation of UC therapy had pooled odds ratio of 4.50 for achieving long-term (after at least 52 weeks) clinical remission (95% CI, 2.12–9.52), 4.15 for remaining free of colectomy (95% CI, 2.53–6.81), 8.40 for achieving long-term MH (95% CI, 3.13–22.53), and 9.70 for achieving long-term corticosteroid-free clinical remission (95% CI, 0.94–99.67), compared with patients without mucosal healing.(48) Therefore, to have endoscopic results either incorporated in the full Mayo score or as a separate analysis of mucosal healing is a patient relevant assessment. By summary, full Mayo score, partial Mayo score, PRO symptomatic score or endoscopic assessment are not only critical clinical assessment for UC disease activity, but also important patient relevant outcomes associated with patients’ general well-being and HRQoL. 5. The Mayo sub score results should be presented separately for Stelara and when possible for the comparators. Partial Mayo scores are discussed in Section 5.2.1.1 and in Appendix 5. Carry-over effects. The results for the individual scores (stool frequency and rectal bleeding) are

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also provided in the CSR sections 6.4.2.3.2 for induction and 6.4.1.4.3 in maintenance). 6. In the document, include surgery and hospitalisation as efficacy outcomes instead of safety. UNIFI Induction trial: UC Disease-related Hospitalisations and Surgeries Through Week 8, the proportions of subjects with UC disease-related hospitalisations were significantly lower for subjects in the ~6 mg/kg and 130 mg ustekinumab group (1.6% and 0.6%, respectively) compared with subjects in the placebo group (4.4%; p=0.0348 and p=0.002, respectively). No subjects in the ~6 mg/kg and 130 mg ustekinumab groups underwent UC disease-related surgery (i.e., colectomy) compared with subjects in the placebo group (0.6%). UNIFI Maintenance trial: UC Disease-related Hospitalisations and Surgeries Through Week 44 Fewer subjects in the combined ustekinumab group had a UC disease-related hospitalisation (7 [2.0%] subjects) compared with the placebo group (10 [5.7%] subjects) (p=0.035). Numerically fewer subjects in the combined ustekinumab group had a UC disease- related hospitalisation or surgery (8 [2.3%] subjects) compared with the placebo group (10 [5.7%] subjects; p=0.071, respectively). Additionally, fewer subjects in the combined ustekinumab group had a UC disease-related hospitalization (7 [2.0%] subjects) compared with the placebo group (10 [5.7%] subjects; p=0.035. 7. Include results for generic and specific quality of life outcome measures for Stelara when outcomes are available. UNIFI Induction trial: Clinically significant improvement from Baseline in Total IBDQ Score at Week 8 Clinically significant improvements in IBDQ from baseline in total IBDQ score at Week 8 was reached for both the ~6 mg/kg and 130 mg ustekinumab groups. When considering a >20-point improvement from baseline in total IBDQ score at Week 8, significantly greater proportions of subjects in the ~6 mg/kg and 130 mg ustekinumab groups had improvements (62.1% and 61.3%, respectively) compared with subjects in the placebo group (37.0%; p<0.001 for both comparisons). This was important as >20 point improvement is considered a clinically important objective end point for clinical improvement for UC patients. When considering a ≥16-point improvement from baseline in total IBDQ score at Week 8, significantly greater proportions of subjects in the ~6 mg/kg and 130 mg ustekinumab groups had improvements (68.6% and 66.6%, respectively) compared with subjects in the placebo group (44.2%; p<0.001 for both comparisons). Change from Baseline in the SF-36 Physical and Mental Component Scores at Week 8 At Week 8, median increases from baseline in the Physical Component Summary (PCS) scores were significantly greater for subjects in the ~ 6mg/kg and 130 mg ustekinumab groups (4.1 and 4.4, respectively compared with subjects in the placebo group (1.6; p<0.001 for both comparisons).

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At Week 8, median increases from baseline in the Mental Component Summary (MCS) scores were significantly greater for subjects in the ~6 mg/kg and 130 mg ustekinumab groups (3.6 and 3.8, respectively) compared with subjects in the placebo group (1.6; p<0.001 for both comparisons). Change from baseline in EQ-5D Index, EQ-5D Dimensions, and Health State VAS Scores at Week 8 At baseline, the median EQ-5D index and health state VAS scores were similar across all treatment groups. At Week 8, the median changes from baseline in EQ-5D and health state VAS were significantly greater for subjects in the ~ 6mg/kg and 130 mg ustekinumab groups compared with those in the placebo group (p<0.001 for both comparisons, for both the EQ-5D index and health state VAS). At baseline, the distributions for each of the five dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were generally consistent across treatment groups. At Week 8, significantly greater proportions of subjects had improvement in the dimensions of usual activities, pain/discomfort and anxiety/depression for each ustekinumab group compared to placebo (p≤0.002). An improvement in the self-care dimension was also noted in the ~6 mg/kg group (p=0.004) compared with the placebo group. UNIFI Maintenance trial: Improvement of ≥5-points from induction baseline in the SF-36 Physical and Mental Component Scores at Week 44 Among subjects with a ≥5-point improvement (from induction baseline) in the SF-36 PCS score at maintenance baseline, significantly greater proportions of the ustekinumab q8w and q12w groups maintained their ≥5-point improvement through maintenance Week 44 (62.4% and 59.5%, respectively) compared with subjects in the placebo group (38.3%, p=0.002 and p=0.004, respectively). In addition, significantly greater proportions of subjects in the ustekinumab q8w and q12w groups had a ≥5-point improvement from baseline in the SF-36 PCS score at Week 44 (53.4% and 50.0%, respectively) compared with subjects in the placebo group (30.3%; p<0.001 for both comparisons). Among subjects with a ≥5-point improvement (from induction baseline) in the SF-36 MCS score at maintenance baseline, significantly greater proportions of the ustekinumab q8w and q12w groups maintained their ≥5-point improvement through maintenance Week 44 (59.8% and 58.3%, respectively) compared with subjects in the placebo group (36.1%, p=0.001 and p=0.002, respectively). In addition, significantly greater proportions of subjects in the ustekinumab q8w and q12w groups had a ≥5-point improvement from baseline in the SF-36 MCS score at Week 44 (54.0% and 47.1%, respectively) compared with subjects in the placebo group (28.6%; p<0.001 for both comparisons). Clinically significant improvement from Baseline in Total IBDQ Score at Week 44 Clinically significant improvements in IBDQ from induction baseline in total IBDQ score at Week 44 was reached for both the ustekinumab q8w and q12w groups. When considering a >20-point improvement from baseline in total IBDQ score at Week 44, significantly greater proportions of subjects in the q8w and q12w groups had improvements (69.9% and 66.3%, respectively) compared with subjects in the placebo group (42.9%; p<0.001 for both comparisons). When considering a ≥16-

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point improvement from induction baseline in total IBDQ score at Week 44, significantly greater proportions of subjects in the q8w and q12w groups had improvements (73.3% and 68.6%, respectively) compared with subjects in the placebo group (47.4%; p<0.001 for both comparisons). Change from baseline in EQ-5D Index, EQ-5D Dimensions, and health state VAS scores through Week 44 At maintenance baseline, the median EQ-5D index and EQ-5D health state VAS scores were similar across all treatment groups. Over time through Week 44, the EQ-5D index and EQ-5D health state VAS scores were maintained for subjects in the ustekinumab q8w and q12w groups and decreased (worsened) for subjects in the placebo group. At maintenance baseline, the distribution for each of the five dimensions of mobility, self-care, usual activities, pain/discomfort, and anxiety/depression were generally consistent across treatment groups. Overall, at Week 44, greater proportions of subjects in the ustekinumab q8w and q12w groups reported EQ-5D dimension scores that improved or were maintained from maintenance baseline compared with subjects in the placebo group. 8. Discuss adverse events of interest, except for infections. The adverse events of interest for the technology and comparator treatments are described in Table 66. See also Appendix 2 for more details. Table 66. Common safety concerns for the technology and comparators (SmPC) Technology/Comparators Common undesirable effects as per SmPC  Infections and infestations (i.e. infections of the respiratory tract, intestine, skin and soft tissue, ear, oral, reproductive tract, urinary tract, fungal, and joint)  Neoplasms benign, malignant and unspecified (i.e. skin cancer excluding melanoma, benign neoplasm)  Blood and lymphatic system disorders (i.e. leukopenia, anaemia, leucocytosis, thrombocytopenia)  Immune system disorders (i.e. hypersensitivity, allergies)  Metabolism and nutrition disorders (i.e. lipids increased, hypokalaemia, uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemia, dehydration) Adalimumab(106)  Psychiatric disorders (i.e. mood alterations [including depression], anxiety, insomnia)  Nervous system disorders (i.e. headache, paraesthesias [including hypoesthesia], migraine, nerve root compression)  Eye disorders (i.e. visual impairment, conjunctivitis, blepharitis, eye swelling)  Ear and labyrinth disorders (i.e. vertigo)  Cardiac disorders (i.e. tachycardia)  Vascular disorders (i.e. hypertension, flushing, haematoma)  Respiratory, thoracic and mediastinal disorders (i.e. asthma, dyspnoea, cough)

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 Gastrointestinal disorders (i.e. abdominal pain, nausea and vomiting, GI haemorrhage, dyspepsia, gastroesophageal reflux disease, sicca syndrome)  Hepato-biliary disorders (i.e. elevated liver enzymes)  Skin and subcutaneous tissue disorders (i.e. rash [including exfoliative rash], worsening or new onset of psoriasis [including palmoplantar pustular psoriasis]), urticaria, bruising [including purpura], dermatitis [including eczema], onychoclasis, hyperhidrosis, alopecia, pruritus)  Musculoskeletal and connective tissue disorders (i.e. musculoskeletal pain, muscle spasms [including blood creatine phosphokinase increased])  Renal and urinary disorders (i.e. renal impairment, haematuria)  General disorders and administration site conditions (i.e. injection site reaction [including injection site erythema])  Investigations (i.e. coagulation and bleeding disorders [including activated partial thromboplastin time prolonged], autoantibody test positive [including double stranded DNA antibody], blood lactate dehydrogenase increased)  Injury, poisoning and procedural complications (i.e. impaired healing)  Infections and infestations (i.e. viral infection [i.e. influenza, herpes virus infection], bacterial infections [i.e. sepsis, cellulitis, abscess])  Blood and lymphatic system disorders (i.e. neutropenia, leucopenia, anaemia, lymphadenopathy)  Immune system disorders (i.e. allergic respiratory symptom)  Psychiatric disorders (i.e. depression, insomnia)  Nervous system disorders (i.e. headache, vertigo, dizziness, hypoaesthesia, paraesthesia)  Eye disorders (i.e. conjunctivitis)  Cardiac disorders (i.e. tachycardia, palpitation)  Respiratory, thoracic and mediastinal disorders (i.e. upper Infliximab(105) respiratory tract infection, sinusitis, lower respiratory tract infection (e.g. bronchitis, pneumonia), dyspnoea, epistaxis)  Gastrointestinal disorders (i.e. abdominal pain, nausea, gastrointestinal haemorrhage, diarrhoea, dyspepsia, gastroesophageal reflux, constipation)  Hepato-biliary disorders (i.e. hepatic function abnormal, transaminases increased)  Skin and subcutaneous tissue disorders (i.e. new onset or worsening psoriasis including pustular psoriasis [primarily palm & soles], urticaria, rash, pruritus, hyperhidrosis, dry skin, fungal dermatitis, eczema, alopecia)  Musculoskeletal and connective tissue disorders (i.e. arthralgia, myalgia, back pain)  Renal and urinary disorders (i.e. urinary tract infection)

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 General disorders and administration site conditions (i.e. infusion-related reaction, pain, chest pain, fatigue, fever, injection site reaction, chills, oedema)  Infections and infestations (i.e. upper respiratory tract infection [nasopharyngitis, pharyngitis, laryngitis and rhinitis], bacterial infections [such as cellulitis], lower respiratory tract infection [such as pneumonia], viral infections [such as influenza and herpes], bronchitis, sinusitis, superficial fungal infections, abscess  Blood and lymphatic system disorders (i.e. leukopenia [including neutropenia], anaemia)  Immune system disorders (i.e. allergic reactions [bronchospasm, hypersensitivity, urticarial], autoantibody positive)  Psychiatric disorders (i.e. depression, insomnia)  Nervous system disorders (i.e. dizziness, headache, paraesthesia)  Respiratory, thoracic and mediastinal disorders (i.e. asthma Golimumab(107) and related symptoms (such as wheezing and bronchial hyperactivity)  Gastrointestinal disorders (i.e. dyspepsia, gastrointestinal and abdominal pain, nausea, gastrointestinal inflammatory disorders [such as gastritis and colitis], stomatitis)  Hepato-biliary disorders (i.e. alanine aminotransferase increased, aspartate aminotransferase increased)  Skin and subcutaneous tissue disorders (i.e. pruritus, rash, alopecia, dermatitis)  General disorders and administration site conditions (i.e. pyrexia, asthenia, injection site reaction (such as injection site erythema, urticaria, induration, pain, bruising, pruritus, irritation and paraesthesia), chest discomfort)  Injury, poisoning and procedural complications (i.e. bone fractures)  Infections and infestations (i.e. nasopharyngitis, bronchitis, gastroenteritis, upper respiratory tract infection, influenza, sinusitis, pharyngitis)  Nervous system disorders (i.e. headache, paraesthesia)  Vascular disorders (i.e. hypertension)  Respiratory, thoracic and mediastinal disorders (i.e. oropharyngeal pain, nasal congestion, cough) Vedolizumab(113)  Skin and subcutaneous tissue disorders (i.e. rash, pruritus, eczema, erythema, night sweats, acne)  Musculoskeletal and connective tissue disorders (i.e. arthralgia, muscle spasms, back pain, muscular weakness, fatigue, pain in the extremity)  General disorders and administration site conditions (i.e. pyrexia)

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 Infections and infestations (i.e. pneumonia, influenza, herpes zoster, urinary tract infection, sinusitis, bronchitis, nasopharyngitis, pharyngitis)  Blood and lymphatic system disorders (i.e. anaemia)  Nervous system disorders (i.e. headache)  Vascular disorders (i.e. hypertension)  Respiratory, thoracic and mediastinal disorders (i.e. cough) Tofacitinib(53)  Gastrointestinal disorders (i.e. abdominal pain, vomiting, diarrhoea, nausea, gastritis, dyspepsia)  Skin and subcutaneous tissue disorders (i.e. rash)  Musculoskeletal and connective tissue disorders (i.e. arthralgia)  General disorders and administration site conditions (i.e. pyrexia, oedema, peripheral, fatigue)  Investigations (i.e. blood creatine phosphokinase increased)  Infections and infestations (i.e. upper respiratory tract infection, nasopharyngitis)  Nervous system disorders (i.e. dizziness, headache)  Respiratory, thoracic and mediastinal disorders (i.e. oropharyngeal pain) Ustekinumab  Gastrointestinal disorders (i.e. diarrhoea, nausea, vomiting) (technology)(10)  Skin and subcutaneous tissue disorders (i.e. pruritus)  Musculoskeletal and connective tissue disorders (i.e. back pain, myalgia, arthralgia)  General disorders and administration site conditions (i.e. fatigue, injection site erythema, injection site pain)

9. Explain why you do not think it is possible to do a safety NMA. See Section 5.2.2. 10. Include the most recent European guidelines and whether they are congruent with country-specific guidelines, if different summarize differences. See Section 2.3. 11. Provide up to date epidemiological data and specify the source, include Sweden and Poland. See Section 2.2. 12. Comprehensive literature search should be included in the submission file. See Section 5.1, 5.2, and throughout Section 5.

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analyses from ULTRA 2. Aliment Pharmacol Ther. 2013;37(2):204-13. doi: 10.1111/apt.12145. Epub 2012 Nov 23.

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Appendix 1. Clinical effectiveness SLR: Search strategies

Table 67. Search terms for MEDLINE and MEDLINE-IN-PROCESS via www.pubmed.com

Hits Hits Hits Topic # Search terms (14/08/20 ( 22/01/20 (28/03/20 Sources 18) 19) 19) POPULATI 1 colitis, ulcerative[mesh] 32,007 32,511 32,699 NICE(189) ON 2 proctitis[mesh] 2,929 2,91 2,966 3 inflammatory bowel 73,272 74,664 75,222 diseases[mesh] 4 inflamm* colon*[tiab] or 70,454 73,058 74,196 inflamm* bowel[tiab] or colon* inflamm* [tiab] or bowel inflamm*[tiab] 5 ulcer* colitis[tiab] 38,635 39,602 40,060 6 pancolitis[tiab] or 20,167 20,943 21,307 rectitis[tiab] or proctocolitis[tiab] or procto-colitis[tiab] or colorectitis[tiab] or rectocolitis[tiab] or recto-colitis[tiab] or recto-sigmoiditis[tiab] or rectosigmoiditis[tiab] or procto-sigmoiditis[tiab] or proctosigmoiditis[tiab] or proctitis[tiab] or UC[tiab] or colitis gravis[tiab] 7 "total colitis"[tiab] or 632 646 650 "sub-total colitis"[tiab] or "extensive colitis"[tiab] or "left-sided colitis"[tiab] or "universal colitis"[tiab] 8 #1 OR #2 OR #3 OR #4 127,739 131,289 132,884 OR #5 OR #6 OR #7 Intervention 9 Ustekinumab[mesh] or 1,363 1,473 1,534 Cochrane(1 and ustekinumab[tw] or 90-194) Comparator stelara[tw] OR "CNTO s 1275"[tw] OR "CNTO- 1275"[tw] 10 Infliximab[mesh] or 13,062 13,435 13,627 infliximab[tw] or remicade[tw] or "MAb cA2"[tw] or "Monoclonal Antibody cA2"[tw] or cA2, Monoclonal

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Antibody[mesh] or flixabi[tw] or inflectra[tw] or remsima[tw] 11 adalimumab[mesh] or 6,873 7,165 7,360 Adalimumab[tw] or humira[tw] or Antibody, D2E7[mesh] or "D2E7 Antibody"[tw] or amgevita[tw] or cyltezo[tw] or imraldi[tw] or solymbic[tw] 12 golimumab[Supplement 943 1,004 1,039 ary Concept] or Golimumab[tw] or Simponi[tw] or "CNTO 148"[tw] or "CNTO- 148"[tw] 13 Vedolizumab[Suppleme 569 643 693 ntary Concept] or Vedolizumab[tw] or ENTYVIO[tw] or MLN- 02[tw] or MLN02[tw] or "MLN 02"[tw] or LDP- 02[tw] or "LDP 02"[tw] or MLN0002[tw] or MLN-0002[tw] or "MLN 0002"[tw] or "LDP0002"[tw] or "LDP- 0002"[tw] or "LDP 0002"[tw] 14 tofacitinib 866 971 1,024 [Supplementary Concept] or Tofacitinib[tw] or XELJANZ[tw] or tasocitinib[tw] or "cp690550"[tw] or "cp 690550"[tw] or "cp 690 550"[tw] or "CP 690,550"[tw] or "CP- 690550"[tw] or "CP- 690,550"[tw] 15 "anti-tumour necrosis 227,323 233,607 236,290 factor"[tw] or "anti- tumor necrosis factor"[tw] or "anti- tnf"[tw] or “tumour necrosis factor”[tw] or “tumor necrosis factor”[tw] or “tumour necrosis factor inhibitor”[tw] or “tumor

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necrosis factor inhibitor”[tw] or “tumour necrosis factor blocker”[tw] or “tumor necrosis factor blocker”[tw] or “tumour necrosis factor receptor”[tw] or “tumor necrosis factor receptor”[tw] or “TNF”[tw] 16 “anti-alpha4*”[tw] or 170 172 172 “anti alpha4*”[tw] or “antialpha4*”[tw] or “alpha4beta7 antibod*”[tw] 17 “Janus Kinases”[mesh] 17,185 17,985 18,326 or “janus kinase”[tw] or “jak”[tw] or “jakinibs”[tw] or “janus associated kinase”[tw] 18 "interleukin*”[tw] or “IL- 318,752 325,981 328,947 12”[tw] or “IL-23”[tw] 19 #9 OR #10 OR #11 OR 475,550 487,418 492,520 #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 STUDY 20 "Randomised 120,001 122,917 124,825 SIGN(195) TYPE Controlled Trials as Topic"[mesh] 21 "Random 95,417 97,317 98,269 Allocation"[mesh] 22 "Double-Blind 147,070 149,151 150,358 Method"[mesh] 23 "Single-Blind 25,542 26,153 26,494 Method"[mesh] 24 "Clinical Trial, Phase 18,315 18,575 18,750 I"[pt] 25 "Clinical Trial, Phase 29,504 29,978 30,320 II"[pt] 26 "Clinical Trial, Phase 14,043 14,541 14,804 III"[pt] 27 "Clinical Trial, Phase 1,573 1,642 1,682 IV"[pt] 28 "Controlled Clinical 554,387 563,235 567,426 Trial"[pt] 29 "Randomised 466,666 475,221 479,286 Controlled Trial"[pt] 30 "Multicenter Study"[pt] 237,680 244,184 247,586 31 "Clinical trial"[pt] 804,533 816,129 821,741

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32 Clinical Trials as 316,511 321,016 323,725 Topic[mesh] 33 "clinical trial*"[tw] 663,573 672,554 677,184 34 "single?blind"[tw] or 211,307 214,932 216,788 "double?blind"[tw] or "triple?blind"[tw] 35 Placebos[mesh] 34,036 34,119 34,282 36 Placebo?[tw] 196,858 201,008 202,775 37 "randomly allocated"[tw] 24,610 25,527 25,900 38 #20 OR #21 OR #22 1,354,870 1,382,569 1,395,952 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35 OR #36 OR #37 Exclusion 39 "Case Reports"[pt] OR 3,755,267 3,821,859 3,916,682 SIGN(195) Comment[pt] OR Editorial[pt] OR "Historical article"[pt] OR Letter[pt] OR "case report"[ti] 40 Animals[mesh] NOT 4,484,686 4,538,127 4,538,127 Humans[mesh] 41 #39 OR #40 8,138,486 8,256,933 8,376,044 Combined: 42 #8 AND #19 AND #38 2,144 2,225 2,264 Population + Intervention 43 #42 NOT #41 1,874 1,944 1,978 and comparator s + Study type (44 (#42 NOT #41) Filters: Publicatio 130 26 ) Publication date n date not restriction restricted 2nd update: 2018/01/01 for the first to 2019/12/31 search 3rd update: 01/2019- 03/2019 TOTAL 44 Limit to: English 1,752 - - 45 Limit to: English - 130 26

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Table 68. Search terms for Embase via www.embase.com

Hits Hits Hits Topic # Search terms (28/03/201 Sources (14/08/2018) ( 22/01/2019) 9) POPULATION 1 ‘ulcerative colitis'/de 67,815 76,346 77,354 NICE(189) 2 proctitis/de 5,888 6,010 6,064 3 "inflammatory bowel 23,224 25,154 26,073 diseases"/de 4 (inflamm* NEAR/2 (colon* OR 69,159 71,836 73,094 bowel)):ab,ti 5 (ulcer* NEAR/1 colitis):ab,ti 55,063 56,489 56,489 6 pancolitis:ab,ti OR rectitis:ab,ti 38,737 40,179 OR proctocolitis:ab,ti OR 'procto colitis':ab,ti OR colorectitis:ab,ti OR rectocolitis:ab,ti OR 'recto sigmoiditis':ab,ti OR 57,295 rectosigmoiditis:ab,ti OR 'procto sigmoiditis':ab,ti OR proctosigmoiditis:ab,ti OR proctitis:ab,ti OR uc:ab,ti OR 'colitis gravis':ab,ti 7 ((total OR 'sub total' OR 1,394 1,427 subtotal OR extensive OR 'left 1,445 sided' OR universal) NEAR/1 colitis):ab,ti 8 #1 OR #2 OR #3 OR #4 OR #5 133,092 138,059 140,252 OR #6 OR #7 Intervention 9 'ustekinumab'/de OR 4,759 5,198 Cochrane( and ustekinumab:ab,ti OR 190-194) 5,373 Comparators stelara:ab,ti OR 'cnto 1275':ab,ti OR 'cnto-1275':ab,ti 10 'infliximab'/de OR 44,359 45,814 infliximab:ab,ti OR remicade:ab,ti OR 'mab ca2':ab,ti OR 'monoclonal 46,441 antibody ca2':ab,ti OR 'ca2, monoclonal antibody':ab,ti OR flixabi:ab,ti OR inflectra:ab,ti OR remsima:ab,ti 11 'adalimumab'/de OR 27,634 29,011 adalimumab:ab,ti OR humira:ab,ti OR ((d2e7 NEAR/1 antibody):ab,ti) OR 29,645 amgevita:ab,ti OR cyltezo:ab,ti OR imraldi:ab,ti OR solymbic:ab,ti 12 'golimumab'/de OR 5,231 5,639 5,822 'golimumab':ab,ti OR

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simponi:ab,ti OR 'cnto 148':ab,ti OR 'cnto-148':ab,ti 13 'vedolizumab'/de OR 2,170 2,421 vedolizumab:ab,ti OR entyvio:ab,ti OR mln02:ab,ti OR 'mln 02':ab,ti OR 'ldp 2,540 02':ab,ti OR mln0002:ab,ti OR 'mln 0002':ab,ti OR 'ldp0002':ab,ti OR 'ldp- 0002':ab,ti OR 'ldp 0002':ab,ti 14 'tofacitinib'/de OR 2,948 3,275 tofacitinib:ab,ti OR xeljanz:ab,ti OR tasocitinib:ab,ti OR 'cp690550':ab,ti OR 'cp 3,445 690550':ab,ti OR 'cp 690 550':ab,ti OR 'cp 690,550':ab,ti OR 'cp-690550':ab,ti OR 'cp- 690,550':ab,ti 15 'anti-tumour necrosis 265,287 138,059 factor':ab,ti OR 'anti-tumor necrosis factor':ab,ti OR 'anti- tnf':ab,ti OR 'tumour necrosis factor':ab,ti OR 'tumor necrosis factor':ab,ti OR 'tumour necrosis factor inhibitor':ab,ti OR 'tumor necrosis factor 278,073 inhibitor':ab,ti OR 'tumour necrosis factor blocker':ab,ti OR 'tumor necrosis factor blocker':ab,ti OR 'tumour necrosis factor receptor':ab,ti OR 'tumor necrosis factor receptor':ab,ti OR 'tnf':ab,ti 16 'anti-alpha4*':ab,ti OR 'anti 23 23 alpha4*':ab,ti OR 23 'antialpha4*':ab,ti OR 'alpha4beta7 antibod*':ab,ti 17 'janus kinases'/de OR 'janus 22,828 24,024 kinase':ab,ti OR 'jak':ab,ti OR 24,581 'jakinibs':ab,ti OR 'janus associated kinase':ab,ti 18 interleukin*:ab,ti OR 'il-12':ab,ti 272,979 280,673 283,636 OR 'il-23':ab,ti 19 #9 OR #10 OR #11 OR #12 514,710 530,726 OR #13 OR #14 OR #15 OR 538,193 #16 OR #17 OR #18 STUDY TYPE 20 ‘randomised controlled trial'/de 650,378 680,174 SIGN(195) OR 'randomised controlled trial 691,804 (topic)'/de 21 ‘random allocation'/de 78,655 80,472 81,192 22 ‘double-blind method'/de 151,508 156,605 158,537

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23 ‘single-blind method'/de 32,049 33,626 34,205 24 ‘phase 1 clinical trial'/de OR 62,656 65,113 66,485 'phase 1 clinical trial (topic)'/de 25 ‘phase 2 clinical trial'/de OR 97,861 101,284 103,025 'phase 2 clinical trial (topic)'/de 26 ‘phase 3 clinical trial'/de OR 66,316 69,954 71,632 'phase 3 clinical trial (topic)'/de 27 ‘phase 4 clinical trial'/de OR 4,438 4,711 4,777 'phase 4 clinical trial (topic)'/de 28 ‘clinical trial (topic)'/de OR 1,048,163 1,054,373 1,056,937 'clinical trial'/de 29 ‘multicenter study'/de OR 215,577 229,657 235,175 'multicenter study (topic)'/de 30 'clinical trial*':ab,ti 437,200 456,258 463,983 31 'single*blind':ab,ti OR 2,717 2,816 'double*blind':ab,ti OR 2,846 'triple*blind':ab,ti 32 ‘placebo'/de 327,085 334,428 337,031 33 ‘placebo*':ab,ti 274,893 282,893 285,841 34 ‘randomly allocated':ab,ti 30,212 31,472 31,944 35 #20 OR #21 OR #22 OR #23 1,952,175 2,015,333 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 2,040,131 OR #31 OR #32 OR #33 OR #34 Exclusion 36 ‘case report'/it OR 'case 4,260,713 4,362,107 SIGN(195) report/de' OR 'case study'/de OR 'case study'/it OR 'abstract report'/de OR 'abstract report'/it OR 'letter'/de OR 'comment' OR 'comment'/it OR letter/it OR 4,406,881 'short survey'/it OR 'conference review'/it OR 'review'/it OR 'review'/de OR 'conference review'/de OR ‘meta analysis'/de OR 'observational study'/de 37 ‘animal experiment'/it OR 5,916,847 6,086,161 'animal experiment'/de OR 'animal model'/de OR 'animal 6,148,624 model'/it OR 'nonhuman'/de OR 'nonhuman'/it 38 #36 OR #37 9,497,469 9,748,523 9,847,607 Combined: 39 #8 AND #19 AND #35 5,292 5,463 Population + 5,617 Intervention and 40 #39 NOT #38 2,831 2,940 comparators + 3,014 Study type (41 2nd update: #40 AND [2018- Publication 470 39 ) 2019]/py date not

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3rd update: 2019/py restricted for the first search TOTAL 41 #40 AND english:la 2,757 - - 42 #41 AND english:la - 282 38

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Table 69. Search terms in Cochrane Library via http://www.cochranelibrary.com/

Hits Hits Hits Topic # Search terms ( 22/01/201 (28/03/2019 Sources (14/08/2018) 9) ) POPULATION 1 MeSH descriptor: [Colitis, 1,310 1338 1,338 Ulcerative] explode all trees NICE(189) 2 MeSH descriptor: [Proctitis] 132 131 131 explode all trees 3 MeSH descriptor: [Inflammatory 2,743 2819 2,819 Bowel Diseases] explode all trees 4 (inflamm* near/2 (colon* or 2,073 2239 1,881 bowel)):ab,ti 5 (ulcer* near/1 colitis):ab,ti 3,003 2881 2,881 6 pancolitis:ab,ti or rectitis:ab,ti or 3,769 3232 3,232 proctocolitis:ab,ti or 'procto colitis':ab,ti or colorectitis:ab,ti or rectocolitis:ab,ti or 'recto sigmoiditis':ab,ti or rectosigmoiditis:ab,ti or 'procto sigmoiditis':ab,ti or proctosigmoiditis:ab,ti or proctitis:ab,ti or uc:ab,ti or 'colitis gravis':ab,ti 7 ((total or 'sub total' or subtotal 61 48 48 or extensive or 'left sided' or universal) near/1 colitis):ab,ti 8 #1 OR #2 OR #3 OR #4 OR #5 7,677 7,436 6,411 OR #6 OR #7 Intervention 9 MeSH descriptor: 108 116 116 Cochrane(1 and [Ustekinumab] explode all trees 90-194) Comparators 10 ustekinumab:ti,ab,kw or 416 408 408 stelara:ti,ab,kw or 'cnto 1275':ti,ab,kw or 'cnto- 1275':ti,ab,kw 11 MeSH descriptor: [Infliximab] 628 646 646 explode all trees 12 MeSH descriptor: [Antibodies, 9,499 9979 9,979 Monoclonal] explode all trees 13 infliximab:ti,ab,kw or 1,814 1678 1,678 remicade:ti,ab,kw or 'mab ca2':ti,ab,kw or 'monoclonal antibody ca2':ti,ab,kw or flixabi:ti,ab,kw or inflectra:ti,ab,kw or remsima:ti,ab,kw 14 MeSH descriptor: [Adalimumab] 520 549 549 explode all trees 15 adalimumab:ti,ab,kw or 2,028 1,848 1,848 humira:ti,ab,kw or (d2e7 near/1

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antibody):ti,ab,kw or amgevita:ti,ab,kw or cyltezo:ti,ab,kw or imraldi:ti,ab,kw or solymbic:ti,ab,kw 16 'golimumab':ti,ab,kw or 466 430 435 simponi:ti,ab,kw or 'cnto 148':ti,ab,kw or 'cnto- 148':ti,ab,kw 17 vedolizumab:ti,ab,kw or 271 274 274 entyvio:ti,ab,kw or mln02:ti,ab,kw or 'mln 02':ti,ab,kw or 'ldp 02':ti,ab,kw or mln0002:ti,ab,kw or 'mln 0002':ti,ab,kw or 'ldp0002':ti,ab,kw or 'ldp- 0002':ti,ab,kw or 'ldp 0002':ti,ab,kw 18 tofacitinib:ti,ab,kw or 430 430 430 xeljanz:ti,ab,kw or tasocitinib:ti,ab,kw or 'cp690550':ti,ab,kw or 'cp 690550':ti,ab,kw or 'cp 690 550':ti,ab,kw or 'cp 690,550':ti,ab,kw or 'cp- 690550':ti,ab,kw or 'cp- 690,550':ti,ab,kw 19 'anti-tumour necrosis 12,174 1,1051 11,051 factor':ti,ab,kw or 'anti-tumor necrosis factor':ti,ab,kw or 'anti- tnf':ti,ab,kw or 'tumour necrosis factor':ti,ab,kw or 'tumor necrosis factor':ti,ab,kw or 'tumour necrosis factor inhibitor':ti,ab,kw or 'tumor necrosis factor inhibitor':ti,ab,kw or 'tumour necrosis factor blocker':ti,ab,kw or 'tumor necrosis factor blocker':ti,ab,kw or 'tumour necrosis factor receptor':ti,ab,kw or 'tumor necrosis factor receptor':ti,ab,kw or 'tnf':ti,ab,kw 20 'anti-alpha4*':ti,ab,kw or 'anti 98 87 87 alpha4*':ti,ab,kw or 'antialpha4*':ti,ab,kw or 'alpha4beta7 antibod*':ti,ab,kw 21 MeSH descriptor: [Janus 97 103 103 Kinases] explode all trees 22 'janus kinase':ti,ab,kw or 1,403 1,239 1,247 'jak':ti,ab,kw or

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'jakinibs':ti,ab,kw or 'janus associated kinase':ti,ab,kw 23 "interleukin*":ti,ab,kw or "IL- 18,700 1,7201 17,216 12":ti,ab,kw or "IL-23":ti,ab,kw 24 #9 OR #10 OR #11 OR #12 OR 35,580 3,4025 34,046 #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 Combined: 25 #8 AND #24 1,532 1467 Population + Intervention 1,270 and comparators TOTAL 43 #8 AND #24 (Limit trials) 1,473 1408 44 #8 AND #24 (Limit trials, 2nd 159 update: Limit dates from 01/2018 01/2019) 23 3rd update: Limit dates from 01/2019-03/2019)

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Appendix 2. Comparison of safety profiles for the comparator treatments based on SmPC In this Appendix, a comparison of safety profiles for the relevant comparator treatments (based on SmPC information) is provided, as per the outlined EUnetHTA action points. The information retrieved was related to: warnings and precautions (in general and specifically focused on infections), infections, malignancies, posology, contraindications, and adverse events. If a dash (“-“) was included in the table, no relevant information was retrieved from the SmPC. Table 70. Summary of Warnings and Precautions Ustekinumab Tofacitinib Vedolizumab Adalimumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019 Traceability Registration of batch - - Registration of batch Registration of Registration of number of biologic number of biologic batch number of batch number of products products biologic products biologic products Specific STELARA Treatment should be Entyvio treatment Humira treatment Remicade Simponi is for requirements concentrate for initiated and should be initiated should be initiated treatment is to be subcutaneous use. for solution for infusion is supervised by and supervised by and supervised by initiated and After proper administration intended for use specialist physicians specialist healthcare specialist physicians supervised by training in under the guidance experienced in the professionals experienced in the qualified subcutaneous and supervision of diagnosis and experienced in the diagnosis physicians injection physicians treatment of diagnosis and and treatment of experienced in the technique, patients experienced in the conditions for which treatment of ulcerative conditions for which diagnosis and may self-inject if diagnosis and tofacitinib is indicated. colitis or Crohn’s Humira is indicated. treatment of their physician treatment of Crohn's disease. rheumatoid determines that disease or ulcerative After proper training arthritis, this is appropriate, colitis. Administration in in injection inflammatory with medical healthcare setting technique, patients bowel diseases, follow-up as After proper training equipped to allow may self-inject with ankylosing necessary. in subcutaneous management of acute Humira if their spondylitis, Patients should be injection technique, hypersensitivity physician determines psoriatic arthritis instructed to inject patients or their reactions; continued that it is appropriate or psoriasis. the prescribed caregivers may self- observation during and with medical Remicade should amount of Simponi inject if a physician and after each follow-up as be administered according to the determines that it is infusion (due to necessary. During intravenously. comprehensive appropriate. severe and mild-to- treatment with Remicade instructions for use moderate infusion Humira, other infusions should provided in the related reactions) concomitant be administered pack. therapies (e.g., by qualified

242

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corticosteroids and/or healthcare immunomodulatory professionals agents) should be trained to detect optimised. any infusion- related issues.

Emergency equipment, such as adrenaline, antihistamines, corticosteroids and an artificial airway must be available.

Patients may be pre-treated with e.g., an antihistamine, hydrocortisone and/or paracetamol and infusion rate may be slowed in order to decrease the risk of infusion- related reactions especially if infusion-related reactions have occurred previously Use in specific No overall differences No dose No dose adjustment is The frequency of The incidence of In the Phase III populations: in efficacy or safety in adjustment is required in elderly serious infections serious infections studies in RA, elderly patients age 65 and required in patients. Population among Humira in Remicade- PsA, AS, and UC, older who received patients aged 65 pharmacokinetic treated subjects over treated patients 65 no overall STELARA were years and older. analyses showed no 65 years of age years and older differences in observed compared There are limited effect of age. (3.7%) was higher was greater than adverse events to younger patients in data in patients than for those under in those under 65 (AEs), serious clinical studies in aged 75 years 65 years of age years of age. adverse events approved indications, and older. (1.5%). Some of Some of those had (SAEs), and however the number those had a fatal a fatal outcome. serious infections of patients aged 65 There is a higher outcome. Particular Particular attention in patients age 65 and older is not rate of infections attention regarding regarding the risk or older who

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sufficient to in patients aged the risk for infection for infection should received determine whether 65 years and should be paid when be paid when golimumab were they respond older. treating the elderly. treating the observed differently from elderly. compared with younger patients. younger patients. Because there is a However, caution higher incidence of should be infections in the exercised when elderly population in treating the elderly general, caution and particular should be used in attention paid with treating the elderly. respect to occurrence of infections. There were no patients age 45 and over in the nr-Axial SpA study. Use in specific The safety and The safety and The safety and The safety and Remicade is The European populations: efficacy of STELARA efficacy of tofacitinib efficacy of efficacy of Humira in indicated for Medicines Agency paediatric for the treatment of in children aged 0 to vedolizumab in children aged 4-17 treatment of has deferred the Crohn’s disease or less than 18 years children aged 0 to 17 years have not yet severely active obligation to ulcerative colitis in have not been years old have not been established. No ulcerative colitis, in submit the results children less than established. No data been established. No data are available. children and of studies with 18 years have not yet are available. data are available. There is no relevant adolescents aged Simponi in one or been established. No use of Humira in 6 to 17 years, who more subsets of data are available. children aged less have had an the paediatric than 4 years for this inadequate population in indication. response to ulcerative colitis. conventional therapy including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications for such therapies. Use in specific No dose No dose adjustment No dose No dose No dose Cautioned in populations: recommendation can required for mild to recommendation can recommendation can recommendation subjects with impaired renal be made; not studied moderate renal be made; not studied be made; not studied can be made; not impaired hepatic or hepatic in these populations. impairment; patients in these populations. in these populations. studied in these function. function with severe renal populations. impairment to remain

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on reduced dose. Contraindicated in patients with severe hepatic impairment. Infusion Systemic and Hypersensitivity: post- Infusion-related Rare serious Infliximab has In post-marketing reactions and respiratory marketing cases of reactions (IRR) and analphylactic been associated experience, hypersensitvity hypersensitivity drug hypersensitivity, hypersensitivity reactions observed with acute serious systemic reactions. allergic reactions reactions reported in during clinical infusion-related hypersensitivity Systemic: serious including angioedema clinical studies, trials=> discontinue reactions, reactions hypersensitivity and urticaria; serious majority mild to immediately including (including reactions have been reactions have moderate. anaphylactic anaphylactic reported in occurred. If severe infusion- shock, reaction) have postmarketing, in related reaction , and delayed been reported some cases several anaphylactic reaction hypersensitivity following days after treatment. or other severe reactions golimumab Respiratory: Cases of reaction occurs => administration allergic alveolitis and discontinue eosinophilic immediately pneumonia have If mild to moderate been reported post- IRR occurs, infusion approval rate can be slowed or =>discontinuation interrupted. Latex: needle cover from dry natural rubber Surgery - - - Limited safety Limited safety Limited safety experience; patients experience; experience; to be closely patients to be patients to be monitored for closely monitored closely monitored infections. for infections. for infections.

Vaccinations/ Live-vaccines not Live-vaccines not Similar protective Similar antibody Live-vaccines not Live-vaccines not therapeutic recommended; non- recommended; immunity to response to standard recommended; recommended; infectious live or inactivated prophylactic zoster recombinant hepatitis 23-valent limited data limited data agents vaccines can be co- vaccination should be B surface antigen pneumococcal available, the use available, the use administered considered vaccine. Patients may vaccine and the of live-vaccines of live-vaccines Long-term use does continue to receive influenza trivalent could result in could result in not suppress humoral non-live vaccines. virus vaccine. clinical infections, clinical infections, response to Lower seroconversion Concomitant including including pneumococ- to oral cholera vaccines possible, disseminated disseminated polysaccharide or vaccine; impact on with the exception of infections infections tentanusvaccines other oral vaccines live-vaccines. unknown.

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Life vaccines only if benefit clearly outweighs risks Concurrent use - - - Not recommended; Not Not with anakinra serious infections recommended; recommended; reported. serious infections serious infections and neutropenia and neutropenia reported. reported. Concurrent use - - - Not recommended; Not Not with abatacept associated with recommended; recommended; increased risk of associated with associated with infections. increased risk of increased risk of infections. infections. Concurrent use Caution for use in Not recommended; Not recommended; no Not recommended Not Not with biological combination with concurrent use with clinical trial data for with biologic recommended; recommended; therapies other biologics has not the concurrent use DMARDs; possibility insufficient insufficient immunosuppressants been studied. with biological of increased risk of information; information; or transitioning from immunosuppressants infection, and other possibility of possibility of other are available. potential increased risk of increased risk of immunosuppressive pharmacological infection, and infection, and biologics. interactions. other potential other potential pharmacological pharmacological interactions. interactions. Cardiovascular - Patients treated with - - - - risk tofacitinib should have risk factors (e.g., hypertension, hyperlipidaemia) managed as part of usual standard of care. Heart failure - - - Congestive heart- Cautioned in Congestive heart failure (in studies patients with mild failure reported with other anti- heart failure with TNF blockers TNFs): deterioration (NYHA class I/II). including and increased Contra-indicated in golimumab; some mortality: use with patients with fatal outcomes caution in patients moderate to reported. with mild heart failure severe heart- Cautioned in (NYHA class I/II). failure. patients with mild Contra-indicated in heart failure patients with (NYHA class I/II). Contra-indicated in

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moderate to severe patients with heart-failure. moderate to severe heart- failure. Interstitial lung - Interstitial lung - - - - disease disease: caution in use in patients with history of chronic lung disease. Events of interstitial lung disease (some fatal) have been reported. Asian RA patients know to be at higher risk of interstitial lung disease. Liver enzyme - Liver enzyme - - - Increased liver elevation elevations: enzymes have association with been observed increased incidence with the use of of liver enzyme golimumab. elevation. Caution when considering initiation in patients with elevated ALT or AST, particularly in combination with hepatotoxic products such as MTX. => routine monitoring of liver tests Gastrointestinal - Use with caution in - - - - perforations patients at increased risk (history of diverticulitis, concomitant corticosteroids and/or NSAID use). Haematologic - - - Serious Reports of Reports of reactions haematological pancytopenia, pancytopenia, reactions have been leucopenia, leukopenia, reported: rare reports neutropenia, and neutropenia, of pancytopenia, thrombocytopenia.

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aplastic anaemia, agranulocytosis, central and aplastic anaemia, peripheral and demyelinating events thrombocytopenia. and reports of lupus, lupus-related conditions and Stevens-Johnson syndrome. Neurological - - Patients to be Neurological Associated with Associated with events monitored for any new complications cases of new cases of new onset or worsening of (demyelinating onset or onset or neurological signs disease, including exacerbation of exacerbation of and symptoms. MS, optic neuritis, clinical symptoms clinical symptoms Guillain Barré. and/or and/or Caution in patients radiographic radiographic with existing or evidence of central evidence of central demyelinating nervous system nervous system conditions. demyelinating demyelinating disorders, disorders, including multiple including multiple sclerosis, and sclerosis and peripheral peripheral demyelinating demyelinating disorders, disorders. Caution including Guillain- in patients with Barré syndrome. existing or Caution in patients demyelinating with existing or conditions. demyelinating conditions. Laboratory -  Association with - - - - abnormalities lymphopenia. Lymphocyte counts less than 750 cells/mm3 associated with serious infections. Monitoring and dose adjustment  Associated with neutropenia.

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Monitoring and dose adjustment.  Associated with decreases in haemoglobin. Monitoring and dose adjustment  Lipid monitoring: associated with increases in lipid parameters. Monitoring after 8 weeks and managed per clinical guidelines. Allergy No data - - - - - immunotherapy Lactose - Contains lactose - - - - Serious skin Monitoring of - - - - - conditions exfoliative dermatitis & erytrodermic psoriasis in patients with psoriasis Corticosteroid - - Induction of remission - - - use in Crohn’s disease may take up to 14 weeks in some patients. Exploratory analysis suggests that VDZ may be less effective in Crohn’s patients without concomitant corticosteroid treatment. Autoimmune - - - Discontinue in Discontinue in Discontinue in processes patients with patients with patients with symptoms of lupus symptoms of lupus symptoms of lupus and positive for and positive for and positive for dsDNA. dsDNA. dsDNA.

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Table 71. Warnings and precautions with regard to infections Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 2019 Last update: 2019 Last update: 2019 Not to be No specific text, Not to be used in Not to be initiated in Not to be used in Not to be initiated in Not to be initiated in initiated but contra- patients with active patients with active, patients with active patients with patients with indicated in infections, including severe infections. infections, including serious infection or clinically important, patients with localized infections localized infections. sepsis, chronic active infection. clinically infection or a history important active of recurrent infection (e.g. infections active TB) Serious Serious Serious, and Potential increased Increased risk for Increased risk for Bacterial (including infections bacterial, fungal sometimes fatal, risk for opportunistic serious infections with infection, and sepsis and and risk and viral bacterial, infections or infections anti-TNFs. Reduced serious infections; pneumonia), factors infections mycobacterial, invasive for which the gut is a lung function increases tuberculosis, mycobacterial reported fungal, viral or other defensive barrier. risk. bacterial infections, (including TB), opportunistic infections Serious infections have including sepsis invasive fungal and reported; higher risk in been reported such as and pneumonia, opportunistic Asia and RA patients sepsis, due to bacterial, invasive fungal, viral infections, including on corticosteroids mycobacterial, invasive and other fatalities, have been fungal, parasitic, viral or opportunistic reported other opportunistic infections have infections such as been observed; listeriosis, legionellosis fatal infections and pneumocystosis. observed. Other reported serious infections observed in trials include pneumonia, pyelonephritis, septic arthritis and septicaemia. Hospitalisations or fatal cases associated with infections have been reported. Risk benefit - Risk benefit to be - Risk benefit to be Risk benefit to be Risk benefit to be to be considered in considered in considered for considered for considered  Recurrent -exposure to TB patients who have patients who have infections resided in or resided in or

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 History of serious - travel to areas with TB, travelled to regions travelled to regions or opportunistic endemic mycoses such where invasive where invasive infections as histoplasmose, fungal infections fungal infections  Travelled in areas coccidoidomycose or such as such as of endemic blastomycosis. histoplasmosis, histoplasmosis, mycoses Caution in patients with coccidioidomycosis, coccidioidomycosis,  Underlying history of recurrent or blastomycosis or blastomycosis are conditions infection or predisposing are endemic endemic predisposing to factors, including infections concomitant use of immunosuppressants. Cautious Cautious use in - Caution in patients When considering in - Caution in patients use patients with with controlled chronic patients with a history of with chronic or a chronic infection severe infections or a recurring infections or history of recurrent or history of history of recurring with underlying infection recurring severe infections. conditions which may infections predispose patients, including the use of concomitant immunosuppressive medications. TB TB screening; TB screening; TB screening; TB screening; treatment TB screening; TB screening; screening & treatment of treatment of latent TB treatment of latent TB of latent TB before use treatment of latent treatment of latent pretreatment latent TB before before use; monitoring before use TB before use; TB before use; of latent TB use; monitoring of TB patients monitoring of TB monitoring of TB before use of TB patients patients patients or a history of latent or active TBC Use in Contra- No text; but contra- Contra-indicated Contra-indicated Contra-indicated Contra-indicated patients with indicated indicated in section 4.3 active TB of SmPC Other TB - Benefit risk - Reactivation and de - - related text considerations in novo TB have been patients reported in patients  Exposed to TB treated with Humira  Resided or (pulmonary and extra- travelled in areas pulmonary). of endemic TB Monitoring Instructions to Close monitoring for the Closely monitored for Monitoring closely; Monitor closely; Monitor closely; of patients patients to development of signs infections before, warning for opportunistic warning for invasive patients to be related to recognize and symptoms of during and after infections including fungal infections advised, and to infections infections treatment. invasive fungal avoid exposure to, Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 251

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symptoms of infections not being potential risk factors infections consistently recognised for infection Continuation Not to be Interruption in case of Consider withholding Discontinue Discontinue Discontinue in patients administered serious infection, treatment in patients developing a until infection opportunistic infection who develop a severe serious resolves or sepsis. infection infection Other - Caution in elderly and - Elderly: increased Incidence of serious Caution in elderly cautions diabetic populations frequency of serious infections in and infants in utero (population- infections during Remicade-treated specific) treatment with Humira; patients 65 years some with fatal and older was outcome. greater than in those under 65 years of age; some with fatal outcome. Infections also reported in a higher proportion of paediatric patients compared to adult patients Other - Viral reactivation and - - - - cautions herpes virus (viral reactivation (herpes reactivation zoster): higher herpes & herpes) zoster risk in  Japanese or Korean patients  ALC < 1000 cells/mm3  RA patients who previously received 2 or more bDMARDs  Treatment with tofacitinib 10 mg BID Other - Unknown impact on - Reactivation of hepatitis Reactivation of Reactivation of cautions viral hepatitis B has been reported, hepatitis B has hepatitis B has (viral reactivation, since with fatal cases. occurred, with fatal occurred, with fatal hepatitis) patients were excluded Screening for hepatitis cases. Screening cases. Screening for B. for hepatitis B. hepatitis B. Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 252

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from trials. Screening for viral hepatitis. Other - Risk may be higher with Some integrin -  May mask - cautions increasing degrees of antagonists and some symptoms of lymphopenia: systemic infection such lymphopenia immunosuppressive as fever monitoring; agents have been  Patients with discontinuation on associated with PML. fistulising monitoring criteria in PML monitoring, Crohn’s section 4.2 of SmPC although vedolizumab disease with exerts an acute immunosuppressive suppurative effect specific to the fistulas must gut. not initiate treatment

Table 72. Infections (Section 4.8 of SmPC) Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019 Percentage 1.38 per patient Specific to UC 0.85 per patient year 1.51 per patient year 36% of infliximab- In the controlled of infections year versus 1.35 indication: versus 0.70 with versus 1.46 with treated patients period of pivotal per patient with placebo  Induction: 21.1% placebo placebo and active were treated for trials, infections year in pbo for tofacitinib control. infections compared were observed in controlled versus 15.2% for with 25% 23.0% of studies placebo of placebo-treated golimumab-treated  Maintenance: patients (clinical patients (incidence 35.9% (5 mg BID); study specific) per 100 subject- 39.8% (10 mg years: 132.0; 95% BID) versus CI: 123.3, 141.1) 24.2% (placebo) compared with  Entire treatment 20.2% of control experience: 60.3 patients (incidence per 100 patient per 100 subject- years years: 122.3; 95% CI: 109.5, 136.2). In controlled and uncontrolled portions of the trials with a median

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follow-up of approximately 4 years, the incidence per 100 subject- years of infections was 81.1 events; 95% CI: 79.5, 82.8 for golimumab treated patients.

These results are not specific to the UC indication Incidence of 0.03 (829 patient (specific to UC) 0.07% of patients 0.04% versus 0.03% - - serious years follow-up) Generally similar to the versus 0.06 for with placebo and active infections versus 0.03 with RA studies with placebo. control per patient placebo (385 tofacitinib year patient-years of monotherapy) (1.7 and follow-up) 1.6 per 100 patient years versus 0 for the placebo group and 1.9 for MTX) Additional 0.91% infections - Serious infections Serious infections have - In the controlled clinical per patient year have been reported been reported period of pivotal experience and 0.02 % which include TB, (including rare fatal trials, upper (controlled, serious infections sepsis (some fatal), infections), including TB respiratory tract uncontrolled per patient year salmonella sepsis, (military and extra- infection was the and open (10953 years of listeria meningitis and pulmonary) and reports most common label) follow-up) CMV colitis. of invasive opportunistic adverse reaction Serious infections infections (disseminated reported in 12.6% of were anal abcess, extra-pulmonary golimumab-treated cellulitis, histoplamosis, patients (incidence pneumonia, blastomycosis, per 100 subject- diverticulitis, coccidiodomycosis, years: 60.8; 95% CI: gastro-enteritis pneumocystosis, 55.0, 67.1) and viral candidiasis, compared with infections. aspergillosis and 11.0% of control listeriosis). Most patients (incidence occurred within 8 per 100 subject- months and may reflect years: 54.5; 95% CI: recrudescence. 46.1, 64.0).

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In the controlled period of RA, PsA, AS, and nr-Axial SpA trials, serious infections were observed in 1.2% of golimumab- treated patients and 1.2% of control- treated patients. TB specific In clinical studies, - - Most cases of TB - Greater incidence of information patients with occurred within the first TB in patients latent TB and 8 months of starting receiving concomitant therapy and could golimumab 100mg isoniazide indicate recidual latent compared with treatment did not TB. patients receiving develop TB. golimumab 50mg RA clinical - In the RA studies, the - - In RA clinical - studies frequency of serious studies, the infections was higher incidence of serious in patients >65 years infections including (4.8 per 100 patients pneumonia was years versus 2.4 per higher in infliximab 100 patient years). plus methotrexate- As there is a higher treated patients incidence of infections compared with in the elderly => methotrexate alone caution especially at doses of 6 mg/kg or greater Juvenile RA - - - - Infections occurred - patients in 68% (41/60) of children receiving 3 mg/kg over 52 weeks, 65% (37/57) of children receiving infliximab 6 mg/kg over 38 weeks and 47% (28/60) of children receiving placebo over 14 week

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Paediatric - - - - Infections were - Crohn’s reported in 56.3% of disease randomised patients subjects treated with infliximab Paediatric - - - - Overall incidence of - ulcerative infections in colitis C0168T72 was patients 13/22 (59%) in the every 8 week maintenance treatment group and 14/23 (60.9%) in the every 12 week maintenance treatment group Post- - - - - Infections are the - marketing most common spontaneous serious adverse reporting reaction; some with fatal outcomes. Nearly 50% of reported deaths have been associated with infection. Cases of tuberculosis, sometimes fatal, including miliary tuberculosis and tuberculosis with extra-pulmonary location have been reported

Table 73. Malignancies (Section 4.4 and 4.8 of SmPC) Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019

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Risk with Immunosuppressants Lymphomas have Immunomodulatory In the controlled In the controlled - concurrent like ustekinumab have been observed medicinal products portions of trials with portions of clinical medication the potential to (patients with RA may increase the risk TNF-antagonist, more studies of TNF- increase the risk of may be at higher risk of malignancy (see cases of malignancies blocking agents, malignancy. Some than general 4.8) including lymphoma more cases of patients who received population) => effect have been observed malignancies Stelara in clinical is uncertain (rare occurrence). Including studies developed Post-marketing cases lymphoma have cutaneous and non- Other malignancies of leukemia with TNF- been observed cutaneous were observed in antagonists. A among patients malignancies (see clinical studies and possible risk receiving a TNF 4.8) past-marketing. (lymphoma and blocker compared Effect of tofacitinib is leukaemia and other with control unknown. malignancies) cannot patients. be excluded. NMSC, All patients, in NMSCs have been - All patients, in Melanoma and Melanoma and Melanoma, particular > 60 years, reported. The risk of particular > 60 years, Merkel cell Merkel cell Merkel cell medical history of NMSC may be medical history of carcinoma have carcinoma have carcinoma prolonged higher in patients prolonged been reported in been reported in immunosuppressant treated with immunosuppressant patients treated patients treated therapy or those with tofacitinib 10 mg IBD therapy or those with a with TNF blocker with TNF-blocking a history of PUVA, compared to 5 mg history of PUVA, therapy agents, including should be monitored BID. Periodic skin should be monitored golimumab for non-melanoma examination for non-melanoma skin skin cancer recommended for at cancer. Melanoma and risk patients (see Merkel cell carcinoma 4.8) have also been reported in patients treated with TNF- antagonists. Malignancies - - - Risk of development of Malignancies, Malignancies, in specific malignancies in some fatal, have some fatal, have populations children and been reported been reported adolescents cannot be among children, among children, excluded. No adolescents and adolescents and malignancies reported young adults (up to young adults (up to in paediatric trials . 22 years of age) 22 years of age) treated with TNF- treated with TNF- blocking agents blocking agents (initiation of therapy (initiation of therapy ≤ 18 years of age), ≤ 18 years of age) including in the post marketing setting

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Remicade in the post-marketing setting Hepatosplenic - - - Risk for development - - T-cell of hepatosplenic T-cell lymphoma lymphoma cannot be excluded. Potential risk with the combination of azathioprine or 6-MP should be carefully considered. Rare post- marketing cases of hepatosplenic T-cell lymphoma COPD - - - In a trial with infliximab In an exploratory Caution should be in COPD, more clinical study exercised when malignancies reported evaluating the use using any compared to control, of Remicade in TNF-antagonist in mostly in the lung or patients with COPD patients, as head and neck. moderate to severe well as in patients Caution when using chronic obstructive with an increased any TNF-antagonists pulmonary disease risk of malignancy in COPD patients, as (COPD), more due to well as in heavy malignancies were heavy smoking smokers. reported in Remicade-treated patients compared with control patients. Caution should be exercised in considering treatment of patients with increased risk for malignancy due to heavy smoking. Dysplasia or - - - Not know if Patients with Not known if colon adalimumab treatment ulcerative colitis golimumab carcinoma influences the risk for who are at treatment dysplasia or coon increased risk for influences the risk cancer. Patients with dysplasia or colon for developing ulcerative colitis at carcinoma (for dysplasia or colon

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increased risk (e.g. example, patients cancer. Patients long-standing UC or with long-standing with prior history of PSC) or with a prior ulcerative colitis or dysplasia or colon history should be primary sclerosing carcinoma should screened regularly. cholangitis), or who be screened had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. History of No studies have been Risk benefit - No studies have been - - malignancy conducted in patients considered in conducted in patients with a history of patients with history with a history of malignancy or that of malignancy other malignancy or that continue treatment in than successfully continue treatment in patients who develop treated NMSC) or in patients who develop malignancy => patients developing malignancy => caution caution malignancy Malignancies 0.1 per 100 patients - Results from the 6.8 per 100 patient - In the controlled excluding 829 patient years clinical program to years versus 6.3 per portions of the non- follow-up) years date do not suggest 1000 patient (5291 Simponi Phase IIb melanoma versus 0.26 for an increased risk; patients) years (3444 and Phase III skin cancer in placebo (385 patient however, the number control patients). clinical trials in RA, controlled years of follow-up) of malignancies was PsA, AS, and trials small and long-term UC, the incidence exposure was limited. of non-lymphoma Long-term safety malignancies evaluations ongoing. (excluding non- melanoma skin cancer) was similar between the golimumab and the control groups. Non- 0.48 per 100 patients - - 8.8 per 1000 patient - In the controlled melanoma years versus 0.52 for years versus 3.2 and uncontrolled skin cancer in placebo among control periods of pivotal controlled patients. Of these skin trials with a median trials cancers, squamous

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cell carcinomas follow-up of up to 3 occurred at 2.7 per years, 1000 patient years non-melanoma skin versus 0.6 per 1000 cancer was patient years for diagnosed in 5 control patients. placebo-treated, 10 golimumab 50 mg- treated and 31 golimumab 100 mg-treated subjects with an incidence (95% CI) per 100 subject- years of follow-up of 0.36 (0.26, 0.49) for combined golimumab and 0.87 (0.28, 2.04) for placebo Lymphomas - - - 0.7 per 1000 patient In clinical studies In the controlled in controlled years versus 0.6 per with infliximab in portions of clinical trials 1000 patient years for which 5,780 trials of all the TNF- control patients patients were blocking agents treated, including representing 5,494 golimumab, more patient cases of lymphoma years, 5 cases of have been lymphomas and 26 observed among non-lymphoma patients receiving malignancies were anti-TNF treatment detected as compared with compared with no control patients lymphomas and 1 non-lymphoma malignancy in 1,600 placebo- treated patients representing 941 patient years. Controlled 10935 patient years - - 6427 patients and over - - and non- - Malignancies 26439 patient years of controlled excluding follow-up studies non-

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melanoma - Malignancies skin cancers: excluding 0.53 per 100 non- patient years melanoma (comparable and to expected lymphoma: incidence in 8.5 per 1000 general patient years. population) - Non- - Non- melanoma melanoma skin cancers skin cancer: 9.6 per 1000 0.49 per 100 patient years patient years - Lymphoma: (ratio of 1.3 per 1000 basal versus patient years squamous cell skin cancer comparable to expectations for general population) Post- - - - Post-marketing Post-marketing Rare post- marketing predominantly in RA: cases of marketing cases of - Malignancies: hepatosplenic T- hepatosplenic T- 2.7 per 1000 cell lymphoma cell lymphoma patient years (HSTCL) have (HSTCL) have - Non- been reported in been reported in melanoma patients patients skin cancer: treated with TNF- treated with other 0.2 per 1000 blocking agents TNF-blocking patient years including infliximab. agents - Lymphoma: A risk for the 0.3 per 1000 development for patient years hepatosplenic T- cell lymphoma in patients treated with Remicade cannot be excluded. Cases of

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malignancies, including lymphoma, have also been reported in the post- marketing setting Long-term - - - - In long-term safety - follow-up follow-up of clinical studies with infliximab of up to 5 years, representing 6,234 patients- years (3,210 patients), 5 cases of lymphoma and 38 cases of non- lymphoma malignancies were reported

Table 74. Posology Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019 Elderly No dose adjustment No dose adjustment; No dose adjustment Patient safety card No dose No dose limited data in adjustment adjustment patients > 75 years Hepatic No data CHILD Pugh B: dose No data No data No data No data impairment adjustment CHILD Pugh C: should not be used

Renal No data < 30 mL/min: dose No data No data No data No data impairment reduction Paediatric Psoriasis indication No data No data Paediatric indications: No data No data for 12-18 years; no PJIA as of 2 years old; data for other enthesisis related indications or children arthritis: as of 6 years younger than 12 old; psoriasis as of 4 years. years old; Crohn’s as

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of 6 years old; uveitis as of 2 years old

Table 75. Contraindications Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019 Hypersensitivity Hypersensitivity Hypersensitivity Hypersensitivity Hypersensitivity Hypersensitivity Hypersensitivity to the active substance Infections Active infection (e.g. Serious infections, Active severe Active TB or other Patients with Active tuberculosis TB) active TB or infections (such as serious infections tuberculosis or (TB) or other opportunistic TB, sepsis, CMV, (sepsis or other severe severe infections infections listeriosis and opportunistic infections such as such as sepsis, opportunistic infections) sepsis, abscesses, and opportunistic infections such as and opportunistic infections PML) infections Hepatic No data Severe hepatic No data No data No data Cautioned in impairment impairment subjects with impaired hepatic function Pregnancy - Cautioned Cautioned Cautioned Cautioned Cautioned Breastfeeding - Cautioned Cautioned - Cautioned Cautioned Heart failure - - - Moderate to severe Moderate or Moderate or heart failure (NYHA severe heart failure severe heart class III/IV) (NYHA class III/IV) failure (NYHA class III/IV)

Table 76. Adverse events Ustekinumab Tofacitinib Vedolizumab Adaliumumab Infliximab Golimumab Published: 2009 Published: 2017 Published: 2014 (Humira) (Remicade) Published: 2009 Last update: 2019 Last update: 2018 Last update: 2019 Published: 2009 Published: 2009 Last update: 2019 Last update: 2019 Last update: 2019 Infections Common Common Very common Very common Very common Very common and  Upper  Pneumonia,  Nasopharyngitis  Respiratory tract  Viral infections  Upper respiratory infestations respiratory Influenza, Common infections (e.g. influenza, tract infection tract infection, Herpes zoster,  Bronchitis, (including lower herpes virus (nasopharyngitis, nasopharyngit Urinary tract gastroenteritis, and upper infection) pharyngitis, is, sinusitis infection, upper respiratory respiratory tract Common Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 263

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Uncommon Sinusitis, tract infection, infection,  Bacterial laryngitis and  Cellulitis, Bronchitis, influenza, pneumonia, infections (e.g. rhinitis) dental Nasopharyngiti sinusitis, sinusitis, sepsis, cellulitis, Common infections, s, Pharyngitis pharyngitis pharyngitis, abscess)  Bacterial infections herpes Uncommon Uncommon nasopharyngitis Uncommon (such as cellulitis), zoster, lower  Tuberculosis,  Respiratory tract and pneumonia  Tuberculosis, lower respiratory respiratory Diverticulitis, infection, herpes viral) Fungal infections tract infection (such tract infection, Pyelonephritis, vulvovaginal Common (e.g. candidiasis, as pneumonia), viral upper Cellulitis, candidiasis, oral  Systemic onychomycosis) viral infections respiratory Herpes candidiasis, infections Rare (such as influenza tract infection, simplex, herpes zoster (including sepsis,  Meningitis , and herpes), vulvovaginal Gastroenteritis Very rare candidiasis and Opportunistic bronchitis, sinusitis, mycotic viral, Viral  Pneumonia influenza), infections (such superficial fungal infection infection intestinal as invasive infections, abscess Rare infections fungal infections Uncommon  Sepsis, (including [pneumocystosis,  Sepsis including Urosepsis, gastroenteritis histoplasmosis, septic shock, Disseminated viral), skin and aspergillosis, pyelonephritis TB, soft tissue coccidiodomycos Rare Necrotizing infections is, cryptoccosis,  Tuberculosis, fasciitis, (including blastomycosis], opportunistic Bacteraemia, paronychia, Bacterial infections (such as Staphylococcal cellulitis, impetigo, infections invasive fungal bacteraemia, necrotizing [atypical infections Pneumocystis fasciitis and mycobacterial, [histoplasmosis, jirovecii herpes zoster), listeriosis, coccidioidomycosis pneumonia, ear infections, oral salmonellosis], , pneumocytosis], Pneumonia infections Viral infections bacterial, atypical pneumococcal, (including herpes [cytomegalovirus] mycobacterial Pneumonia simplex, oral , Parasitic infection and bacterial, herpes and tooth infections, protozoal), hepatitis Encephalitis, infections), Hepatitis B B reactivation, Atypical reproductive tract reactivation bacterial arthritis, mycobacterial infections Not known infective bursitis infection, (including  Vaccine Cytomegalovir pyelonephritis), breakthrough us infection, fungal infections, infection (after in Arthritis joint infections utero exposure to bacterial Uncommon infliximab) Very Rare  Neurological  Tuberculosis of infections central (including viral nervous meningitis),

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system, opportunistic Meningitis infections and cryptococcal, tuberculosis Mycobacterium (including avium complex coccidioidomycosi infection s, histoplasmosis and mycobacterium avium complex infection), bacterial infections, eye infections, diverticulitis Neoplasms, - Uncommon - Common Rare Uncommon benign,  Non-  Skin cancer  Lymphoma, Non-  Neoplasms (such malignant melanoma skin excluding Hodgkin’s as skin cancer, and cancers melanoma lymphoma, squamous cell unspecified (including basal Hodgkin’s carcinoma and (including cell carcinoma disease, melanocytic cysts and and squamous Leukaemia, naevus) polyps) cell carcinoma), Melanoma, Rare benign neoplasm Cervical cancer  Lymphoma, Uncommon Not known leukaemia,  Lymphoma, solid  Heptaosplenic T- melanoma, Merkel organ neoplasm cell lymphoma cell carcinoma (including breast (primarily in Not known cancer, lung adolescents and  Hepatosplenic T- neoplasm and young adult cell lymphoma* thyroid neoplasm), males with melanoma Crohn’s disease Rare or ulcerative  Leukaemia colitis), Merkel Not known cell carcinoma  Hepatosplenic T- cell lymphoma, Merkel cell carcinoma (neuroendocrine carcinoma of the skin) Blood and - Common - Very common Common Common lymphatic  Anaemia Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 265

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system Uncommon  Leukopenia  Neutropenia,  Leukopenia disorders  Leukopenia, (including Leucopenia, (including Lymphopenia, neutropenia and Anaemia, neutropenia), Neutropenia agranulocytosis), Lymphadenopath anaemia anaemia y Uncommon Common Uncommon  Thrombocytopenia,  Leukocytosis,  Thrombocytopeni pancytopenia thrombocytopenia a, Lymphopenia, Rare Uncommon Lymphocytosis  Aplastic anaemia,  Idiopathic Rare agranulocytosis thrombocytopenic  Agranulocytosis purpura (including infants Rare exposed in utero  Pancytopenia to infliximab), Thrombotic thrombocytopeni c purpura, Pancytopenia, Haemolytic anaemia, Idiopathic thrombocytopeni c purpura Immune Uncommon - Very Rare Common Common Common system  Hypersensitivi  Anaphylactic  Hypersensitivity,  Allergic  Allergic reactions disorders ty reactions reaction, allergies (including respiratory (bronchospasm, (including Anaphylactic seasonal allergy) system hypersensitivity, rash, shock Uncommon Uncommon urticaria), urticaria)  Sarcoidosis,  Anaphylactic autoantibody Rare vasculitis reaction, Lupus- positive  Serious Rare like syndrome, Rare hypersensitivi  Anaphylaxis Serum sickness  Serious systemic ty reactions or serum hypersensitivity (including sickness-like reactions (including anaphylaxis, reaction anaphylactic angioedema) Rare reaction), vasculitis  Anaphylactic (systemic), shock, Vasculitis, sarcoidosis Sarcoid-like reaction Endocrine - - - - - Uncommon disorders  Thyroid disorder (such as Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 266

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hypothyroidism, hyperthyroidism and goitre Metabolism - Uncommon - Very common - Uncommon and  Dyslipidaemia,  Lipids increased  Blood glucose nutrition Hyperlipidaemi Common increased, lipids disorders a, Dehydration  Hypokalaemia, increased uric acid increased, blood sodium abnormal, hypocalcaemia, hyperglycaemia, hypophosphatemi a, dehydration

Psychiatric Uncommon Uncommon - Common Common Common disorders  Depression  Insomnia  Mood alterations  Depression,  Depression, (including Insomnia insomnia depression), Uncommon anxiety, insomnia  Amnesia, Agitation, Confusion, Somnolence, Nervousness Rare  Apathy Nervous Common Common Very common Very common Very common Common system  Dizziness,  Headache  Headache  Headache  Headache  Dizziness, disorders headache Uncommon Common Common Common headache, Uncommon  Paraesthesia  Paraesthesia  Paraesethesias  Vertigo, paraesthesia  Facial palsy (including Dizziness, Uncommon hypoesthesia), Hypoaesthesia,  Balance disorders migraine, nerve Paraesthesia Rare root compression Uncommon  Demyelinating Uncommon  Seizure, disorders (central  Cerebrovascular Neuropathy and peripheral), accident, tremor, Rare dysguesia neuropath  Transverse Rare myelitis, Central nervous system

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 Multiple sclerosis, demyelinating demyelinating disorders disorders (e.g. (multiple optic neuritis, sclerosis-like Guillain-Barré disease and optic syndrome) neuritis), Peripheral demyelinating disorders (such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy) Eye - - Very rare Common Common Uncommon disorders  Blurred vision  Visual impairment,  Conjunctivitis conjunctivitis, Uncommon  Visual disorders blepharitis, eye  Keratitis, (such as blurred swelling Periorbital vision and Uncommon oedema, decreased visual  Diplopia Hordeolum acuity), Rare conjunctivitis, eye  Endophthalmitis allergy (such as Not known pruritis and

 Transient visual irritation) loss occurring during or within 2 hours of infusion Ear and - - - Common - - labyrinth  Vertigo disorders Uncommon  Deafness, tinnitus Cardiac - - - Common Common Uncommon disorders  Tachycardia  Tachycardia,  Arrhythmia, Uncommon Palpitation ischemic coronary  Myocardial Uncommon artery disorders infarction,  Cardiac failure Rare arrhythmia, (new onset or

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congestive heart worsening),  Congestive heart failure Arrhythmia, failure (new onset Rare Syncope, or worsening)  Cardiac arrest Bradycardia Rare  Cyanosis, Pericardial effusion Not known  Myocardial ischaemia/ myocardial infarction Vascular Common Common Common Common Common - disorders  Hypertension  Hypertension  Hypertension,  Hypotension,  Hypertension flushing, Hypertension, Uncommon haematoma Ecchymosis, Hot  Thrombosis (such Uncommon flush, Flushing as deep venous  Aortic aneurysm, Uncommon and aortic), flushing vascular arterial  Peripheral Rare occlusion, ischaemia,  Raynaud’s thrombophlebitis Thrombophlebitis phenomenon , Haemotoma Rare  Circulatory failure, Petechia, Vasospasm Respiratory Common Common Common Common Very common Common , thoracic  Oropharynge  Cough  Oropharyngeal  Asthma, dyspnea,  Upper respiratory  Asthma and related and al pain Uncommon pain, nasal cough tract infection, symptoms (such as mediastinal Uncommon  Dyspnoea congestion, Uncommon Sinusitis wheezing and disorders  Nasal  Sinus cough  Pulmonary Common bronchial congestion congestion embolism,  Lower respiratory hyperactivity) Rare interstitial lung tract infection Uncommon  Allergic disease, chronic (e.g. bronchitis,  Interstitial lung alveolitis, obstructive pneumonia), disease eosinophilic pulmonary Dyspnoea, pneumonia disease, Epistaxis pneumonitis, Uncommon pleural effusion  Pulmonary Rare oedema,  Pulmonary fibrosis Bronchospasm,

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Pleurisy, Pleural effusion Rare  Interstitial lung disease (including rapidly progressive disease, lung fibrosis and pneumonitis) Gastrointes Common Common Common Very common Very common Common tinal  Diarrhea,  Abdominal  Anal abscess,  Abdominal pain,  Abdominal pain,  Dyspepsia, disorders nausea, pain, vomiting, anal fissure, nausea and Nausea gastrointestinal and vomiting diarrhea, nausea, vomiting Common abdominal pain, nausea, dyspepsia, Common  Gastrointestinal nausea, gastritis, constipation,  GI haemorrhage, haemorrhage, gastrointestinal dyspepsia abdominal dyspepsia, Diarrhea, inflammatory distension, gastroesophageal Dyspepsia, disorders (such as flatulence, reflux disease, Gastroesophage gastritis and colitis), haemorrhoids sicca syndrome al reflux, stomatitis Uncommon Constipation Uncommon  Pancreatitis, Uncommon  Constipation, dysphagia, face  Intestinal gastro- oedema perforation, oesophageal reflux Rare Intestinal disease  Intestinal stenosis, perforation Diverticulitis, Pancreatitis, Cheilitis Hepatobilia - Uncommon - Very common Common Common ry  Hepatic  Elevated liver  Hepatic function  Alanine disorders steatosis enzymes abnormal, aminotransferase Uncommon Transaminases increased,  Cholecystitis and aspartate cholelithiasis, aminotransferase hepatic steatosis, increased bilirubin increased Uncommon Rare  Cholelithiasis,  Hepatitis hepatic disorders reactivation of hepatitis B autoimmune hepatitis Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 270

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Not known  Liver failure

Skin and Common Common Common Very common - Common subcutaneo  Pruritus  Rash  Rash, pruritus,  Rash (including  Pruritus, rash, us tissue Uncommon Uncommon eczema, exfoliative rash) alopecia, dermatitis disorders  Pustular  Erythema erythema, night Common Uncommon psoriasis, skin pruritus sweats, acne  Worsening or new  Bulluous skin exfoliation, onset of reactions, psoriasis acne psoriasis(including (new onset or Rare palmoplantar worsening of pre-  Exfoliative pustular exisitng psoriasis, dermatitis psoriasis), palmar/plantar and urticaria, bruising pustular), urticaria (including Rare purpura),  Lichenoid dermatitis reactions, skin (including exfoliation, eczema), vasculitis onychoclasis, (cutaneous) hyperhidrosis, alopecia, pruritus Uncommon  Night sweats, scar Rare  Erythema multiforme, Stevens-Johnson syndrome, angioedema, cutaneous vasculitis lichenoid skin reaction Not known  Worsening of symptoms of dermatomyositis

Musculoske Common Common Very common Very common - Rare letal and  Back pain,  Arthralgia  Arthralgia  Musculoskeletal  Lupus-like connective myalgia, Uncommon Common pain syndrome tissue arthralgia Common disorders Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 271

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 Musculoskelet  Muscle spasms,  Muscle spasms al pain, joint back pain, (including blood swelling, muscular creatine tendonitis weakness, phosphokinase fatigue, pain in increased) the extremity Uncommon  Rhabdomyolysis, systemic lupus erythematosus Rare  Lupus-like syndrome Renal and - - - Common - Rare urinary  Renal impairment,  Bladder disorders, disorders haematuria renal disorders Uncommon  Nocturia Reproducti - - - Uncommon - Uncommon ve system  Erectile  Breast disorders, and breast dysfunction menstrual disorders disorders General Common Common Common Very common - Common disorders  Fatigue,  Pyrexia,  Pyrexia  Injection site  Pyrexia, asthenia, and injection site oedema Uncommon reaction (including injection site administrati erythema, peripheral,  Infusion site injection site reaction (such as on site injection site fatigue reaction erythema) injection site conditions pain (including: Common erythema, urticaria, Uncommon infusion site pain  Chest pain, induration, pain,  Injection site and Infusion site oedema, prexia bruising, pruritus, reactions irritation), Uncommon irritation and (including Infusion related  inflammation paraesthesia), haemorrhage, reaction, Chills, chest discomfort haematoma, Feeling cold) Rare induration,  Impaired healing swelling and pruritus), asthenia Investigatio - Common - Common - - ns  Blood creatine  Coagulation and phosphokinase bleeding disorders increased (including Uncommon activated partial

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 Hepatic thromboplastin enzyme time prolonged), increased, autoantibody test Transaminase positive (including s increased, double stranded Liver function DNA antibody), test abnormal, blood lactate Gamma dehydrogenase glutamyltransfe increased rase increased, Blood creatinine increased, Blood cholesterol increased, Low density lipoprotein increased, Weight increased Injury, - Uncommon - Common - Common poisoning  Ligament  Impaired healing  Bone fractures and sprain, muscle procedural strain complicatio ns

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Appendix 3. Comparison of baseline characteristics of studies of the technology and comparator treatments Table 77. Baseline patient characteristics of studies used in NMA CRP Weight Disease Mayo Age Males level - Trial Population Phase Arms –Kg duration score (Mean) % mg/L (Mean) (Mean) (mean) (Mean) PBO (n=96) 41.3 72.9 60.8 3.4* 7.8 8.5 Non-biologic NCT00853099 Induction ADA 80/40mg (n=87) 44.4 57.5 58.7 3.1* 8.3 8.6 failure ADA 160/80mg (n=90) 42.5 67.8 60.1 2.2* 7.8 8.6 Cohort 1: PBO (n=149) 41.2 61.7 72.4 NR 7.1 8.6 Induction Cohort 1: VDZ 300mg (n=225) 40.1 58.7 72.4 NR 6.1 8.5

Full patient Cohort 2: VDZ 300mg (n=521) 40.1 57.8 74.2 NR 7.2 8.6 population PBO (n=126) 40.3 55 74.7 NR 7.8 8.4 Maintenance† VDZ 300mg q8w (n=122) 41 57 78.2 NR 6.2 8.4 VDZ 300mg q4w (n=125) 38.6 54 71.8 NR 7.6 8.3 Cohort 1: PBO (n=76) 40.5 62 70 NR 6.1 8.5 GEMINI Induction Cohort 1: VDZ 300mg (n=130) 39.7 53 69.2 NR 5.8 8.4

Non-biologic Cohort 2: VDZ 300mg (n=258) 40.6 59 72.7 NR 6.4 8.5 failure PBO (n=79) 39.5 57 71.3 NR 6.4 8.4 Maintenance† VDZ 300mg q8w (n=72) 41 54 76.1 NR 5.8 8.3 VDZ 300mg q4w (n=73) 38.3 53 70 NR 7 8.2 Cohort 1: PBO (n=63) 41.8 56 74.2 NR 8 8.6 Biologic Failure Induction Cohort 1: VDZ 300mg (n=82) 39.7 61 74.9 NR 6.4 8.7 Cohort 2: VDZ 300mg (n=222) 40.2 55 75.3 NR 8 8.6

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PBO (n=38) 41.6 55 81.2 NR 9.8 8.2 Maintenance† VDZ 300mg q8w (n=43) 41.3 56 79.1 NR 6.8 8.5 VDZ 300mg q4w (n=40) 39.9 53 72.7 NR 8.1 8.4 PBO (n=130) 37* 63.1 78.7 3.2* 5.35* 8.7 Non-biologic ULTRA 1 Induction ADA 80/40mg (n=130) 40* 60 76.8 6.4* 6.91* 9 failure ADA 160/80mg (n=130) 36.5* 63.8 75.5 3.3* 6.06* 8.8 PBO (n=260) 41.3 61.8 77.1 13.1 8.5 8.9 Induction ADA 160/80/40mg (n=248) 39.6 57.3 75.3 14.5 8.1 8.9

Full patient Maintenance - ADA 40mg EOW (n=19) 39.6 36.8 78.5 3.9* 7.23* 8 ULTRA 2 † populatoin responder ADA 40mg weekly (n=20) 39.8 80 78.4 1.4* 7.1* 8.8

Maintenance – ADA 40mg EOW (n=19) 41.2 58.6 73.8 8.3* 4.96* 9.1 † non responder ADA 40mg weekly (n=48) 38.1 60.4 78.3 3.7* 6.79* 9.3 PBO (n=121) 41.4 59.5 76.8 17 6.2 8.4 Non-biologic ACT 1 Induction IFX 5mg (n=121) 42.4 64.5 80 14 5.9 8.5 failure IFX 10mg (n=122) 41.8 59 76.9 16 8.4 8.4 PBO (n=123) 39.3 57.7 76.1 16 6.5 8.3 Non-biologic ACT 2 Induction IFX 5mg (n=121) 40.5 62.8 78.4 13 6.7 8.3 failure IFX 10mg (n=120) 40.3 56.7 79.6 14 6.5 8.5

Full patient PBO (n=123) 41.8 63.1 72.7 4.7* 6* 9.1 OCTAVE-I1 Induction population TFB 10mg (n=476) 41.3 58.2 72.9 4.4* 6.5* 9

Full patient PBO (n=112) 40.4 49.1 73.2 5* 6.2* 8.9 OCTAVE-I2 Induction population TFB 10mg (n=429) 41.1 60.4 74.4 4.6* 6* 9

Full patient PBO (n=234) 41.1 56.4 NR NR 8.1 9 OCTAVE-I1+I2 Induction population TFB 10mg (n=905) 41.2 59.2 NR NR 8.1 9 OCTAVE-S Maintenance‡ PBO (n=198) 43.4 58.6 76.2 1* 7.2* 3.3

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Full patient TFB 5mg (n=198) 41.9 52 73.4 0.7* 6.5* 3.3 population TFB 10mg (n=197) 42.9 55.8 74.6 0.9* 6.8* 3.4 PBO (n=258) 39.7 50.4 NR 9.6 6.4 8.3 Full patient Induction GOL 200/100mg (n=258) 39.7 54.3 NR 11.5 6.4 8.7 populatoin GOL 400/200mg (n=258) 40.9 59.7 NR 12 6.5 8.6 PURSUIT-SC PBO (n=331) 39 52.9 NR 10.7 6 8.3

Non-biologic GOL 100/50mg (n=72) 40.9 55.6 NR 8.2 6.6 8.2 Induction failure GOL 200/100mg (n=331) 40 54.4 NR 11.3 6.4 8.6 GOL 400/200mg (n=331) 40.7 60.7 NR 13.2 6.4 8.5 Maintenance - PBO (n=129) 38 47.3 NR 9.5 6.3 8.2 Patients who GOL 100mg (n=230) 40.3 57 NR 9.6 6.2 8.2 failed conventional therapy + non responders in GOL 100mg (n=405) 41.2 65.9 NR 13.2 6.1 8.6 induction † Non-biologic phases PURSUIT-M failure Maintenance - PBO (n=156) 40.2 48.1 NR 9.6 6.9 8.3 Patients who failed GOL 50mg (n=154) 41.4 50 NR 8.5 6.8 8.1 conventional therapy + responders in GOL 100mg (n=154) 39.1 57.8 NR 8.9 7.2 8.5 induction phases† Induction I: GOL 200mg (n=144) 42.4 68 61.51 4.9 5.08* 8*

Non-biologic M: DB: PBO (n=31) 42.9 61 59.48 4.06 5.74* 8* PURSUIT-J failure Maintenance† M: DB: GOL 100mg (n=32) 39.3 59 64.59 5.31 5.35* 8* M: OL: GOL 100mg (n=60) 42.1 70 60.97 4.68 4.57* 8* NCT00787202 Induction PBO (n=48) 42.5 48 74.6 9.7 8.8 8.2

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TFB 0.5mg (n=31) 43.8 55 75.6 18.8 8.8 8.6

Full patient TFB 3mg (n=33) 42.5 58 73.8 12.6 8.9 8.3 population TFB 10mg (n=33) 43.2 64 75.9 11.3 10.9 8 TFB 15mg (n=49) 41.2 53 74.1 17.1 7.6 8 PBO (n=41) 34.5 60.9 61.2 35.1 4.4 NR Non-biologic Jiang 2015 Induction IFX 3.5mg (n=41) 34.1 58.5 63.1 35.7 4.3 NR failure IFX 5mg (n=41) 34.3 63.4 62.8 35.8 4.4 NR

Non-biologic PBO (n=20) NR NR 72* 12 4.92* NR Probert 2003 Induction failure IFX 5mg (n=23) NR NR 66* 9 6.25* NR

Japis Non-biologic PBO (n=104) 37.8 64.4 60.3 7 7.1 8.5 Induction CTI060297 failure IFX 5mg (n=104) 40 63.5 57.6 10 8.1 8.6 PBO (n=319) 40* 61.8 70* 9.8 5.97* 9* Induction UST 130mg (n=320) 42* 59.4 72* 9.6 5.9* 9*

Full patient UST 6mg/kg (n=322) 41* 60.6 71.8* 12.1 6.03* 9* UNIFI population PBO (n=175) 42* 61.9 71* 3.73 5.56* 4* Maintenance‡ UST 90mg q12w (n=172) 39* 55.8 70* 3.91 5.95* 4* UST 90mg q8w (n=176) 39* 53.4 70* 4.95 6.36* 4* * Median † The baseline values were obtained at the beginning of the induction phase for patients entering the maintenance phase ‡ The baseline values were obtained at the beginning of the maintenance phase Abbreviations: ADA=adalimumab, CrI=credible interval, DB=double blind, EOW=every other week, GOL=golimumab, IFX=infliximab, OL=open label, Pr=Bayesian probability for ustekinumab to be better than its comparator, TOF=tofacitinib, UST=ustekinumab, VDZ=vedolizumab

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Appendix 4. NMA of safety endpoints in maintenance phase Two main types of trial designs exist in UC: On the one hand, treat-through trials in which patients are assigned to placebo or active treatment for the full length of the trial (typically around one year), on the other hand, trials in which patients responding to active treatment after induction are re-randomised to active treatment, or placebo (withdrawal). Importantly, in order to limit the exposure to inactive placebo, there are variations in these re-randomised trials to what maintenance treatment of the patients induced with placebo.  Placebo induction responders are continued on placebo (UNIFI and PURSUIT)  Placebo responders are re-randomised and placebo non-responders are treated separately (OCTAVE)  Placebo responders and non-responders continue on placebo (GEMINI) As a result, the ‘placebo’ safety population of these trials consist of various ‘placebo’ patients consisting of the above mentioned placebo patients. The below section describes multiple examples of how various safety comparison versus ‘placebo’ in the different trials can lead to different conclusions, describes how these conclusions differ from conclusions drawn after detailed analyses from regulators, and provide an overall conclusion on why Janssen proposes that a comparison of conclusions by regulators may provide a more adequate comparison of the safety profile than a network meta-analysis. 1. Exposure is related to efficacy In the ULTRA-II trial, 257 patients were treated with adalimumab, of which 123 (48%) were considered week 8 responders. However, the exposure time on adalimumab was proportionally skewed towards patients that were week 8 responders, as there consisted of 64% of the exposure time of all patients on adalimumab (93.7 patient years out of 146.1 in total). (175, 196) 2. A large proportion of SAEs are related to ulcerative colitis exacerbations, and as a result, efficacy is related to SAEs. In the ULTRA-II trial, the number of SAEs in the overall adalimumab arm is 30.8 E/100PY, whereas in the subgroup of week 8 responders, this is 22.4 E/100PY. (175, 196) In the OCTAVE trial, the proportion of subjects with SAEs was numerically higher in the induction non-responder subgroup (patients who did not have a response at week 8) than in the tofacitinib 10 mg IBD group in cohort 2 (10.0% versus 5.6%). (53) The relationship between efficacy and SAEs is particularly problematic, given the types of placebo arms included (see point 3). 3. The re-randomised trial designs have different, non-homogeneous placebo arms that all form part of the overall placebo safety population.

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More importantly, the trials do not have consistent placebo definitions for their safety population. The below examples demonstrate how this can influence conclusions. a. Infections in the GEMINI-1 trial (158) In the GEMINI-1 trial, the rate of infections is similar in the combined active treatment arms (60%) versus the combined placebo arms (56%). Similarly, in the re-randomised portion of the trial, the rate of infections is similar in the placebo arms (71%) versus the two active arms (71% and 72%). However, in the non-re-randomised arms, the rate seems to differ, with 44% in the placebo arm, and 56% in the non- re-randomised active arm. More importantly, despite the apparent similarity in the infection rates between active and placebo, EMA/CHMP concluded that there is a “difference of 11% in the infection rate between the vedolizumab combined group (42%) versus the non-ITT placebo group (31%) “ and concluded that infections are a risk associated with treatment with vedolizumab. b. SAEs in the GEMINI-1 trial (158) The proportion of SAEs in the overall safety population of the trial seems similar between placebo (13.5% and active arms (12.4%). There are more SAEs in the re-randomised placebo arm (16%) compared to the active arms (8% and 9%), but the opposite is true in the non-randomised part, with 11% for placebo and 15% for active treatment. This difference is pointed out in the EMA/CHMP EPAR noting that “the frequency of SAEs was higher (15%) in patients who had not responded to vedolizumab during induction (non-ITT VDZ Q4w dose group) than in the ITT VDZ Q8w and in the ITT VDZ Q4w” c. Infections in OCTAVE (53) Infections in the re-randomised tofacitinib 10 mg BID arm are 35,71%,, whereas the proportion of infections in the IndNR 10 mg BID group is 26.11%. One could assume that the lower efficacy in the induction non- responders has influenced the exposure time; however, the proportions of infections are only provided as is, and are not provided by exposure time. d. SAEs in OCTAVE (53, 157) In the re-randomised portion of OCTAVE, rates of SAEs are similar between placebo (6.6%) compared to active treatment (5.1% and 5.6%). However, EMA/CHMP’s EPAR states that “the proportion of subjects with SAEs was numerically higher in the IndNR subgroup than the tofacitinib 10mg BID group in cohort 2 (10.0% versus 5.6%” 4. Inclusion and exclusion criteria relevant to infections differ between trials

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UNIFI (inclusion) OCTAVE (exclusion) Hemoglobin ≥8.0 g/dL <9.0 g/dL White blood cell count ≥3 × 103 cells/uL <3.0 x 109/L Neutrophils ≥1.5 × 103 cells /uL <1.2 x 109/L Platelets ≥100 × 103 cells /uL <100 x 109/L Lymphocytes <0.5 x 109/L (<500/mm3)* *Or <0.75 x 109/L [<750/mm3] in the UK

EMA/CHMP’s EPAR for Xeljanz states that “It is noted that in the UC program subjects with screening ALC <0.5 × 109/L were excluded from the Phase 3 UC induction studies, and subjects with confirmed ALC <0.5 × 109/L during treatment were required to be discontinued from the UC studies; this was the case in the RA program.” The current Xeljanz SmPC includes a recommendation not to initiate dosing in patients with an absolute lymphocyte count (ALC) less than 750 cells/mm3 or an absolute neutrophil count (ANC) less than 1,000 cells/mm3 5. The crude incidence analysis of safety provides different results than the analysis per patient years (154)

Golimumab 100 Golimumab 100 Placebo (n=156) Placebo (n=156) mg (n=154) mg (n=154) SAEs 7.7% 14.3% 12.62 E/100PY 17.09E/100PY Infections 28.2% 39.0% 55.09 E/100PY 60.39 E/100PY

6. Integration of safety of the re-randomised trials is not always available for the complete treatment of induction and maintenance, whereas the safety analysis for the treat-through trials covers induction and maintenance Overall, the above examples clearly indicate that a number of factors influence safety results. Different definitions of the placebo safety population, comprising of non-homogeneous placebo arms with different efficacy and exposure can result in spurious conclusions about safety, both for SAEs and infections. Differences exist in inclusion criteria which may influence results on infections. These examples illustrate than unadjusted analysis may lead to conclusions that do not correspond to the conclusions of regulators after detailed analysis. More importantly, while a number of examples are provided above, insufficient information is available for all comparators to enable attempting to correct for these factors. As a result, safety network analysis was not conducted. A comparison of the conclusions of regulators, after their detailed analysis (i.e. the respective labels) is thought to be more meaningful to compare the safety profiles of the different

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comparators. In addition to comparisons of infections (the most relevant AEs for this class), this enables to compare adverse events that are relevant to specific comparators.

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Appendix 5. Carry-over effects

A5.1 UNIFI trial: Carry-over effect In the UNIFI trial, patients were randomised to receive an ustekinumab induction dose of 130mg/kg, 6mg/kg or placebo at week 0. The patients who achieved a response in induction were then re-randomised to receive either an 8 weekly subcutaneous dose, a 12 weekly subcutaneous dose of ustekinumab, or placebo. Due to the trial design the placebo observed in the maintenance trial is not a true placebo. The UNIFI trial demonstrates an evidence of a carry-over effect of induction therapy with ustekinumab affecting maintenance outcomes for patients who received placebo during re-randomisation. This observed carry-over effect of ustekinumab is multi-factorial and likely depends on various factors such as a pharmacokinetic effect, an extended half- life of ustekinumab, the mode of action of ustekinumab (which targets key pathways involved in the immunopathogenesis of UC) and pharmacodynamics. A biomarker called faecal calprotectin (Fcal) has been demonstrated to be a sensitive and specific marker in identifying intestinal inflammation and response to treatment in patients with IBD. The carry-over effect is evident in the change from induction baseline in (Fcal) concentration (mg/kg) over time through week 44 in the re-randomised placebo group. The median Fcal levels were 1487.0 mg/kg at induction baseline and dropped to 338.0mg/kg at the maintenance baseline confirming the carry-over effect. The rates for placebo remained lower than the induction baseline level even by week 44 (931.0mg/kg) (Figure 45). Figure 45. Median Faecal Calprotectin Concentration Through Week 44; Primary Efficacy

Abbreviations: SC: Subcutaneous

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A similar effect is observed with another biomarker called faecal lactoferrin. A decreased concentration of the biomarker can be seen through the maintenance study (Figure 46). Figure 46. Median Faecal Lactoferrin Concentration Through Week 44

Abbreviations: SC: Subcutaneous Similarly, C-reactive protein (CRP) is used as a marker of inflammation in patients with IBD. In UC, elevated CRP has been associated with severe clinical activity, an elevated sedimentation rate, and active disease as detected by colonoscopy. The carry-over effect is visible in change from induction baseline in CRP level concentration (mg/l) over time through week 44 in the re-randomised placebo group. The high median CRP levels at induction baseline (3.42 mg/l) were reduced by approximately 50% at the maintenance baseline (1.48mg/l)). The CRP level was still lower than the induction baseline by week 44 (3.28mg/l) compared to the induction baseline. As shown in Figure 47, the separation between the placebo versus ustekinumab partial Mayo scores starts occurring only beyond week 16 indicating the sustained carry-over effect in the maintenance study.

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Figure 47. Plot of Mean Partial Mayo Score Through Week 44; Primary Efficacy Analysis Set

Abbreviations: SC: Subcutaneous Furthermore, a sustained remission can also be viewed in the placebo group beyond week 8 based on partial Mayo scores, confirming the carry-over effect of the drug into the maintenance phase (Figure 48).

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Figure 48. Proportion of subjects in partial Mayo remission over time through Week 44, Primary efficacy analysis set

Owing to the strong carry-over effect of ustekinumab a less frequent dosing of ustekinumab (12 weekly dose) is able to sustain patients in remission and response. Lastly, this ‘carry-over’ effect from induction to maintenance has been observed in treatment of CD with ustekinumab, with NICE acknowledging its presence.

A5.2 Other phase III trials in UC: Carry-over effect As described above, there is evidence of a carry-over effect of ustekinumab induction therapy. Similar evidence can be seen in other trials for comparators with similar trial designs, however the effects differ between studies due to differences in the induction therapies received. This is evident from a side-by-side comparison of graphs with partial Mayo score over time for maintenance arms. Below are the corresponding graphs for ustekinumab (Figure 49), golimumab (Figure 50) and vedolizumab (Figure 51) trials in UC (where low Mayo scores indicate better response to treatment).  Ustekinumab graph: Low partial mayo score for placebo following induction with ustekinumab showing “carry-over effect” of induction therapy on maintenance  Golimumab and vedolizumab graphs: Increase in partial mayo score for placebo following induction with golimumab and vedolizumab. These placebo arms differ to the one in UNIFI

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Figure 49. Median partial mayo score in the maintenance phase of UNIFI

Figure 50. Median partial mayo score in the maintenance phase of PURSUIT

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Figure 51. Mean partial mayo score in the maintenance phase of GEMINI I

A similar observation can also be made in Crohn’s Disease (CD), further suggesting that this is a clinically relevant result of treatment with ustekinumab. Plots of patients in clinical remission (defined as CDAI≤150) over time for ustekinumab (Figure 52) and adalimumab (Figure 53) trials in CD are provided below.  Ustekinumab graph: Few patients lose their remission status following induction with active treatment showing “carry-over effect” of induction therapy on maintenance  Adalimumab graph: Remission rates for placebo decrease following induction with adalimumab

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Figure 52. Proportion of patients in clinical remission in maintenance phase of UNITI

Figure 53. Proportion of patients in clinical remission in maintenance phase of CHARM

The observations made from the graphs of partial mayo score in UC trials are reflected in the outcome data for clinical response. Clinical response measured at the end of the maintenance phase for both non-biologic failure and biologic

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failure patients based on the re-randomised arms in UC studies are provided in Table 78. The re-randomised placebo response rates range between 26.6% to 50.6% in the non-biologic failure group and 15.8% to 38.6% in the biologic failure group across studies. In both patient populations the highest re-randomised placebo response rate was observed in the UNIFI trial for patients following ustekinumab induction therapy suggesting the highest carry-over effect, due to the longer durability of the treatment effect. This illustrates that efficacy in the maintenance placebo arms (following active induction treatment) is not comparable. In order to explore the placebo arm heterogeneity, a chi-square test was conducted based on the re-randomised arms to test for differences. Significant p- values were observed for both populations based on this test, demonstrating heterogeneity between the re-randomised placebo arms which can be explained by the evidence of a difference in carry-over effects. Therefore, the maintenance re-randomised placebo arms are heterogeneous and not appropriate common comparators for a NMA.

Table 78 Clinical response at the end of maintenance for induction responders to placebo (re-randomised arms) by population and chi-squared test

Trial Non-biologic failure Biologic failure

GEMINI I 26.6% 15.8%

OCTAVE Sustain 24.8% 14.6%

PURSUIT-M 31.2% N/A

UNIFI 50.6% 38.6%

Chi-squared test for heterogeneity

p-value <0.001 <0.001

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Appendix 6 NMA sensitivity analyses

A6.1 One-Year NMA results with ustekinumab 130mg induction Non-biologic failure patients: clinical response

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Table 79 NMA results for clinical response - non-biologic failure patients –one- year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr UST 130mg/kg - UST 90mg Q12W Treatment UST 130mg/kg - UST 90mg Q8W induction responders + UST Induction responders and 90mg Q8W induction non- induction non-responders vs. responders vs. 6.27 [3.12 ; 12.94] 5.41 [2.86 ; 10.50] PBO-PBO 100.00% 100.00% VDZ 300mg – VDZ 300mg Q8W induction 1.28 [0.41 ; 3.88] 1.10 [0.37 ; 3.21] responders + VDZ 66.56% 57.07% 300mg Q4W induction non-responders VDZ 300mg – VDZ 300mg Q4W Induction 1.51 [0.49 ; 4.61] 1.31 [0.44 ; 3.82] responders and induction 76.57% 68.69% non-responders IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.84 [0.74 ; 4.60] 1.59 [0.67 ; 3.79] responders and induction 90.43% 85.15% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.93 [0.78 ; 4.83] 1.67 [0.70 ; 3.98] responders and induction 92.11% 87.56% non-responders GOL 200/100mg – GOL 100mg E4W Induction 2.68 [1.14 ; 6.48] 2.32 [1.03 ; 5.32] responders and induction 98.81% 97.87% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.80 [1.19 ; 6.75] 2.42 [1.07 ; 5.55] responders and GOL 99.06% 98.35% 100mg E4W induction non-responders ADA 160/80/40mg – 3.43 [1.44 ; 8.28] 2.96 [1.31 ; 6.81] ADA 40mg EOW 99.74% 99.53% TOF 10mg - TOF 5mg induction responders + 1.80 [0.73 ; 4.46] 1.55 [0.66 ; 3.67] TOF 10mg induction 89.73% 84.14% non-responders TOF 10mg - TOF 10mg Induction responders 1.48 [0.59 ; 3.70] 1.28 [0.54 ; 3.04] and induction non- 80.04% 71.06% responders UST 130mg/kg - UST 90mg Q12W induction 1.16 [0.52 ; 2.58] responders + UST 90mg 63.92% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 0.86 [0.39 ; 1.92]

responders and induction 36.08% non-responders

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Table 80 NMA results for clinical response pooled - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 5.76 [3.36 ; 10.04] PBO-PBO 100.00% 1.27 [0.50 ; 3.17] VDZ 300mg – VDZ 300mg pooled 69.59% 1.73 [0.81 ; 3.67] IFX pooled – IFX pooled 92.28% 2.49 [1.26 ; 4.95] GOL 200/100mg – GOL pooled 99.58% 3.15 [1.50 ; 6.67] ADA 160/80/40mg – ADA 40mg EOW 99.88% 1.50 [0.70 ; 3.18] TOF 10mg - TOF pooled 85.40%

Non-biologic failure patients: clinical remission

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Table 81 NMA results for clinical remission - non-biologic failure patients – one- year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr UST 130mg/kg - UST 90mg Q12W Treatment UST 130mg/kg - UST 90mg Q8W induction responders + UST Induction responders and 90mg Q8W induction non- induction non-responders vs. responders vs. 4.60 [2.16 ; 9.86] 4.62 [2.28 ; 9.51] PBO-PBO 99.99% 100.00% VDZ 300mg – VDZ 300mg Q8W induction 1.35 [0.52 ; 3.51] 1.36 [0.54 ; 3.41] responders + VDZ 73.43% 74.53% 300mg Q4W induction non-responders VDZ 300mg – VDZ 300mg Q4W Induction 1.23 [0.39 ; 3.87] 1.23 [0.41 ; 3.77] responders and induction 63.70% 64.41% non-responders IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.69 [0.63 ; 4.46] 1.70 [0.66 ; 4.33] responders and induction 85.38% 86.50% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.71 [0.64 ; 4.51] 1.72 [0.67 ; 4.39] responders and induction 85.90% 87.03% non-responders GOL 200/100mg – GOL 100mg E4W Induction 1.97 [0.77 ; 5.08] 1.98 [0.80 ; 4.92] responders and induction 92.08% 93.05% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.45 [0.95 ; 6.42] 2.46 [0.99 ; 6.24] responders and GOL 96.77% 97.35% 100mg E4W induction non-responders ADA 160/80/40mg – 2.22 [0.87 ; 5.63] 2.23 [0.91 ; 5.45] ADA 40mg EOW 95.36% 96.10% TOF 10mg - TOF 5mg induction responders + 1.40 [0.52 ; 3.75] 1.41 [0.54 ; 3.65] TOF 10mg induction 74.75% 75.80% non-responders TOF 10mg - TOF 10mg Induction responders 1.32 [0.48 ; 3.54] 1.32 [0.50 ; 3.45] and induction non- 70.57% 71.55% responders UST 130g/kg - UST 90mg Q12W induction 1.00 [0.45 ; 2.20] responders + UST 90mg 49.60% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 1.00 [0.45 ; 2.23]

responders and induction 50.40% non-responders

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Table 82 NMA results for clinical remission pooled doses - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 4.62 [2.53 ; 8.67] PBO-PBO 100.00% 1.33 [0.59 ; 3.03] VDZ 300mg – VDZ 300mg pooled 75.23% 1.71 [0.75 ; 3.90] IFX pooled – IFX pooled 89.81% 2.17 [1.01 ; 4.75] GOL 200/100mg – GOL pooled 97.64% 2.19 [0.99 ; 4.91] ADA 160/80/40mg – ADA 40mg EOW 97.27% 1.37 [0.58 ; 3.19] TOF 10mg - TOF pooled 76.31%

Non-biologic failure patients: mucosal healing

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Table 83 NMA results for mucosal healing - non-biologic failure patients – one- year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr UST 130mg/kg - UST 90mg Q12W Treatment UST 130mg/kg - UST 90mg Q8W induction responders + UST Induction responders and 90mg Q8W induction non- induction non-responders vs. responders vs. 4.93 [2.42 ; 10.20] 4.35 [2.23 ; 8.56] Placebo – Placebo 100.00% 100.00% IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.30 [0.51 ; 3.28] 1.14 [0.47 ; 2.79] responders and induction 70.78% 61.43% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.23 [0.49 ; 3.11] 1.09 [0.44 ; 2.64] responders and induction 66.96% 57.15% non-responders GOL 200/100mg – GOL 100mg E4W Induction 2.44 [1.01 ; 5.95] 2.15 [0.93 ; 5.05] responders and induction 97.67% 96.29% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.55 [1.06 ; 6.24] 2.25 [0.97 ; 5.30] responders and GOL 98.17% 97.02% 100mg E4W induction non-responders ADA 160/80/40mg – 2.57 [1.05 ; 6.34] 2.27 [0.95 ; 5.38] ADA 40mg EOW 98.01% 96.81% TOF 10mg - TOF 5mg induction responders + 1.92 [0.76 ; 4.84] 1.69 [0.69 ; 4.12] TOF 10mg induction 91.50% 87.40% non-responders TOF 10mg - TOF 10mg Induction responders 1.54 [0.60 ; 3.90] 1.36 [0.55 ; 3.31] and induction non- 81.64% 74.62% responders UST 130mg/kg - UST 90mg Q12W induction 1.14 [0.52 ; 2.48] responders + UST 90mg 62.55% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 0.88 [0.40 ; 1.92]

responders and induction 37.45% non-responders 1.42 [0.54 ; 3.72] 1.25 [0.49 ; 3.16] VDZ 300mg – VDZ 76.22% 68.15% 300mg Q8W

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Table 84 NMA results for mucosal healing pooled doses - non-biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 4.59 [2.61 ; 8.25] PBO-PBO 100.00% 1.18 [0.54 ; 2.57] IFX pooled – IFX pooled 66.04% 2.30 [1.14 ; 4.72] GOL 200/100mg – GOL pooled 98.96% 2.40 [1.09 ; 5.31] ADA 160/80/40mg – ADA 40mg EOW 98.51% 1.60 [0.72 ; 3.52] TOF 10mg - TOF pooled 87.86% 1.32 [0.56 ; 3.13] VDZ 300mg – VDZ 300mg Q8W 73.99%

Biologic failure patients: clinical response Table 85 NMA results for clinical response - biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.29 [2.27 ; 8.22] 2.75 [1.30 ; 5.72] PBO-PBO 100.00% 99.56% VDZ 300mg – VDZ 1.56 [0.45 ; 5.34] 0.99 [0.27 ; 3.58] 300mg Q8W Induction 75.87% 49.55% responders VDZ 300mg – VDZ 1.67 [0.47 ; 5.94] 1.07 [0.29 ; 3.97] 300mg Q4W Induction 78.94% 53.91% responders ADA 160/80/40mg – 1.80 [0.61 ; 5.06] 1.15 [0.37 ; 3.43] ADA 40mg EOW 86.07% 59.64% TOF 10mg - TOF 5mg 1.47 [0.61 ; 3.49] 0.94 [0.36 ; 2.39] Induction responders 80.52% 44.68% TOF 10mg - TOF 10mg 1.07 [0.45 ; 2.51] 0.68 [0.26 ; 1.72] Induction responders 55.92% 21.06% UST130mg/kg - UST 1.56 [0.71 ; 3.50] 90mg Q12W Induction 86.62% responders UST 130mg/kg - UST 0.64 [0.29 ; 1.40] 90mg Q8W Induction 13.38% responders

Biologic failure patients: clinical remission

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Table 86 NMA results for clinical remission - biologic failure patients – one-year base case mimicking a treat-through approach and including UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 6mg/kg - UST 90mg Q8W UST 6mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.57 [1.88 ; 11.52] 2.91 [0.96 ; 8.37] PBO-PBO 99.96% 97.04% VDZ 300mg – VDZ 0.83 [0.20 ; 3.31] 0.52 [0.11 ; 2.31] 300mg Q8W Induction 39.64% 19.94% responders VDZ 300mg – VDZ 0.87 [0.17 ; 4.44] 0.55 [0.09 ; 3.07] 300mg Q4W Induction 43.46% 24.80% responders ADA 160/80/40mg – 1.12 [0.27 ; 4.40] 0.71 [0.15 ; 3.07] ADA 40mg EOW 56.50% 32.51% TOF 10mg - TOF 5mg 1.03 [0.28 ; 3.61] 0.65 [0.15 ; 2.55] Induction responders 51.94% 27.23% TOF 10mg - TOF 10mg 0.71 [0.20 ; 2.44] 0.45 [0.11 ; 1.72] Induction responders 29.50% 12.36% UST 6mg/kg - UST 90mg 1.57 [0.58 ; 4.67] Q12W Induction 80.88% responders UST 6mg/kg - UST 90mg 0.64 [0.21 ; 1.73] Q8W Induction 19.12% responders

A6.2 One-Year NMA results with ustekinumab 130mg induction - Asian patient populations Non-biologic failure patients: clinical response

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Table 87. NMA results for clinical response - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders and induction induction responders + UST 90mg non-responders vs. Q8W induction non-responders vs. 6.26 [3.13 ; 12.95] 5.42 [2.85 ; 10.50] PBO-PBO 100.00% 100.00% VDZ 300mg – VDZ 300mg Q8W induction 1.27 [0.41 ; 3.88] 1.10 [0.37 ; 3.21] responders + VDZ 300mg 66.44% 56.81% Q4W induction non- responders VDZ 300mg – VDZ 300mg Q4W Induction 1.51 [0.49 ; 4.61] 1.30 [0.44 ; 3.84] responders and induction 76.48% 68.45% non-responders IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.84 [0.74 ; 4.60] 1.59 [0.66 ; 3.80] responders and induction 90.50% 85.20% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.93 [0.78 ; 4.83] 1.67 [0.70 ; 3.98] responders and induction 92.21% 87.65% non-responders GOL 200/100mg – GOL 100mg E4W Induction 2.68 [1.14 ; 6.50] 2.32 [1.03 ; 5.31] responders and induction 98.81% 97.84% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.80 [1.19 ; 6.77] 2.42 [1.07 ; 5.56] responders and GOL 99.08% 98.33% 100mg E4W induction non-responders ADA 160/80/40mg – ADA 3.23 [1.46 ; 7.36] 2.80 [1.32 ; 6.01] 40mg EOW 99.80% 99.64% TOF 10mg - TOF 5mg induction responders + 1.79 [0.73 ; 4.47] 1.55 [0.65 ; 3.68] TOF 10mg induction non- 89.71% 84.01% responders TOF 10mg - TOF 10mg 1.48 [0.60 ; 3.70] 1.28 [0.54 ; 3.04] Induction responders and 79.99% 71.03% induction non-responders UST 130mg/kg - UST 90mg Q12W induction 1.16 [0.52 ; 2.59] responders + UST 90mg 63.96% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 0.87 [0.39 ; 1.92]

responders and induction 36.04% non-responders

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Table 88. NMA results for clinical response pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 5.75 [3.36 ; 10.03] PBO-PBO 100.00% 1.28 [0.50 ; 3.18] VDZ 300mg – VDZ 300mg pooled 69.62% 1.73 [0.81 ; 3.66] IFX pooled – IFX pooled 92.25% 2.49 [1.27 ; 4.95] GOL 200/100mg – GOL pooled 99.58% 2.97 [1.52 ; 5.85] ADA 160/80/40mg – ADA 40mg EOW 99.93% 1.50 [0.70 ; 3.19] TOF 10mg - TOF pooled 85.40%

Non-biologic failure patients: clinical remission

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Table 89. NMA results for clinical remission - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr UST 130mg/kg - UST 90mg Q12W Treatment UST 130mg/kg - UST 90mg Q8W induction responders + UST Induction responders and 90mg Q8W induction non- induction non-responders vs. responders vs. 4.59 [2.16 ; 9.83] 4.61 [2.28 ; 9.44] PBO-PBO 99.99% 100.00% VDZ 300mg – VDZ 300mg Q8W induction 1.14 [0.46 ; 2.83] 1.14 [0.48 ; 2.74] responders + VDZ 60.89% 61.68% 300mg Q4W induction non-responders VDZ 300mg – VDZ 300mg Q4W Induction 1.12 [0.36 ; 3.50] 1.12 [0.37 ; 3.40] responders and induction 57.51% 57.96% non-responders IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.69 [0.63 ; 4.45] 1.69 [0.66 ; 4.33] responders and induction 85.33% 86.43% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.71 [0.64 ; 4.51] 1.71 [0.67 ; 4.38] responders and induction 85.90% 87.02% non-responders GOL 200/100mg – GOL 100mg E4W Induction 1.96 [0.77 ; 5.07] 1.97 [0.80 ; 4.91] responders and induction 92.03% 93.04% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.45 [0.95 ; 6.40] 2.46 [0.99 ; 6.22] responders and GOL 96.74% 97.34% 100mg E4W induction non-responders ADA 160/80/40mg – 1.82 [0.76 ; 4.38] 1.83 [0.79 ; 4.24] ADA 40mg EOW 90.99% 92.15% TOF 10mg - TOF 5mg induction responders + 1.40 [0.52 ; 3.74] 1.41 [0.54 ; 3.63] TOF 10mg induction 74.67% 75.80% non-responders TOF 10mg - TOF 10mg Induction responders 1.32 [0.48 ; 3.53] 1.32 [0.50 ; 3.43] and induction non- 70.53% 71.47% responders UST 130g/kg - UST 90mg Q12W induction 1.00 [0.45 ; 2.20] responders + UST 90mg 49.65% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 1.00 [0.45 ; 2.23]

responders and induction 50.35% non-responders

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Table 90. NMA results for clinical remission pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 4.62 [2.53 ; 8.65] PBO-PBO 100.00% 1.14 [0.52 ; 2.51] VDZ 300mg – VDZ 300mg pooled 62.57% 1.70 [0.74 ; 3.89] IFX pooled – IFX pooled 89.70% 2.17 [1.01 ; 4.74] GOL 200/100mg – GOL pooled 97.64% 1.83 [0.86 ; 3.89] ADA 160/80/40mg – ADA 40mg EOW 94.19% 1.36 [0.58 ; 3.19] TOF 10mg - TOF pooled 76.22%

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Non-biologic failure patients: mucosal healing Table 91. NMA results for mucosal healing - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr UST 130mg/kg - UST 90mg Q12W Treatment UST 130mg/kg - UST 90mg Q8W induction responders + UST Induction responders and 90mg Q8W induction non- induction non-responders vs. responders vs. 4.93 [2.42 ; 10.18] 4.34 [2.23 ; 8.56] Placebo – Placebo 100.00% 100.00% IFX 5mg/kg – IFX 5mg/kg E8W Induction 1.30 [0.51 ; 3.28] 1.14 [0.46 ; 2.79] responders and induction 70.72% 61.30% non-responders IFX 10mg/kg – IFX 10mg/kg E8W Induction 1.23 [0.49 ; 3.12] 1.08 [0.44 ; 2.64] responders and induction 66.85% 56.95% non-responders GOL 200/100mg – GOL 100mg E4W Induction 2.43 [1.01 ; 5.93] 2.14 [0.92 ; 5.03] responders and induction 97.67% 96.22% non-responders GOL 200/100mg – GOL 50mg E4W Induction 2.55 [1.06 ; 6.23] 2.25 [0.96 ; 5.29] responders and GOL 98.16% 96.99% 100mg E4W induction non-responders ADA 160/80/40mg – 2.42 [1.06 ; 5.55] 2.13 [0.97 ; 4.70] ADA 40mg EOW 98.20% 97.05% TOF 10mg - TOF 5mg induction responders + 1.92 [0.75 ; 4.85] 1.69 [0.69 ; 4.11] TOF 10mg induction 91.41% 87.38% non-responders TOF 10mg - TOF 10mg Induction responders 1.53 [0.60 ; 3.89] 1.35 [0.55 ; 3.31] and induction non- 81.60% 74.46% responders UST 130mg/kg - UST 90mg Q12W induction 1.14 [0.52 ; 2.48] 1.00 [1.00 ; 1.00] responders + UST 90mg 62.52% 100.00% Q8W induction non- responders UST 130mg/kg - UST 90mg Q8W Induction 0.88 [0.40 ; 1.92]

responders and induction 37.48% non-responders VDZ 300mg – VDZ 1.33 [0.55 ; 3.26] 1.17 [0.50 ; 2.77] 300mg Q8W 73.66% 64.40%

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Table 92. NMA results for mucosal healing pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking a treat-through approach including Asian population and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 4.59 [2.61 ; 8.23] PBO-PBO 100.00% 1.18 [0.54 ; 2.57] IFX pooled – IFX pooled 66.11% 2.30 [1.14 ; 4.70] GOL 200/100mg – GOL pooled 98.97% 2.26 [1.12 ; 4.60] ADA 160/80/40mg – ADA 40mg EOW 98.86% 1.60 [0.72 ; 3.53] TOF 10mg - TOF pooled 87.80% 1.24 [0.57 ; 2.73] VDZ 300mg – VDZ 300mg Q8W 70.94%

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A6.3 One-Year NMA results with ustekinumab 130mg induction - approach mimicking response based design Non-biologic failure patients: clinical response Table 93. NMA results for clinical response - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.08 [2.00 ; 8.39] 3.52 [1.80 ; 6.94] PBO-PBO 99.99% 99.99% VDZ 300mg – VDZ 0.88 [0.25 ; 2.95] 0.76 [0.22 ; 2.47] 300mg Q8W Induction 41.88% 32.58% responders VDZ 300mg – VDZ 1.08 [0.31 ; 3.67] 0.94 [0.27 ; 3.10] 300mg Q4W Induction 54.99% 45.68% responders IFX 5mg/kg – IFX 1.00 [0.38 ; 2.56] 0.86 [0.34 ; 2.14] 5mg/kg E8W Induction 49.65% 37.27% responders IFX 10mg/kg – IFX 1.08 [0.41 ; 2.78] 0.93 [0.37 ; 2.32] 10mg/kg E8W Induction 56.26% 43.99% responders GOL 200/100mg – GOL 1.52 [0.61 ; 3.77] 1.31 [0.55 ; 3.15] 100mg E4W Induction 81.63% 72.70% responders GOL 200/100mg – GOL 1.59 [0.64 ; 3.96] 1.37 [0.57 ; 3.32] 50mg E4W Induction 84.26% 76.17% responders ADA 160/80/40mg – 1.93 [0.77 ; 4.81] 1.67 [0.69 ; 4.02] ADA 40mg EOW 92.04% 87.21% TOF 10mg - TOF 5mg 1.29 [0.50 ; 3.30] 1.12 [0.44 ; 2.75] Induction responders 70.27% 59.21% TOF 10mg - TOF 10mg 1.05 [0.40 ; 2.69] 0.91 [0.36 ; 2.25] Induction responders 54.10% 41.63% UST 130mg/kg - UST 1.16 [0.53 ; 2.54] 90mg Q12W Induction 64.38% responders UST 130mg/kg - UST 0.86 [0.39 ; 1.89] 90mg Q8W Induction 35.62% responders

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Table 94. NMA results for clinical response pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 3.76 [2.15 ; 6.73] PBO-PBO 100.00% 0.89 [0.30 ; 2.48] VDZ 300mg – VDZ 300mg pooled 41.67% 0.96 [0.42 ; 2.13] IFX pooled – IFX pooled 45.87% 1.42 [0.68 ; 2.96] GOL 200/100mg – GOL pooled 82.48% 1.78 [0.80 ; 3.99] ADA 160/80/40mg – ADA 40mg EOW 92.07% 1.08 [0.48 ; 2.40] TOF 10mg - TOF pooled 57.02%

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Non-biologic failure patients: clinical remission Table 95. NMA results for clinical remission - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg UST 130mg/kg - UST 90mg Q8W Induction responders vs. Q12W Induction responders vs. 3.53 [1.49 ; 8.31] 3.53 [1.58 ; 7.91] PBO-PBO 99.77% 99.88% VDZ 300mg – VDZ 0.84 [0.19 ; 3.42] 0.84 [0.20 ; 3.31] 300mg Q8W Induction 40.26% 40.01% responders VDZ 300mg – VDZ 0.77 [0.18 ; 3.11] 0.77 [0.18 ; 3.02] 300mg Q4W Induction 36.00% 35.69% responders IFX 5mg/kg – IFX 1.11 [0.37 ; 3.24] 1.11 [0.39 ; 3.12] 5mg/kg E8W Induction 57.75% 57.93% responders IFX 10mg/kg – IFX 1.17 [0.39 ; 3.40] 1.17 [0.41 ; 3.28] 10mg/kg E8W Induction 61.12% 61.52% responders GOL 200/100mg – GOL 1.22 [0.42 ; 3.49] 1.21 [0.44 ; 3.36] 100mg E4W Induction 64.17% 64.61% responders GOL 200/100mg – GOL 1.56 [0.53 ; 4.57] 1.56 [0.56 ; 4.42] 50mg E4W Induction 79.23% 80.16% responders ADA 160/80/40mg – 1.72 [0.57 ; 5.07] 1.72 [0.60 ; 4.88] ADA 40mg EOW 83.50% 84.48% TOF 10mg - TOF 5mg 1.14 [0.37 ; 3.41] 1.14 [0.38 ; 3.28] Induction responders 58.96% 59.29% TOF 10mg - TOF 10mg 1.06 [0.34 ; 3.18] 1.06 [0.36 ; 3.06] Induction responders 53.85% 54.00% UST 130mg/kg - UST 1.00 [0.41 ; 2.41] 90mg Q12W Induction 50.06% responders UST 130mg/kg - UST 1.00 [0.41 ; 2.44] 90mg Q8W Induction 49.94% responders

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Table 96. NMA results for clinical remission pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled 3.55 [1.80 ; 7.28] PBO-PBO 99.99% 0.80 [0.22 ; 2.64] VDZ 300mg – VDZ 300mg pooled 36.17% 1.15 [0.46 ; 2.88] IFX pooled – IFX pooled 61.53% 1.36 [0.57 ; 3.30] GOL 200/100mg – GOL pooled 75.54% 1.73 [0.66 ; 4.57] ADA 160/80/40mg – ADA 40mg EOW 86.83% 1.10 [0.42 ; 2.88] TOF 10mg - TOF pooled 58.01%

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Non-biologic failure patients: mucosal healing Table 97. NMA results for mucosal healing - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.26 [1.94 ; 9.39] 3.68 [1.74 ; 7.83] PBO-PBO 99.98% 99.97% VDZ 300mg – VDZ 0.86 [0.23 ; 3.13] 0.74 [0.20 ; 2.64] 300mg Q8W Induction 41.17% 32.49% responders VDZ 300mg – VDZ 0.83 [0.22 ; 3.00] 0.72 [0.19 ; 2.53] 300mg Q4W Induction 39.12% 30.49% responders IFX 5mg/kg – IFX 0.93 [0.33 ; 2.57] 0.80 [0.30 ; 2.16] 5mg/kg E8W Induction 44.77% 33.39% responders IFX 10mg/kg – IFX 0.88 [0.31 ; 2.42] 0.76 [0.28 ; 2.04] 10mg/kg E8W Induction 40.55% 29.42% responders GOL 200/100mg – GOL 1.56 [0.59 ; 4.12] 1.35 [0.53 ; 3.45] 100mg E4W Induction 81.78% 73.31% responders GOL 200/100mg – GOL 1.64 [0.63 ; 4.34] 1.42 [0.55 ; 3.64] 50mg E4W Induction 84.28% 76.66% responders ADA 160/80/40mg – 1.65 [0.60 ; 4.44] 1.42 [0.54 ; 3.72] ADA 40mg EOW 83.59% 76.03% TOF 10mg - TOF 5mg 1.67 [0.59 ; 4.62] 1.44 [0.52 ; 3.88] Induction responders 83.31% 75.98% TOF 10mg - TOF 10mg 1.30 [0.46 ; 3.61] 1.12 [0.41 ; 3.03] Induction responders 68.86% 58.60% UST 6mg/kg - UST 90mg 1.16 [0.50 ; 2.65] Q12W Induction 63.79% responders UST 6mg/kg - UST 90mg 0.86 [0.38 ; 1.98] Q8W Induction 36.21% responders

Table 98. NMA results for mucosal healing pooled doses - non-biologic failure patients – 1-year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Pr Treatment Ustekinumab 130mg/kg - Ustekinumab 90mg pooled

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3.94 [2.09 ; 7.65] PBO-PBO 100.00% 0.78 [0.24 ; 2.35] VDZ 300mg – VDZ 300mg pooled 33.26% 0.84 [0.35 ; 2.01] IFX pooled – IFX pooled 34.90% 1.47 [0.67 ; 3.28] GOL 200/100mg – GOL pooled 82.68% 1.52 [0.63 ; 3.70] ADA 160/80/40mg – ADA 40mg EOW 82.42% 1.37 [0.55 ; 3.31] TOF 10mg - TOF pooled 75.27%

Biologic failure patients: clinical response Table 99. NMA results for clinical response - biologic failure patients – 1- year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 3.22 [1.56 ; 6.70] 1.76 [0.69 ; 4.22] PBO-PBO 99.91% 88.58% VDZ 300mg – VDZ 1.41 [0.31 ; 6.50] 0.77 [0.15 ; 3.84] 300mg Q8W Induction 67.38% 37.42% responders VDZ 300mg – VDZ 1.60 [0.34 ; 7.91] 0.87 [0.16 ; 4.64] 300mg Q4W Induction 72.22% 43.22% responders ADA 160/80/40mg – 1.08 [0.30 ; 3.65] 0.59 [0.14 ; 2.20] ADA 40mg EOW 54.87% 21.72% TOF 10mg - TOF 5mg 1.22 [0.44 ; 3.33] 0.66 [0.20 ; 2.03] Induction responders 64.85% 24.00% TOF 10mg - TOF 10mg 0.82 [0.30 ; 2.20] 0.45 [0.14 ; 1.35] Induction responders 34.98% 7.84% UST 130mg/kg - UST 1.83 [0.74 ; 4.84] 1.00 [1.00 ; 1.00] 90mg Q12W Induction 90.23% 100.00% responders UST 130mg/kg - UST 0.55 [0.21 ; 1.35] 90mg Q8W Induction 9.77% responders

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Biologic failure patients: clinical remission Table 100. NMA results for clinical remission - biologic failure patients – 1- year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 130mg/kg - UST 90mg Q8W UST 130mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.96 [1.68 ; 16.06] 2.50 [0.57 ; 9.86] PBO-PBO 99.81% 89.41% VDZ 300mg – VDZ 0.69 [0.05 ; 6.07] 0.34 [0.02 ; 3.49] 300mg Q8W Induction 37.12% 18.53% responders VDZ 300mg – VDZ 0.74 [0.06 ; 6.93] 0.37 [0.02 ; 3.93] 300mg Q4W Induction 40.05% 20.76% responders ADA 160/80/40mg – 1.75 [0.30 ; 9.36] 0.87 [0.12 ; 5.52] ADA 40mg EOW 73.82% 44.13% TOF 10mg - TOF 5mg 1.03 [0.19 ; 5.07] 0.51 [0.07 ; 2.99] Induction responders 51.21% 23.22% TOF 10mg - TOF 10mg 0.62 [0.11 ; 2.96] 0.31 [0.04 ; 1.76] Induction responders 27.50% 9.39% UST 130mg/kg - UST 1.98 [0.58 ; 8.28] 90mg Q12W Induction 85.81% responders UST 130mg/kg - UST 0.50 [0.12 ; 1.72] 90mg Q8W Induction 14.19% responders

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Biologic failure patients: mucosal healing Table 101. NMA results for mucosal healing - biologic failure patients – 1- year – Sensitivity analysis mimicking response based design and UST 130mg induction Median OR [CrI] Median OR [CrI] Pr Pr Treatment UST 6mg/kg - UST 90mg Q8W UST 6mg/kg - UST 90mg Q12W Induction responders vs. Induction responders vs. 4.52 [1.71 ; 12.64] 2.38 [0.65 ; 7.94] PBO-PBO 99.88% 90.95% VDZ 300mg – VDZ 0.78 [0.09 ; 5.43] 0.40 [0.04 ; 3.18] 300mg Q8W Induction 40.14% 19.68% responders VDZ 300mg – VDZ 0.66 [0.07 ; 4.55] 0.34 [0.03 ; 2.67] 300mg Q4W Induction 34.09% 15.69% responders ADA 160/80/40mg – 1.57 [0.34 ; 6.83] 0.82 [0.14 ; 4.13] ADA 40mg EOW 72.44% 40.53% TOF 10mg - TOF 5mg 1.00 [0.23 ; 4.10] 0.52 [0.10 ; 2.49] Induction responders 50.12% 20.96% TOF 10mg - TOF 10mg 0.71 [0.16 ; 2.82] 0.37 [0.07 ; 1.72] Induction responders 31.26% 10.29% UST 6mg/kg - UST 90mg 1.90 [0.62 ; 6.80] Q12W Induction 86.54% responders UST 6mg/kg - UST 90mg 0.53 [0.15 ; 1.62] Q8W Induction 13.46% responders

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Appendix 7. Multiple imputation sensitivity analysis Methods The objective of this sensitivity analysis was to accounting for variation in the estimates used for imputing missing placebo response rates and assess the impact on the results. To do this, values used for the imputation were sampled multiple times to capture the uncertainty in the underlying data. NMAs were run for each of the sampled inputs and the results were combined to assess the impact. Clinical response in the non-biologic failure population was assessed in the sensitivity analysis. The following steps were undertaken:  Sample, multiple time, the values used for the imputation of placebo outcomes based on the underlying distribution of the data.  Include the sampled values in the re-calculated outcomes for placebo where the data were missing (i.e. where imputation were required), to construct datasets for the NMA for each sampled value.  Re-run the NMAs for each of the constructed datasets  Combine the posterior simulations for the treatment effects across the NMAs to attain a pooled posterior distribution for each treatment effect  Summarise the pooled posterior distribution to represent the treatment effects accounting for variation in the imputed placebo data and compare the results to the base case The imputed placebo data for clinical response comprised of the following for the non-biologic failure population:  Clinical response at the end of maintenance among induction responders receiving placebo o The value used for this imputation was based on a weighted average of data from the placebo arms of ACT I, PURSUIT and UNIFI  Clinical response at the end of maintenance among induction non- responders receiving placebo o The value used for this imputation was based on data from the placebo arm of ACT I The imputation values are summarised in Table 102 for both induction responders and induction non-responders. To reflect the uncertainty in the individual trials for the weighted average estimate corresponding to induction responders, a meta-analysis of the individual trial data was undertaken using the inverse weighting (I-W) approach. This was sampled from for the multiple imputation approach.

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Table 102 Clinical response at the end of maintenance for patients receiving placebo from UNIFI, ACT I and PURSUIT for non-biologic failure patients Patient group Study N n % SE LCI UCI

UNIFI 57 27 47.37% 0.066 34.5% 60.3%

ACT I 45 18 40.00% 0.073 25.7% 54.3%

Induction responders PURSUIT 103 37 35.92% 0.047 26.7% 45.1%

Weighted - - 40.00% 0.034 33.3% 46.7% average Meta- analysis - - 40.00% 0.038 32.6% 47.4% (I-W) Induction non- ACT I 76 6 7.89% - 1.83% 13.9% responders LCI: lower 95% confidence interval; N: total number of patients in the arm; n=number of patients with an event; UCI: upper 95% confidence interval, SE: standard error

An assumption regarding the underlying distribution of the imputed values needed to be made. Two distributions were considered to represent these values: 1. Beta distribution: beta distributions are a family of continuous probability distributions defined between the interval 0 and 1 parametrised by two shape parameters α and β 2. Normal distribution: normal distributions are a family of continuous law usually used to represents mean statistics due to the CLT property To determine an ‘optimal’ number of simulations required, the estimated sampled density was plotted against the density of the selected distributions to visually assess the fit for different numbers of samples. A close fit indicated that a sufficient numbers of samples had been taken. The following studies required the use of imputed values for placebo outcomes at the end of maintenance:  OCTAVE and GEMINI I for induction responders  UNIFI, PURSUIT and OCTAVE for induction non-responders The sampled values were then included in the re-calculation of placebo outcomes for these studies as described in Section 5.3.2.1. The values for induction responders and induction non-responders were sampled independently as these were based on different sets of studies. The NMAs were then re-run for each of the datasets produced based on the sampling and re-calculation of outcomes. Oct 2015 © EUnetHTA, 2015. Reproduction is authorised provided EUnetHTA is explicitly acknowledged 313

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Results Based on a visual inspection of the sampled density vs. the underlying distributions, a total of 100 simulations was considered to be an optimal number of samples to take considering the fit in addition to computation time. The plots of the sampled versus underlying distributions, for both beta and normal distributions, for each of the imputed values, are provided in Figure 54. Figure 54 Sampled versus underlying distribution of the imputed values for clinical response at the end of maintenance of induction responders and induction non responders (based on 100 samples) a) Induction responders – beta distribution b) Induction responders – normal distribution

c) Induction non-responders – beta d) Induction non-responders – normal distribution distribution

The NMAs were run 100 times based on the sampled datasets and the treatment effects based on the combined posterior distributions are summarised in Figure 55 alongside the results of the base case (referred to as ‘NMA’ in the plots).

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Figure 55 Results of the multiple imputation NMAs for each distribution (beta and normal) for ustekinumab 6mg/kg-ustekinumab pooled versus comparators

The results from the multiple imputation approach are shown to be similar to the results from the base case NMA both in terms of the median odds ratios and 95% credible intervals. The credible intervals only slightly increase using the multiple imputation approach. This demonstrates that the results of the NMA remain robust to the use of fixed values for the imputations. This can be explained due to the small uncertainty around the means of the imputed values. The beta distribution sampling is associated with larger variances compared to the base case NMA and the normal distribution samples. The normal distribution samples are associated with consistently higher odds ratios when compared to the other two approaches, with relatively unchanged credible intervals due to the low variance associated to the imputed endpoint data from the NMA.

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Appendix 8. Flow diagrams of the trials of the technology and comparators

A8.1 Flow diagrams of the trials of the technology by the pMAH

Figure 56. UNIFI Induction trial flow diagram

Abbreviations: IV: Intravenous

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Figure 57. UNIFI Maintenance trial flow diagram

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A8.2 Flow diagram of the comparator trials identified in the SLR

A8.3 Infliximab trial flow diagrams

Figure 58. Jiang 2015 flow diagram(150)

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Figure 59. Japic CTI060298 flow diagram (152)

Figure 60. ACT 1 flow diagram(153)

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Figure 61. ACT 2 flow diagram(153)

Other trials extracted for infliximab, such as Probert 2003 and Silva 2017,(149, 151) did not include a flow diagram in the publication.

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A8.4 Adalimumab trial flow diagrams

Figure 62. ULTRA 1 trial (Induction) flow diagram(148)

Left: Original protocol; Right: Amendment 3

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Figure 63. ULTRA 1 trial (Maintenance) flow diagram (Original Protocol)(148)

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Figure 64. ULTRA 1 trial (Maintenance) flow diagram (Amendment 3)(148)

Figure 65. ULTRA 2 trial flow diagram(149)

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Figure 66. NCT00853099 trial flow diagram(149)

Other publications which studied adalimumab, such as Silva 2017 and VARSITY did not include a patient flow diagram.

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A8.5 Golimumab trial patient flow diagrams

Figure 67. PURSUIT-M trial flow diagram(106)

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Figure 68. PURSUIT-J trial flow diagram(96)

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Figure 69. PURSUIT-SC trial flow diagram

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A8.6 Vedolizumab trial flow diagrams

Figure 70. NCT02039505 trial (Induction) flow diagram

Figure 71. NCT02039505 trial (Induction) flow diagram

Other publications which studied vedolizumab, such as GEMINI 1(158), Kobayashi 2018(159), NCT02039505(160), and VARSITY did not include a patient flow diagram.

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A8.7 Tofacitinib trial flow diagrams

The publications which studied tofacitinib, such as OCTAVE Induction 1 (OCTAVE-I1)(157), OCTAVE Induction 2 (OCTAVE-I2)(156), OCTAVE Sustain (OCTAVE-S)(157), and NCT00787202(156), did not include a patient flow diagram.

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Appendix 9. Results of the induction safety NMA Overall and serious adverse events A total of six studies were included in the analyses of overall and serious adverse events based on the induction phases of the trials. The input data from the six studies included are presented in Figure 72. The proportion of patients experiencing any adverse event in the active arms ranged from 37.5% in PURSUIT-SC (GOL 200/100mg) to 58.3% in ULTRA II (ADA 160/80mg). In the UNIFI trial, the proportion of patients experiencing any adverse event were 41.4% and 50.0% in the 130mg and 6mg/kg treatment arms, respectively. The proportion of in the placebo arms across all trials ranged from 38.2% in PURSUIT-SC to 66.3% in ULTRA II; UNIFI reported 48.0% in the placebo arm. The proportion of patients experiencing a serious adverse event in the active arms ranged from 2.7% in PURSUIT-SC (GOL 200/100mg) to 6.1% in ULTRA II (ADA 160/80mg). In the UNIFI trial, the proportions of patients experiencing a serious adverse event were 3.7% and 3.1% in the 130mg and 6mg/kg treatment arms, respectively. The proportions in the placebo arms across all trials ranged from 6.0% in OCTAVE I & II to 8.5% in ULTRA II; UNIFI reported 6.6% in the placebo arm. Figure 72. Data inputs for overall and serious adverse events (induction)

The NMA results are displayed in Table 103 for overall AEs and serious adverse events. Only fixed effects model results are presented, given there is only one

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study informing each pair of treatments in the networks and therefore no data to inform a random effects model. Compared to other treatments, ustekinumab 130mg was likely to be associated with a lower likelihood of overall adverse events (probability for ustekinumab to be better, Pr=73 to 99%) and ustekinumab 6mg/kg was associated with a similar likelihood compared to the other treatments. Both ustekinumab 130mg and 6mg/kg showed a lower likelihood of SAEs compared to placebo (Pr=95 to 98%) and similar likelihoods compared to other treatments. Table 103. Network meta analysis results for overall and serious adverse events (induction) Overall AE Serious AE Treatment Median OR[CrI] Median OR[CrI] Median OR[CrI] Median OR[CrI] Ustekinumab Ustekinumab 6 Ustekinumab Ustekinumab 6 130 mg vs. mg/kg vs 130 mg vs. mg/kg vs 0.77 [0.56; 1.05] 1.08 [0.79; 1.48] 0.55 [0.26; 1.12] 0.45 [0.2; 0.97] Placebo Pr=95% Pr=30% Pr=95% Pr=98% Vedolizumab 0.73 [0.45; 1.19] 1.03 [0.64; 1.68] 0.96 [0.31; 2.80] 0.80 [0.25; 2.37] 300mg Pr=90% Pr=45% Pr=53% Pr=66% Golimumab 0.88 [0.59; 1.33] 1.24 [0.83; 1.86] 0.90 [0.36; 2.21] 0.74 [0.28; 1.90] 200/100mg Pr=73% Pr=15% Pr=59% Pr=73% Adalimumab 0.79 [0.51; 1.23] 1.12 [0.72; 1.75] 1.29 [0.43; 3.96] 1.06 [0.34; 3.37] Pr=85% Pr=31% Pr=33% Pr=46% 160/80mg Ustekinumab 1.41 [1.04; 1.93] 0.83 [0.34; 1.98] Pr=1% Pr=67% 130mg Ustekinumab 0.71 [0.52; 0.97] 1.21 [0.51; 2.95] 6mg/kg Pr=99% Pr=33% 0.8 [0.52; 1.23] 1.13 [0.74; 1.74] 0.88 [0.32; 2.27] 0.73 [0.25; 1.95] Tofacitinib 10mg Pr=85% Pr=28% Pr=60% Pr=74% The statistic Pr stands for the Bayesian pairwise probability to perform better. Lower probabilities reflect better safety profile of ustekinumab versus comparators. Further details on the interpretation of Bayesian statistics are provided in Section 5.3.6.4.

Overall and serious infections A total of six studies were included in the analyses of overall and serious infections based on the induction phases of the trials. The input data from the six studies included are presented in Figure 73. The proportion of patients experiencing an infection in the active arms ranged from 11.8% in PURSUIT-SC (GOL 200/100mg) to 20.9% in OCTAVE I & II (TOF 10mg). In the UNIFI trial, the proportions of patients experiencing an infection were 15.9% and 15.3% in the 130mg and 6mg/kg treatment arms, respectively. The proportions in the placebo arms across all trials ranged from 12.1% in PURSUIT-SC to 20.7% in ULTRA II; UNIFI reported 15.0% in the placebo arm.

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The proportion of patients experiencing a serious infection in the active arms ranged from 0.0% in ULTRA I (ADA 160/80mg) to 1.2% in ULTRA II (ADA160/80mg). In the UNIFI trial, the proportion of patients experiencing a serious infection were 0.6% and 0.3% in the 130mg and 6mg/kg treatment arm, respectively. The proportion of serious infections in the placebo arm across all trials ranged from 0.0% in OCTAVE I & II to 2% in GEMINI I; UNIFI reported 1.3% in the placebo arm. Curiously, for all trials, except OCTAVE, there were more patients experiencing serious infections in the placebo arm compared to the active arms, complicating the interpretation of these results. For the ULTRA I and OCTAVE studies, there were zero counts in the adalimumab and placebo arms, respectively, which can lead to convergence issues for the NMAs. Therefore, as suggested in the Cochrane handbook, a common approach of adding 0.5 events to each of the treatment arms of the studies was taken for these two trials. Figure 73. Data inputs for overall and serious infections (induction)

The NMA results are displayed in Table 104 for overall infections and serious infections. Only fixed effects model results are presented, given there is only one study informing each pair of treatments in the networks and therefore no data to inform a random effects model.

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Table 104. NMA results for overall and serious infections Overall infections Serious infections Treatment Median OR[CrI] Median OR[CrI] Median OR[CrI] Median OR[CrI] Ustekinumab Ustekinumab 6 Ustekinumab Ustekinumab 6 130 mg vs. mg/kg vs 130 mg vs. mg/kg vs 1.07 [0.69; 1.64] 1.02 [0.66; 1.58] 0.45 [0.05; 2.49] 0.19 [0.01; 1.50] Placebo Pr=38% Pr=46% Pr=82% Pr=94% Vedolizumab 1.16 [0.58; 2.24] 1.11 [0.56; 2.15] 1.57 [0.11; 18.69] 0.63 [0.02; 10.41] 300mg Pr=34% Pr=38% Pr=36% Pr=62% Golimumab 1.14 [0.66; 1.95] 1.09 [0.63; 1.88] 0.88 [0.08; 8.55] 0.36 [0.01; 4.81] 200/100mg Pr=32% Pr=38% Pr=54% Pr=77% Adalimumab 1.11 [0.58; 2.09] 1.06 [0.55; 2.01] 3.88 [0.21; 155.9] 1.57 [0.03; 77.35] 160/80mg Pr=38% Pr=43% Pr=18% Pr=40% Ustekinumab 0.96 [0.63; 1.47] 0.41 [0.01; 5.36] 130mg Pr=58% Pr=75% Ustekinumab 1.05 [0.68; 1.60] 2.42 [0.19; 78.68] 6mg/kg Pr=42% Pr=25% 0.73 [0.40; 1.30] 0.7 [0.39; 1.25] 0.05 [0; 1.30] 0.02 [0; 0.70] Tofacitinib 10mg Pr=86% Pr=89% Pr=96% Pr=99%

Summary of results The results for ustekinumab versus all other treatments showed similarities in the rates of AEs for overall AEs, SAEs and overall infections, or lower likelihoods in some cases (tofacitinib was associated with a higher likelihood of infection compared to ustekinumab). The results for serious infections are uncertain due to low counts across arms and zero events in some of the arms. As discussed with EUNETHTA at the scoping meeting, rates of SAEs may be influenced by efficacy. Hence, their interpretation from a strictly safety perspective is limited. Limitations A number of limitations are associated with the analysis of safety data for network meta analysis. Network meta analyses of safety for maintenance phase were not feasible due to different definitions of the placebo safety population, comprising of non-homogeneous placebo arms with different efficacy and exposure could have result in spurious conclusions about safety, both for SAEs and infections. Differences exist in inclusion and exclusion criteria which may influence results on infections since they differ between trials (this applies to the induction results as well). Full details on the limitations can be found in the NMA report (Section 4.5). Another limitation faced in the analysis was associated with low counts of events or zero events for serious infections data (zero count in the placebo arm of OCTAVE I & II and in the adalimumab arm of ULTRA I), that led to wider credible intervals and considerable uncertainty in the results.

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Last, the induction dose is relatively higher than the maintenance dose for ustekinumab versus other comparators. As a result, the induction NMA results are unlikely to be reflective of the overall 1-year safety results.