Accepted Manuscript
Efficacy of Ustekinumab in Inducing Endoscopic Healing in Patients with Crohn’s Disease
Paul Rutgeerts, Christopher Gasink, Daphne Chan, Yinghua Lang, Paul Pollack, Jean-Frederic Colombel, Douglas C. Wolf, Douglas Jacobstein, Jewel Johanns, Philippe Szapary, Omoniyi J. Adedokun, Brian G. Feagan, William J. Sandborn
PII: S0016-5085(18)34655-9 DOI: 10.1053/j.gastro.2018.06.035 Reference: YGAST 61941
To appear in: Gastroenterology Accepted Date: 8 June 2018
Please cite this article as: Rutgeerts P, Gasink C, Chan D, Lang Y, Pollack P, Colombel J-F, Wolf DC, Jacobstein D, Johanns J, Szapary P, Adedokun OJ, Feagan BG, Sandborn WJ, Efficacy of Ustekinumab in Inducing Endoscopic Healing in Patients with Crohn’s Disease, Gastroenterology (2018), doi: 10.1053/j.gastro.2018.06.035.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Efficacy of Ustekinumab in Inducing Endoscopic Healing in Patients with Crohn’s Disease
Short title: Ustekinumab for Endoscopic Healing in Patients with Crohn’s Disease
Paul Rutgeerts,1 Christopher Gasink, 2 Daphne Chan, 2 Yinghua Lang, 2 Paul Pollack, 2 Jean-
Frederic Colombel, 3 Douglas C Wolf, 4 Douglas Jacobstein, 2 Jewel Johanns, 2 Philippe Szapary,2
Omoniyi J Adedokun, 2 Brian G Feagan, 5 William J Sandborn 6
1 University Hospital Gasthuisberg, Leuven, Belgium; 2Janssen Research &Development, LLC,
Spring House, PA; 3The Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of
Medicine at Mount Sinai, New York, NY; 4Atlanta Gastroenterology Associates, Atlanta, GA;
5Robarts Clinical Trials, Robarts Research Institute, Western University, London, Ontario,
Canada, 6 University of California San Diego, La Jolla, CA MANUSCRIPT Grant Support: This study was funded by Janssen Research & Development, LLC (Spring
House, PA). This study was designed and conducted by the UNITI-1, -2, and IM-UNITI Steering
Committee, Janssen Pharmaceutical Research & Development, LLC who jointly analyzed and interpreted the data, and contributed to the manuscript: Dr. Rutgeerts prepared the first draft of the manuscript, and the UNITI-1, -2, and IM-UNITI Steering Committee made the decision to publish.
Abbreviations used in this paper: CD, Crohn’s disease; CDAI, Crohn’s disease activity index;
CI, confidence ACCEPTED interval; CRP, C-reactive protein; IBD, inflammatory bowel disease; IV, intravenous; SC, subcutaneous; SES-CD, simplified endoscopic activity scores for Crohn’s disease; TNF, tumor necrosis factor; q8w, every 8 weeks; q12w, every 12 weeks
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Address for Correspondence: Paul Rutgeerts, MD, PhD Universitaire Ziekenhuizen Leuven, Inwendige Geneeskunde, UZ Gasthuisberg; Herestraat 49 – B-3000, Leuven, Belgium; Telephone: 32-16-344225; Fax: 32-16-344419; Email: [email protected] The corresponding author had full access to all of the data and takes full responsibility for the veracity of the data and data analysis.
Financial Disclosure/Potential Financial/Nonfinancial Conflicts of Interest: Author disclosures: Paul Rutgeerts has received consulting fees from AbbVie Laboratories, Janssen Research &
Development, LLC, Merck Research Laboratories, MerckSerono, UCB Pharma, Millenium/Takeda, Galapagos, Pfizer, Genentech/Hoff MANUSCRIPTman LaRoche, Neovacs, Bristol Myers Squibb, Robarts, Tillotts, Pfizer, and Falk Pharma; served as a Scientific Advisory Board member for AbbVie Laboratories, Janssen Research & Development, LLC, Merck Research
Laboratories, MerckSerono, UCB Pharma, Millenium/Takeda, Galapagos, Pfizer,
Genentech/Hoffman LaRoche, Neovacs, Bristol Myers Squibb, Robarts, Tillotts, Pfizer, and Falk
Pharma; received payments for lectures/speakers bureau from AbbVie Laboratories, Janssen
Research & Development, Merck Research Laboratories; and research grants from AbbVie
Laboratories, Janssen Research & Development, Merck Research Laboratories. ACCEPTED Jean-Frederic Colombel has received consulting fees from AbbVie, Amgen, Boehringer-
Ingelheim, Celgene Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen Research &
Development, LLC, Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres,
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Shire, Takeda, Theradiag, Theravance Biopharma; served as a Scientific Advisory Board member for AbbVie, Amgen, Boehringer-Ingelheim, Celgene Corporation, Celltrion, Enterome,
Ferring, Genentech, Janssen Research & Development, LLC, Medimmune, Merck & Co., Pfizer,
Protagonist, Second Genome, Seres, Shire, Takeda, Theradiag, Theravance Biopharma; received payments for lectures/speakers bureau from AbbVie, Amgen, Boehringer-Ingelheim, Celgene
Corporation, Celltrion, Enterome, Ferring, Genentech, Janssen Research & Development, LLC,
Medimmune, Merck & Co., Pfizer, Protagonist, Second Genome, Seres, Shire, Takeda,
Theradiag, Theravance Biopharma; and research grants from AbbVie, Takeda, Janssen Research
& Development, LLC; and stock options from Intestinal Biotech Development, Genfit.
Douglas C Wolf has received consulting fees from AbbVie, Celgene, Daiichi Sankyo, Janssen
Research & Development, LLC, Prometheus, Salix, Takeda and UCB Pharma; speaker fees from AbbVie, Daiichi Sankyo, Janssen Research & DevelopmMANUSCRIPTent, LLC, Takeda, and UCB Pharma; research support from AbbVie, Celgene, Genentech, Luitpold, Janssen Research &
Development, LLC, Prometheus Laboratories, Salix, Takeda, and UCB Pharma.
Brian G Feagan has received consulting fees from Abbott/AbbVie, Ablynx, Actogenix, Akebia
Therapeutics, Akros, Albireo Pharma, Allergan, Amgen, Applied Molecular Transport Inc.,
Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Avir Pharma, Baxter Healthcare Corp.,
Biogen Idec, Boehringer-Ingelheim, Bristol-Myers Squibb, Calypso Biotech, Celgene,
Elan/Biogen, EnGene, Ferring Pharma, Roche/Genentech, Galapagos, GiCare Pharma, Gilead,
Given Imaging ACCEPTED Inc., GSK, Inception IBD Inc, Ironwood Pharma, /Janssen Research &
Development, LLC, Kyowa Kakko Kirin Co Ltd., Lexicon, Lilly, Lycera BioTech, Merck,
Mesoblast Pharma, Millennium, Nektar, Nestles, Nextbiotix, Novonordisk, Pfizer, Prometheus
Therapeutics and Diagnostics, Progenity, Protagonist, Receptos, Roche/Genentech, Salix
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Pharma, Serano, Shire, Sigmoid Pharma, Synergy Pharma Inc., Takeda, Teva Pharma, TiGenix,
Tillotts, UCB Pharma, Vertex Pharma, Vivelix Pharma, VHsquared Ltd., Warner-Chilcott,
Wyeth, Zealand, Zyngenia; grant/research support from AbbVie Inc., Amgen Inc.,
AstraZeneca/MedImmune Ltd., Atlantic Pharmaceuticals Ltd., Boehringer-Ingelheim, Celgene
Corporation, Celltech, Genentech Inc/Hoffmann-La Roche Ltd., Gilead Sciences Inc.,
GlaxoSmithKline (GSK), Janssen Research & Development LLC., Pfizer Inc., Receptos
Inc./Celgene International, Sanofi, Santarus Inc., Takeda Development Center Americas Inc.,
Tillotts Pharma AG, UCB; served as a Scientific Advisory Board member for Abbott/AbbVie,
Allergan, Amgen, Astra Zeneca, Atlantic Pharma, Avaxia Biologics Inc., Boehringer-Ingelheim,
Bristol-Myers Squibb, Celgene, Centocor Inc., Elan/Biogen, Ferring, Galapagos,
Genentech/Roche, Janssen Research & Development, LLC, Merck, Nestles, Novartis,
Novonordisk, Pfizer, Prometheus Laboratories, Protagonist, Salix Pharma, Takeda, Teva, TiGenix, Tillotts Pharma AG, UCB Pharma; MANUSCRIPT has been on the Speakers Bureau for Abbott/AbbVie, Janssen Research & Development, LLC, Lilly, Takeda, Tillotts, and UCB
Pharma; and is a member of the Board of Directors for Robarts Clinical Trials Inc, Western
University, London.
William J Sandborn reports grants, personal fees and non-financial support from Abbvie; grants and personal fees from Prometheus Laboratories, grants and personal fees from AbbVie, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Takeda, grants and personal fees fromACCEPTED Atlantic Pharmaceuticals, grants and personal fees from Janssen Research & Development, LLC, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from Genentech, grants and personal fees from Nutrition Science Partners, personal fees from Kyowa Hakko Kirin, personal fees from Millennium Pharmaceuticals, personal fees from
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Celgene Cellular Therapeutics, personal fees from Santarus, personal fees from Salix
Pharmaceuticals, personal fees from Catabasis Pharmaceuticals, personal fees from Vertex
Pharmaceuticals, personal fees from Warner Chilcott, personal fees from Gilead Sciences, personal fees from Cosmo Pharmaceuticals, personal fees from Ferring Pharmaceuticals, personal fees from Sigmoid Biotechnologies, personal fees from Tillotts Pharma, personal fees from Am Pharma BV, personal fees from Dr. August Wolff, personal fees from Avaxia
Biologics, personal fees from Zyngenia, personal fees from Ironwood Pharmaceuticals, personal fees from Index Pharmaceuticals, personal fees from Nestle, personal fees from Lexicon
Pharmaceuticals, personal fees from UCB Pharma, personal fees from Orexigen, personal fees from Luitpold Pharmaceuticals, personal fees from Baxter Healthcare, personal fees from
Ferring Research Institute, personal fees from Amgen, personal fees from Novo Nordisk, personal fees from Mesoblast Inc., personal fees from Shire, personal fees from Ardelyx Inc., personal fees from Actavis, personal fees from Seat MANUSCRIPTtle Genetics, personal fees from MedImmune (AstraZeneca), personal fees from Actogenix NV, personal fees from Lipid Therapeutics Gmbh, personal fees from Eisai, personal fees from Qu Biologics, personal fees from Toray Industries
Inc., personal fees from Teva Pharmaceuticals, personal fees from Eli Lilly, personal fees from
Chiasma, personal fees from TiGenix, personal fees from Adherion Therapeutics, personal fees from Immune Pharmaceuticals, personal fees from Celgene, personal fees from Arena
Pharmaceuticals, personal fees from Ambrx Inc., personal fees from Akros Pharma, personal fees from Vascular Biogenics, personal fees from Theradiag, personal fees from Forward
Pharma, personalACCEPTED fees from Regeneron, personal fees from Galapagos, personal fees from Seres
Health, personal fees from Ritter Pharmaceuticals, personal fees from Theravance, personal fees
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P from Palatin, personal fees from Biogen, personal fees from Western University (owner of
Robarts Clinical Trials).
Christopher Gasink, Daphne Chan, Yinghua Lang, Paul Pollack, Douglas Jacobstein, Jewel
Johanns, Omoniyi J Adedokun , and Philippe Szapary are employees of Janssen Research &
Development, LLC.
Writing assistance: James P. Barrett, BS of Janssen Scientific Affairs, LLC. provided editorial and writing support.
Data analysis : Yinghua Lang , and Jewel Johanns (Janssen Research & Development, LLC) were involved in the design of the clinical studies and analyses of the data. Omoniyi J Adedokun
(Janssen Research & Development, LLC) was involved in the design of the pharmacokinetic portion of the study and pharmacokinetic data analysis and interpretation. MANUSCRIPT Author contributions: Paul Rutgeerts, Christopher Gasink, Daphne Chan, Yinghua Lang, Paul
Pollack, Jean-Frederic Colombel, Douglas C Wolf, Douglas Jacobstein, Jewel Johanns,
Philippe Szapary, Omoniyi J Adedokun, Brian G Feagan, and William J Sandborn were involved in the design and conduct of the clinical studies, contributing data for analyses, interpretation of data analyses; drafting and critical revision of the manuscript; and approval of the final manuscript for submission.
Some of the data displayed in this article were presented at the 2016 United European
GastroenterologyACCEPTED Week (oral presentation; Barcelona, Spain), 2016 American Academy of
Gastroenterology Annual meeting (poster; Las Vegas, NV), and Advanced in Inflammatory
Bowel Disease 2016 (poster; Orlando, FL).
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(Abstract Word count: 397, Max: 260; Manuscript: 7125, Max: 7000 including abstract, figure and table legends, and references)
MANUSCRIPT
ACCEPTED
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ABSTRACT (Word count: 397, Max: 260)
BACKGROUND & AIMS : We evaluated the ability of ustekinumab, a monoclonal antibody against the p40 subunit of interleukins 12 and 23, to induce endoscopic healing in patients with moderate to severe Crohn’s disease (CD).
METHODS : We performed an endoscopy sub-study of 334 patients with moderate to severe CD participating in 3 randomized, controlled, phase 3 studies to determine the safety and efficacy of ustekinumab induction and maintenance therapy. All patients underwent colonoscopy at baseline and week 8 of the induction studies and at week 44 of the maintenance study; all colonoscopies were assessed by a blinded central reader. During the induction studies, patients were randomly assigned to groups given intravenous ustekinumab (130 mg or 6 mg/kg) or placebo. At the baseline timepoint of the maintenance study (week 8 of the induction studies), patients with a clinical response to ustekinumab were randomlyMANUSCRIPT assigned to groups given subcutaneous ustekinumab (90 mg every 12 weeks or 8 weeks) or placebo. Additional maintenance analysis populations were patients who did not respond to ustekinumab or placebo during the induction studies, and patients who responded to placebo during the induction studies; we performed a post-hoc pooled analysis of randomly assigned and non-randomly assigned patients of the maintenance study. We analyzed data from patients with an ulcer in at least 1 segment at baseline of the induction studies. The primary endpoint was change in the simplified endoscopic activity score for CD (SES-CD), from baseline, at week 8. We also assessed the efficacy of maintenance therapy.ACCEPTED RESULTS : Patients given ustekinumab had a greater reduction in SES-CD from the induction baseline timepoint until week 8 than placebo (reduction of 2.8 in patients given ustekinumab vs a reduction of 0.7 points in patients given placebo; P=.012). Results were similar among patients
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P in different induction studies and patients given different doses of ustekinumab. At week 44, reductions in the SES-CD from the induction baseline were greater in patients given ustekinumab (for combined groups, a reduction of 2.5; P=.176 and for every 8 weeks, a reduction of 3.1; P=.107) than patients given placebo (reduction of 1.9 points). Maintenance results were similar for the larger pooled post-hoc analysis.
CONCLUSIONS : In an analysis of data from 3 trials of patients with moderate to severe CD, ustekinumab (intravenous induction and subcutaneous maintenance) reduces SES-CD, compared with placebo. We observed significant reductions in endoscopic disease activity at week 8 of induction therapy with ustekinumab.
(ClinicalTrials.gov numbers, NCT01369329, NCT01369342, and NCT01369355.)
Key words: UNITI, IM-UNITI, mucosal ulcers, clinically important improvement MANUSCRIPT
ACCEPTED
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INTRODUCTION
Traditional management of Crohn’s disease (CD) has used improvement of patient’s symptoms as the treatment goal. In recent years, endoscopy an objective measure of mucosal healing has been endorsed for this purpose. Although no randomized, controlled study has shown that treatment to an endoscopically-defined target is superior to a strategy solely based upon control of symptoms, extensive observational data indicate that endoscopic healing is associated with improved outcomes, including symptom-free remission, reduced surgeries, reduced hospitalizations, and improved quality of life.1-6 Similar associations also have been shown for clinical remission alone. 7,8 Nevertheless, it is reasonable to propose that evaluation of endoscopically defined disease activity in addition to symptom-based endpoints may provide greater assurance that changes in clinical symptoms reflect changes in the underlying inflammatory process of CD. MANUSCRIPT There is an unmet medical need exists for additional treatment options that can effectively reduce both clinical and endoscopic disease activity. Among currently approved therapies for CD, evidence of endoscopic improvement and endoscopic healing of the mucosa has been reported for tumor necrosis factor (TNF)-antagonists,9-13 and vedolizumab, a humanized, gut-specific
α4β7 integrin-antagonist.14 Results for anti-IL23p19 antibody risankizumab 15 and the Janus kinase 1-selective inhibitor, filgotinib 16 currently in development for CD have recently been reported. ACCEPTED Ustekinumab (STELARA ®, Janssen Biotech, Inc, Horsham, PA) is an anti-interleukin
(IL)12/23p40 monoclonal antibody that has been approved for treatment of psoriasis and psoriatic arthritis, and most recently for patients with moderately-to-severely active CD.17
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In this prospective substudy within the UNITI-1 and -2 induction, and IM-UNITI maintenance studies, we evaluated the efficacy of ustekinumab for the induction and maintenance of endoscopic healing in patients with moderately-to-severely active CD.
MATERIALS AND METHODS
Patients
This endoscopy substudy enrolled patients at participating sites within the Phase 3 development program for ustekinumab in CD, which consisted of three randomized, placebo-controlled studies that evaluated the safety and efficacy of ustekinumab induction (UNITI-1 and -2) and maintenance (IM-UNITI) therapy in patients with moderately to severely active CD (Figure 1).
Detailed methods and results for clinical efficacy and safety endpoints from these studies have been recently reported.17 All patients who completed MANUSCRIPT UNITI-1 or -2 were eligible to enroll in IM- UNITI, unless they met any exclusion criteria during the induction studies. There were no other inclusion or exclusion criteria specific to patient participation in this substudy. Institutional review boards or ethics committees at participating sites approved the protocol, and patients provided written informed consent to participate in the endoscopy substudy. All authors had access to the data, and reviewed and approved the final manuscript.
Study Design
Induction StudiesACCEPTED
Induction studies were 8 weeks in duration and identical in design, except for the study population (Figure 1). UNITI-1 included patients who had previously failed or were intolerant to
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≥1 TNF antagonist and UNITI-2 included patients who had previously failed conventional therapy (i.e., corticosteroids and immunosuppressives), had evidence of active inflammation
(elevated serum C-reactive protein concentration [CRP; >3 mg/L] or elevated fecal calprotectin
[>250 mg/kg]) or endoscopic evidence of active CD), and had not previously demonstrated inadequate response or intolerance to a TNF antagonist. Stable doses of protocol-specified concomitant CD medications were permitted. Endoscopic demonstration of active disease was not an inclusion criterion for UNITI-1 or -2, though it was required to be in the analysis population of this substudy.
Patients were randomly assigned (1:1:1 ratio) to receive a single IV (intravenous) administration of placebo or 1 of 2 induction doses of ustekinumab at week 0: Ustekinumab 130 mg or tiered ustekinumab dosing by weight approximating 6 mg/kg (i.e., 260 mg [weight ≤55 kg], 390 mg [weight >55 kg and ≤85 kg], and 520 mg [weight >85MANUSCRIPT kg]; hereafter referred to as ustekinumab 6 mg/kg). Randomization was not stratified by baseline endoscopic disease severity (i.e.,
Simplified Endoscopic Disease Severity Score for CD [SES-CD]).
Maintenance Study
Based on their response to induction therapy at week 8, patients entered the 44-week maintenance study, as either randomized or nonrandomized patients, to evaluate the efficacy of ustekinumab treatment through a total of approximately 1 year (52 weeks) of treatment (Figure 1). ACCEPTED
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Randomized population
Patients in clinical response to IV ustekinumab induction comprised the primary analysis population. At week 8 of induction (i.e., week 0 of maintenance), these patients were randomly assigned in a 1:1:1 ratio to receive subcutaneous (SC) therapy with either placebo, ustekinumab
90 mg q12w (with final dose at week 36), or ustekinumab 90 mg q8w (with final dose at week
40). Randomization was not stratified by baseline endoscopic disease severity (or SES-CD).
Beginning at week 8 of maintenance, randomized patients who subsequently lost response
(defined as a CDAI score ≥220 points and ≥100-point increase from the maintenance week 0
CDAI score) at any scheduled visit (up to week 32) could receive ustekinumab 90 mg SC q8w in a blinded fashion.
Nonrandomized population MANUSCRIPT Patients in clinical response to IV placebo induction received SC placebo throughout the maintenance study.
Patients not in clinical response to IV placebo induction received ustekinumab 130 mg IV at week 0 of maintenance, and if they achieved clinical response at week 8 of maintenance, received one dose of ustekinumab 90 mg SC and 90 mg SC q12w thereafter.
Patients not in clinical response to ustekinumab IV induction received ustekinumab 90 mg SC at week 0 of maintenance.ACCEPTED Those who achieved clinical response at week 8 of maintenance continued ustekinumab 90 mg SC q8w.
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Patients not in clinical response to IV induction therapy (ustekinumab or placebo) who received ustekinumab treatment at week 0 of maintenance and did not achieve clinical response at week 8 of maintenance discontinued from the study.
Endoscopic Assessments
Patients who agreed to participate in the endoscopic substudy underwent ileocolonoscopy at least eight days before or on the day of the following scheduled visits: week 0 of induction (i.e., induction baseline), week 8 of induction (i.e., maintenance baseline), and week 44 of maintenance.
Two measures were used for the evaluation of endoscopic disease activity and endoscopic healing of the mucosa after treatment: (1) SES-CD score and (2) detection of presence/absence of mucosal ulceration including aphthous lesions. MANUSCRIPT The SES-CD score is based on the evaluation of four endoscopic components (presence/size of ulcers, proportion of mucosal surface covered by ulcers, proportion of mucosal surface affected by any other lesions, and presence/type of narrowing/strictures) across five ileocolonic segments
(ileum, right colon, transverse colon, left colon, and rectum).18 Each endoscopic component is scored from 0 to 3 for each segment, resulting in a total score of up to 15 for each component, except for the narrowing component which can only attain a maximum total score of 11 because by definition, the presence of a narrowing that cannot be passed can be only observed once. In summary, an overallACCEPTED total SES-CD score is derived from the sum of all the component scores and can range from 0 to 56, with higher scores indicating more severe disease.
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A single reader (PR) at a central facility evaluated and scored all endoscopies. The reader was blinded to treatment group and visit throughout the induction and maintenance studies. The reader recorded whether the endoscopy was evaluable or not evaluable (due to absence of or poor-quality recording, poor bowel preparation, or other reasons). For each evaluable endoscopy, the reader scored each ileocolonic segment using the SES-CD, and recorded the presence or absence of mucosal ulcerations in each segment.
Analysis Populations, Endpoints and Statistical Evaluation
Analysis Populations
Patients were eligible for inclusion in the SES-CD endpoint analyses if they had a baseline SES-
CD score ≥3 regardless of involved gastrointestinal area(s); patients with ≥1 large ulcer in any segment at baseline would achieve this score. The stricturing/narrowing SES-CD component MANUSCRIPT score was excluded for analysis population eligibil ity, but not for actual scoring and analyses (i.e., patients included in analyses had at least one ulcer in at least one segment at induction baseline).
The analyses of endoscopic endpoints in induction were based on randomized patients who had eligible endoscopy data at baseline; in these analyses, the induction studies (UNITI-1 and
UNITI-2) were pooled and the induction ustekinumab treatment groups were combined for analysis. The key analyses of endoscopic endpoints in maintenance were based on randomized patients in maintenanceACCEPTED (i.e., patients who were in clinical response to ustekinumab induction) with eligible endoscopy data at baseline of induction; for these analyses, the ustekinumab maintenance treatment groups were combined.
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Endpoints
The primary endpoint in this endoscopy substudy was the change from baseline in the SES-CD score at week 8 of the induction study. Major secondary endpoints (in the order of testing) were the change from baseline in SES-CD at week 44, mucosal healing at week 44, and mucosal healing at week 8 of induction. Other secondary endpoints assessed at week 8 of induction and week 44 of maintenance included endoscopic response, endoscopic remission, and clinically- meaningful endoscopic improvement.
Mucosal healing was defined as the complete absence of any mucosal ulcerations among patients who presented with ulceration in at least one ileocolonic segment at induction baseline.
Endoscopic response was defined as a reduction of ≥50% from induction baseline in SES-CD score. 19 Endoscopic remission was defined as a total SES-CD score of ≤2. 20 Clinically- meaningful endoscopic improvement was defined MANUSCRIPT as a reduction from induction baseline in SES-CD score ≥3 points (Supplemental Appendix).
Data Handling and sensitivity analyses
The SES-CD score at induction baseline was calculated based on all segments scored at baseline.
The SES-CD score at post-baseline visits was calculated based on segments scored at baseline.
For endpoints other than mucosal healing, segments that were scored only at post-baseline visits were excluded since it was not possible to evaluate the changes in disease activity in a segment without a baselineACCEPTED evaluation of the same segment. For missing segments at post-baseline visits, the baseline score for each of the missing segments was carried forward.
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The determination of ulceration status at baseline and post-baseline visits was based on the presence or absence of ulceration across all segments evaluated at that visit. Any segments that were not evaluated or missing post-baseline had their ulceration status at baseline carried forward, if available. For mucosal healing, segments that were evaluated only at post-baseline visits were included, i.e., if ulcerations were present, mucosal healing was not attained at that visit.
Treatment failure rules (i.e., CD-related surgery due to lack of efficacy, initiated protocol- specified prohibited medication, or loss of response (for maintenance endpoints) were applied for all endoscopy endpoints and were applied separately in induction and maintenance. If a treatment failure event occurred during induction, baseline values for SES-CD score (at week 0 of induction) were assigned for week 8 of induction, regardless of the observed data, and patients were considered as not achieving mucosal healing MANUSCRIPTat week 8 of induction. If a treatment failure event occurred during maintenance, baseline values for SES-CD score (at week 0 of induction) were assigned for week 44 of maintenance, regardless of the observed data, and patients were considered as not achieving mucosal healing at week 44 of maintenance. Treatment failure rules overrode other data handling rules.
Sensitivity analyses were performed for the primary endpoint and major secondary endpoints.
The first sensitivity analysis (observed data) was based on all observed segments scored at the designated analysis time point and excluded patients who had no data for any segment. In the second sensitivityACCEPTED analysis (observed cases), patients who had a segment that was evaluated at baseline and was missing post-baseline were excluded. In both analyses, patients with missing data who had a treatment failure were still included in the analysis; their baseline data was carried forward.
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Subgroups by study populations (i.e., by induction study, UNITI-1 and UNITI-2), and by induction dose subgroups (i.e., by ustekinumab 130 mg, ustekinumab 6 mg/kg) were evaluated for primary endpoint and secondary endpoints at week 8 of induction. Subgroups by maintenance dose (ustekinumab 90 mg SC q12w, ustekinumab 90 mg SC q8w) were evaluated for the first and second major secondary endpoints at week 44 of maintenance.
Pharmacokinetics
Serum ustekinumab concentrations were evaluated at weeks 0, 3, 6, and 8 during induction and every 4 weeks during maintenance using a validated electrochemiluminescent immunoassay
(ECLIA) method on the Meso Scale Discovery (MSD ®) platform (Gaithersburg, MD, USA). The lowest quantifiable concentration in a sample for the ECLIA method using the MSD platform was 0.1688 g/mL. Endoscopic endpoints were summarized by ustekinumab concentration quartiles using descriptive statistics. MANUSCRIPT
Statistical Evaluation
This endoscopy substudy was a separate experiment within the Phase 3 CD development program for ustekinumab. As such, control of Type 1 error was applied independently in this substudy from the Type 1 error control for the clinical efficacy endpoints in the individual induction and maintenance studies. A hierarchical multiple testing procedure was used to control the overall Type 1 error rate at the 0.05 level of significance over the primary endpoint (change from baseline in ACCEPTEDthe SES-CD score at Week 8) and the first, second, and third major secondary endpoints (change from baseline in the SES-CD score at Week 44, mucosal healing at Week 44, mucosal healing at Week 8, respectively). That is, the first major secondary endpoint will be tested only if the primary endpoint is positive, and the subsequent endpoint(s) will be tested only
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P if the preceding endpoint in the hierarchy is positive. P-values for the subsequent endpoint(s) are considered nominal and should be interpreted with caution when the preceding endpoint(s) in the hierarchy are not positive. Analyses of other secondary endpoints were to proceed regardless of the results of the hierarchical multiple-testing procedure; P-values for other secondary endpoints are considered nominal and should be interpreted with caution.
The analyses of endoscopic endpoints described were prespecified, except as noted. All testing was performed at the 0.05 (2-sided) level of significance. The change from baseline in the SES-
CD score at the designated analysis timepoint was compared between ustekinumab and placebo using an analysis of covariance on the van der Waerden normal scores, with baseline SES-CD score and induction study as covariates. The χ2 test was used to compare the proportion of patients achieving mucosal healing, clinically-meaningful endoscopic improvement, endoscopic remission, and endoscopic response between the combMANUSCRIPTined ustekinumab treatment group and the placebo group. In the case of rare events, Fisher’s exact test was used for treatment comparisons.
Statistical Power
It was estimated that approximately 210 randomized patients from the induction studies would have eligible endoscopy data at baseline. Assuming a mean (±Standard Deviation) change in
SES-CD score of -2 (±7) at week 8 in the placebo group and -5 (±7) in the ustekinumab group,
70 patients in the placebo group and 140 patients in the ustekinumab treatment groups would yield an overall powerACCEPTED of approximately 80%, at a significance level of 0.05 (2-sided).
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Post-hoc Analyses
To explore the long-term effects of ustekinumab maintenance on endoscopic disease activity in the full study population (i.e., all patients who participated in the maintenance phase of the endoscopy substudy), the randomized and nonrandomized maintenance populations were pooled.
The intention of these exploratory analyses was to further investigate the relative long-term effectiveness of the two ustekinumab SC maintenance regimens, compared with placebo
(Supplemental Appendix).
RESULTS
Patient disposition, demographics, and clinical characteristics.
Induction Population
Overall, 334 of 1409 patients in the induction stud MANUSCRIPTies were enrolled in the endoscopy substudy, including 142 patients in UNITI-1 and 192 patients in UNITI-2. Of 334 enrolled patients, 289
(86.5%) had evaluable endoscopy data (i.e., at least one ileocolonic segment evaluated) at baseline, and 252 of 289 (87.2%) had ulcerations or met baseline SES-CD eligibility criteria
(SES-CD ≥3) (Figure 1). Baseline characteristics for the substudy induction population are summarized in Table 1. Disease characteristics (including endoscopic disease severity) among randomized patients with baseline ulcerations or eligible SES-CD score in UNITI-1 were consistent with those for a TNF-antagonist refractory population with longer disease duration and higher CRP ACCEPTEDconcentrations and disease activity than that seen for a conventional CD therapy population (UNITI-2) (Table 1). Because of the substudy nature and SES-CD score not being a stratification variable for the induction studies, some differences in baseline disease
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P characteristics were observed between patients who received ustekinumab and those received placebo (Table 1). The endoscopy substudy population was representative of a study population derived from the combined induction study populations (Table S1).
Baseline ulceration status had perfect concordance with eligibility based on baseline SES-CD score, demonstrating compatibility in the two approaches to define a minimum threshold for baseline endoscopic disease activity. The proportion of evaluable patients with baseline ulcerations (also meeting baseline SES-CD eligibility criteria) was similar between the induction studies (89.9% in UNITI-1 and 85.3% in UNITI-2). A slightly greater proportion of these patients in the analysis population came from UNITI-2 versus UNITI-1 (57.5% and 42.5%, respectively).
Overall, 9.5% of the patients did not enter IM-UNITI, including 12.4% and 7.7% in the placebo and ustekinumab groups, respectively. Proportions MANUSCRIPT of patients that terminated induction study participation before week 8 were 3.1% and 0.6% in the placebo and ustekinumab groups, respectively (Figure 1).
Medication history was generally comparable between patients randomized to placebo or ustekinumab induction with few differences. Overall, the proportions of patients receiving each class of CD medication in the endoscopy substudy induction population were similar to those of the overall induction study population (Table S2).
Randomized MaintenanceACCEPTED Population
Overall, 70 randomized patients (placebo, N=32; ustekinumab, N=63) participated in the endoscopy substudy. The demographic and baseline disease characteristics, concomitant
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P medication use, and endoscopic severity of patients in the endoscopy substudy randomized maintenance population were similar to those of the overall randomized maintenance population
Table S3).
Overall, 11.4% (8/70) of patients terminated study participation before week 44 of maintenance
(Figure 1). A greater proportion of patients in the ustekinumab group (7/46, 15.2%) terminated study participation (primarily due to withdrawal of consent; 5/46, 10.9%), compared with the placebo group (1/24, 4.2%; lost-to-follow-up; Figure 1).
Disease characteristics of patients randomized to placebo or ustekinumab maintenance were generally comparable (Table 1). A few differences were observed in relation to baseline disease activity between the two treatment groups. A greater proportion of patients in the placebo group compared with the ustekinumab group were reported by the investigator to have current strictures (12.5%, vs 2.2%), or current or past strMANUSCRIPTictures (50.0% vs. 15.2%). However, these differences were not borne out endoscopically at baseline. Median CRP was lower in the placebo group compared with the ustekinumab group at baseline (9.8 vs 12.7 mg/L, respectively).
Nonrandomized Maintenance Population
Characteristics of the endoscopy substudy nonrandomized maintenance population at induction baseline were generally similar across treatment groups and similar overall to those of the endoscopy substudy randomized population, including baseline demographics, CD characteristics, concomitantACCEPTED CD medications, and TNF antagonist medication history (Table S3). The only notable difference between randomized and nonrandomized patients at induction baseline was the median CRP level, which was higher in the randomized patients (median, 9.1 to
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14.5 mg/L in each treatment group) than in the nonrandomized patients (median, 3.8 to 6.8 m/L in each treatment group).
Endoscopic disease activity and severity at induction baseline was generally similar across treatment groups and was generally comparable to those for the endoscopy substudy induction population. Compared with the endoscopy substudy randomized maintenance population, slightly lower endoscopic disease activity was observed in the nonrandomized population (Table
S3).
SES-CD Change from Baseline at Week 8
The mean change from baseline in SES-CD score at week 8 of induction (primary endpoint) was significantly greater in the ustekinumab group than in the placebo group (-2.8 vs. -0.7, P =.012;
Figure 2A; Table S4) with an absolute difference (i.e., treatment effect) between groups of 2.1 MANUSCRIPT points (95% confidence interval, 0.8 to 3.4). Sensi tivity analyses were used to examine the possible influence of missing data; observed data and observed cases analyses were consistent with the results of the primary endpoint analysis (Tables S5 and S6)
Within each induction study, mean change from baseline in SES-CD at week 8 of induction was greater in the ustekinumab group than in the placebo group (Figures 2B and 2C; Tables S7), consistent with the integrated induction analysis. Additionally, the treatment effect between the ustekinumab group and the placebo group in each induction study (2.5 points in UNITI-1 and 1.7 points in UNITI-2)ACCEPTED was also consistent with that observed for the integrated induction population (2.1 points; Figure 2A).
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The treatment effect between the ustekinumab group and the placebo group for each induction dose group (1.8 points for ustekinumab 130 mg vs placebo and 2.3 points for ustekinumab 6 mg/kg vs placebo) were also consistent with that observed in the integrated induction population
(2.1 points for both ustekinumab doses vs placebo). A numerically greater treatment effect versus placebo was observed for ustekinumab 6 mg/kg compared with the ustekinumab 130 mg induction dose (Figures 2B, 2C; Tables S4, S7).
There was no apparent difference in the change in SES-CD scores from baseline in the evaluable study population when summarized by segment (Table S8).
Other Secondary Endpoints at Week 8
For the results presented below, statements of significance are based on nominal p-values without adjustment for multiplicity. MANUSCRIPT Clinically-meaningful endoscopic improvement (i.e., reduction ≥3 points in SES-CD from baseline) at week 8 of induction was achieved in a significantly greater proportion of patients in the ustekinumab group (47.7%) than in the placebo group (29.9%; P=.005; Figure 3A). Results were consistent within each induction study (Figure 3B) and each induction dose (Tables S9).
The proportion of patients with endoscopic response at week 8 of induction was numerically greater in the ustekinumab group than in the placebo group (20.6% vs 13.4%, P=.144;
Figure 3A). In the subgroup analysis by induction study, a significantly greater proportion of patients in the ustekinumabACCEPTED group than in the placebo group achieved endoscopic response in
UNITI-1 (13.6% vs 0.0%, P=.012). However, the treatment difference was minimal between the ustekinumab and placebo groups in UNITI-2 (25.8% vs 23.2%, P=.844) (Figure 3A). In the
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P subgroup analysis by induction dose, a numerically greater proportion of patients achieved endoscopic response with each ustekinumab induction dose compared with placebo
(ustekinumab 6 mg/kg: 21.7%; ustekinumab 130 mg: 19.4%; placebo: 13.4%; P=.142 and
P=.289, respectively), which was consistent with the pattern observed in the integrated induction population (Table S10).
The proportion of patients with endoscopic remission at week 8 of induction was numerically greater in the ustekinumab group than in the placebo group (7.7% vs 4.1%, P=.252; Figure 3A).
A numerically greater proportion of patients achieved endoscopic remission with ustekinumab compared with placebo in each induction study (UNITI-1: 3.0% vs 0.0%, P=.523; UNITI-2:
11.2% vs 7.1%, P=.567; Figure 3B), which was consistent with the pattern observed in the integrated induction population. Likewise, a numerically greater proportion of patients achieved endoscopic remission with each ustekinumab MANUSCRIPT induction dose compared with placebo (ustekinumab 6 mg/kg: 8.4%; ustekinumab 130 mg: 6.9%; placebo: 4.1%%; P=.350 and P=.498, respectively), which was consistent with the pattern observed in the integrated induction population (Table S11).
A numerically greater proportion of patients achieved mucosal healing at week 8 (third major secondary endpoint) in the ustekinumab group (9.0%) than in the placebo group (4.1%, P =.141;
Figure 3A. Similar results were observed in the subgroup analyses by induction study and by dose (Figure 3B and Table S12); and in the sensitivity analyses. (Tables S13 and S14). ACCEPTED SES-CD Change from Baseline at Week 44
The change from baseline in the SES-CD score at week 44 of maintenance (first major secondary endpoint) in the randomized maintenance group numerically favored the ustekinumab group
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(Figure 4; Table S15). Maintenance of the initial improvements during induction was observed in both placebo (1.9) and combined ustekinumab treatment group (2.5, P=.176) at maintenance week 44 but the treatment difference between groups was not statistically significant. Since this endpoint was not statistically significant, P-values for all other major secondary endpoints are also not statistically significant; nominal p-values are provided for these endpoints. Consistent results were observed in the prespecified sensitivity analyses. In the subgroup analysis by dose group the 90 mg q8w (3.1, P=.107) dose showed the greatest change from baseline and was numerically greater than that seen with the 90 mg q12w dose (1.6 for 90 mg, P=.637) and placebo (Figure 4; Table S15).
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Other Secondary Endpoints at Week 44
For the results presented below, statements of significance are based on nominal p-values without adjustment for multiplicity.
The proportion of patients with clinically-meaningful endoscopic improvement at week 44 of maintenance was also numerically greater in the ustekinumab group (37.0%) than in the placebo group (25.0%, P=.312; Figure 4). When analyzed by maintenance dose, the proportion of patients who achieved clinically-meaningful endoscopic improvement at week 44 of maintenance was numerically greater among those randomized to ustekinumab 90 mg SC q8w maintenance (41.4% vs 25.0% for placebo; P=.210) and among those patients who were randomized to ustekinumab 90 mg SC q12w maintenance (29.4% vs 25.0% for placebo;
P=.734), compared with induction responders who were randomized to placebo maintenance (Figure 4). MANUSCRIPT The rate of endoscopic response at week 44 of maintenance was numerically greater in the ustekinumab group (17.4%) than in the placebo group (4.2%, P=.151; Figure 4). In a post-hoc subgroup analysis by maintenance dose, the rate of endoscopic response at week 44 of maintenance was significantly greater for ustekinumab 90 mg SC q8w (24.1%, P=.043), and numerically greater for ustekinumab 90 mg SC q12w (5.9%, P=.802), than for placebo (4.2%).
The potential dose effect observed was consistent with those described earlier in the subgroup analyses by maintenanceACCEPTED dose for the first major secondary endpoint at week 44 of maintenance. The rate of endoscopic remission at week 44 of maintenance was numerically greater in the ustekinumab group than in the placebo group (10.9% vs 4.2%; P=.656).
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The proportion of patients with mucosal healing at week 44 (major secondary endpoint) was numerically greater in the ustekinumab group (13.0%) than in the placebo group (4.2%, P=.409;
Figure 4). Similar results were observed in the sensitivity analyses. When evaluated by maintenance dose, mucosal healing rates were numerically greater for patients randomized to maintenance ustekinumab 90 mg SC q8w (17.2%), or 90 mg SC q12w (5.9%), than for placebo
(4.2%; P=.204 and P=1.00, respectively). Consistent with the observations made in the subgroup analysis by maintenance dose for the change from baseline in SES-CD at week 44 of maintenance, a potential dose effect was observed (Figure 4).
Other analyzed maintenance populations
Among nonrandomized patients who received ustekinumab (N=75; ustekinumab 90 mg SC q12w, or ustekinumab 90 mg SC q8w) in the maintenance study, the mean change from induction baseline in SES-CD score was -1.1 at week MANUSCRIPT 0 of maintenance and -3.1 at week 44 of maintenance. Among placebo induction responders who continued placebo in maintenance
(N=27), mean change from baseline in SES-CD score was -2.5 at week 0 of maintenance and -
2.0 at week 44 of maintenance (Table S16).
In the post hoc pooled randomized and nonrandomized maintenance population, the change in
SES-CD from induction baseline and rates of all the endpoints were greater in the ustekinumab treated patients compared to placebo, with greater effects being consistently seen with the 90 mg q8w dose (SupplementalACCEPTED Appendix).
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Pharmacokinetics and endoscopic disease activity
There was no association between serum ustekinumab concentration quartiles and clinically- meaningful endoscopic improvement at week 8 (Figure S1). At week 44, there was a trend for increasing rates of endoscopic response and remission with serum ustekinumab concentration quartiles (Figure S2A, S2B). Patients with serum ustekinumab concentrations <0.5 µg/mL had substantially lower endoscopic response or remission.
DISCUSSION
Ustekinumab, an anti-IL12/23p40 monoclonal antibody, is effective induction and maintenance therapy for patients with moderately-to-severely active CD. Given the growing recognition of the importance of endoscopic outcomes in CD,21 the Ustekinumab Endoscopy Substudy was prospectively designed as a dedicated evaluation of the efficacy of ustekinumab on endoscopic
MANUSCRIPT17 healing based upon aggregate data from the three Ph ase 3 clinical trials.
Ustekinumab was effective for reducing endoscopic inflammation as evidenced by a significant reduction from baseline in the SES-CD score compared with placebo at week 8 of induction (the pre-specified primary endpoint of the study). Furthermore, the decrease in SES-CD from baseline was consistently greater for each ustekinumab induction dose compared with placebo, with the approved 6 mg/kg dose achieving both statistical significance in comparison with placebo, and a numerically greater treatment effect compared with the lower 130 mg dose. When each induction studyACCEPTED was evaluated separately, the decrease from baseline in SES-CD was also consistently greater in the ustekinumab groups compared with the placebo group, achieving statistical significance in patients who had failed TNF antagonist therapy (UNITI-1). Although a relatively higher absolute change in SES-CD from baseline was seen in ustekinumab-treated
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P patients who had failed conventional therapy (UNITI-2), 70% of whom were naïve to TNF- antagonists, a substantial improvement was also observed in patients assigned to placebo.
Minimal data are available regarding the magnitude and drivers of endoscopic placebo response.
Notably patients enrolled in the UNITI-2 trial had active inflammation confirmed by biomarkers
(CRP or fecal calprotectin) or by endoscopy (in case of normal biomarkers). Our finding that a substantial placebo effect exists requires confirmation and additional evaluation directed to identifying determinants have also been observed for two other biologics.16,22 Among the endoscopy patient cohort (baseline SES-CD >2), treatment with eldelumab 10 and 20 mg/kg resulted in greater mean reductions from baseline in SES-CD compared with placebo, -3.44, -
3.57, and -0.94, respectively. 19 In the FITZROY study, mucosal healing at week 10 was not different between the combined filgotinib 100- and 200-mg group (5 [4%]) and placebo (1 [2%];
P=.82).16 Further investigations are needed to confirm the role of endoscopic endpoints in clinical trials. MANUSCRIPT
All endpoints in the randomized maintenance population were numerically superior in ustekinumab-treated patients though the small number of patients in this population preclude definitive conclusions. Nonetheless, all endpoints showed a consistent trend towards superiority of ustekinumab treatment over placebo, more pronounced in the 90mg q8w group. Since the randomized maintenance population was an enriched responder population (i.e., all patients were responders to ustekinumab induction based on clinical signs and symptoms), it is possible that patients randomizedACCEPTED to placebo maintenance were still benefiting from ustekinumab induction and a later evaluation time point would be necessary to detect the optimal separation between ustekinumab and placebo for endoscopic endpoints. The long duration of efficacy after IV ustekinumab is likely due to its long serum half-life of approximately 3 weeks and an additional
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P period where drug effect remained. This observation would support the use of a treat-through design for assessment of endoscopic response. Additionally, because the endoscopy study was performed as a substudy of the larger IM-UNITI program, inclusion and randomization criteria were based on clinical criteria and entry into the endoscopy study was not a requirement for participation in the larger study. Hence, the number of patients who were randomized into the maintenance population was small and contributed to the lack of statistical power. In addition to the overall small sample size of the randomized group, the sample size for the ustekinumab 90 mg SC q8w group (n=29) was larger as that for the 90 mg SC q12w group (n=17).
To examine if the trends seen in the randomized population would be consistent when including all available patients in the substudy, an exploratory post-hoc analysis was conducted in the pooled randomized and nonrandomized maintenance population. The results of these post-hoc analyses were consistent with those of the primaryMANUSCRIPT randomized maintenance population, demonstrating greater benefit in ustekinumab-treate d patients, particularly with 90 mg q8w.
Differences between ustekinumab and placebo were statistically significant for clinically- meaningful change in SES-CD and for endoscopic response, and showed clear numeric differences for mucosal healing and change from baseline in SES-CD, especially for the 90 mg q8w regimen, where p-values were <.05 for endoscopic response and ≥3point change (Figure 4).
The totality of the evidence therefore supports the efficacy of ustekinumab in maintaining endoscopic healing; however, future studies, preferably employing a treat-through design are needed to confirmACCEPTED this.
Despite growing appreciation of the importance of endoscopic healing in CD, there are few published papers describing the efficacy of biologics on endoscopic healing in randomized- controlled studies. Comparison of these trial results are hampered by the different scoring
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P systems used (Crohn’s Disease Endoscopic Index Score vs. SES-CD), different endpoint definitions, and the timing of endpoint evaluations. The single endpoint shared by these studies has been that of complete mucosal healing, which all studies have defined as the absence of mucosal ulceration in patients who presented with ulcerations at baseline.
Rates of mucosal healing (absence of ulcerations) with induction have ranged from 5% at week
10 for certolizumab 10 in the MUSIC study to 31% for infliximab 10 at week 10in 10/32 as- observed ACCENT I week-2 responders. The adalimumab EXTEND mucosal healing primary endpoint allowed apthous ulcerations to be present and 27% (nonresponder imputation) at week
12,12 but a subsequent report examining an SES-CD <2 cutoff that ensures absence of ulcerations showed 20% at week 12 for adalimumab 13 (vs 12% with placebo). Recent data with vedolizumab show absence of ulcerations in 15% of patients at week 26, but with a large difference seen between TNF-antagonist-naïve and TNF-antagonist-faiMANUSCRIPTlure populations, (24% and 7%, respectively). 14 Recent Phase 2 studies also have shown low rates of complete mucosal healing with risankizumab 15 (7% at week 12) and filgotinib 16 (4% at week 10). It is unclear if the difference in the rate of mucosal healing observed with ustekinumab (9% at week 8 for pooled ustekinumab and 9.6% for 6 mg/kg IV dose vs. 4.1% for placebo) compared to some of the TNF antagonist studies is related to the earlier timing of the endpoint (week 8), the method of analysis
(nonresponders imputation for ustekinumab, as-observed for infliximab), differences in study populations and changes in enrolled populations over time (eg, more treatment-refractory patients), or a mechanisticACCEPTED difference between TNF antagonists and agents acting through other pathways. Although notable differences seen in the placebo groups across these studies (and populations within this study) also confirm the importance of these differences in patient populations. Collective data and experience suggest that study population (treatment history
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P and/or disease duration, in particular) are major determinants of the ability to attain mucosal healing, rendering comparisons of endoscopic endpoints across study populations difficult, if not impossible. Thus, comparative effectiveness studies (ideally head-to-head) will be needed to identify and clarify relative efficacy differences among agents.
The strengths of this study included the use of centrally-read endoscopies and a rigorous pre- specified statistical analysis plan. However, some limitations exist including relatively small sample size of the randomized maintenance population in comparison with the overall population. The analysis of the pooled populations from IM-UNITI was carried out to address this deficiency; however, these results should be interpreted with caution given the post hoc nature of this analysis. Voluntary enrollment of patients in this substudy could possibly have resulted in participation bias. Additionally, there were between-group differences in baseline endoscopic disease severity which were due in part MANUSCRIPTto the substudy design and SES-CD score not being a stratification variable. Future trials stud ying endoscopic change should take baseline endoscopic criteria into consideration.
Differences in the assessment tools and definition of endpoints make comparison of results difficult, and standardization of the approach to assessing mucosal healing will be important in future studies. The high placebo rates observed in conventional-failure patients who were naïve to biologic treatments will need to be evaluated further and may impact assumptions regarding the use of endoscopic assessment in the lowering of placebo rates in clinical trials and caution against dismissingACCEPTED the importance of a placebo comparator as has been suggested elsewhere.23
Both the planned and post-hoc evaluations of maintenance endoscopic endpoints provided evidence supporting a potential beneficial role for ustekinumab maintenance to achieve long-
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P term control of mucosal inflammation. Future trials with treat-through design would better delineate long-term endoscopic improvement.
In conclusion, this study provides evidence for the efficacy of ustekinumab for inducing endoscopic healing. Results were robust across sensitivity analyses and consistent across subgroup analyses by induction study and dose. Ustekinumab therefore joins the TNF antagonists currently approved for the treatment of CD in demonstrating the ability to reduce endoscopic inflammation.
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TABLES AND FIGURES
Table 1: Demography, disease characteristics, and endoscopic information at baseline of
induction; randomized patients with eligible SES-CD score or ulcerations at induction
baseline
Figure 1: Endoscopy Study Flow Diagram
Figure 2: Change from baseline in SES-CD Score at week 8 (pooled ustekinumab vs.
placebo) (A), by induction dose (B), by induction study (C); randomized patients
with eligible SES-CD score at baseline of the induction studies
Key: IV, intravenous; SES-CD, Simplified Endoscopic Disease Severity Score for Crohn’s disease; TNF, tumor necrosis factor.
Figure 3: Endoscopy assessments at week 8 (pooled ustekinumab vs. placebo) (A), by induction study (B); randomized MANUSCRIPT patients with eligible SES-CD score or ulcerations at induction baseline
Figure 4: Change from induction baseline in SES-CD Score at week 44 by maintenance
dose; randomized patients with eligible SES-CD scores or ulcerations at induction
baseline
Key: SES-CD, Simplified Endoscopic Disease Severity Score for Crohn’s disease; q8w, every 8 weeks; q12w, every 12 weeks.
Note: Combined ustekinumab group includes the ustekinumab 90 mg q8w and 90 mg q12w groups. ACCEPTED
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Table 1: Demography, disease characteristics, and endoscopic information at baseline of induction; randomized patients with eligible SES-CD score or ulcerations at induction baseline UNITI-1 and UNITI-2 IM-UNITI Placebo Ustekinumab a Total Placebo Ustekinumab b Total (N=97) (N=155) (N=252) (N=24) (N=46) (N=70) Age (years) Mean (SD) 40.2 (13.58) 40.3 (12.91) 40.3 (13.15) 40.5 (12.10) 39.5 (14.45) 39.8 (13.61) Sex, n (%) Male 51 (52.6) 68 (43.9) 119 (47.2) 12 (50.0) 17 (37.0) 29 (41.4) Crohn’s Disease duration (yrs) Mean (SD) 10.7 (9.00) 11.4 (9.79 11.1 (9.48) 12.1 (10.31) 10.0 (9.81) 10.7 (9.96) Median 8.59 8.25 8.46 8.62 6.30 7.61 IQ range (4.18; 13.03) (3.13; 17.40) (3.81; 15.83) (5.11; 15.88) (2.35; 13.81) (2.94; 14.38) Involved GI areas, n (%) N 97 154 251 24 46 70 Ileum only 19 (19.6) 29 (18.8) 48 (19.1) 2 (8.3) 6 (13.0) 8 (11.4) Colon only 21 (21.6) 24 (15.6) 45 (17.9) 5 (20.8) 8 (17.4) 13 (18.6) Ileum and colon 57 (58.8) 101 (65.6) 158 (62.9) 17 (70.8) 32 (69.6) 49 (70.0) Proximal gastrointestinal tract 14 (14.4) 21 (13.6) 35 (13.9) 4 (16.7) 8 (17.4) 12 (17.1) Perianal 26 (26.8) 54 (35.1) 80 (31.9) 8 (33.3) 12 (26.1) 20 (28.6) CDAI score Mean (SD) 306.7 (61.38) 318.8 (62.11) 314.1 (61.98) 329.2 (64.52) 317.7 (64.83) 321.6 (64.49) Median 301.0 318.0 311.0 340.5 315.0 324.0 IQ range (253.0; 347.0) (267.0; 359.0) (260.5; 357.0) (268.0; 368.0) (260.0; 360.0) (261.0; 360.0) CRP (mg/L) Median 7.5 9.3 8.4 9.8 12.7 11.3 IQ range (1.8; 22.7) (4.4; 23.6) (3.4; 23.2) (3.0; 18.6) (5.6; 30.4) (4.9; 27.4) Crohn's Disease Complications, n (%) N 97 155 MANUSCRIPT252 24 46 70 Intra-abdominal abscess (Past) 7 (7.2) 20 (12.9) 27 (10.7) 3 (12.5) 5 (10.9) 8 (11.4) Sinus tracts / perforation c 7 (7.2) 13 (8.4) 20 (7.9) 3 (12.5) 2 (4.3) 5 (7.1) Fistula c 33 (34.0) 58 (37.4) 91 (36.1) 9 (37.5) 13 (28.3) 22 (31.4) Current 13 (13.4) 25 (16.1) 38 (15.1) 3 (12.5) 4 (8.7) 7 (10.0) Bowel Stricturing c 34 (35.1) 57 (36.8) 91 (36.1) 12 (50.0) 7 (15.2) 19 (27.1) Current 6 (6.2) 12 (7.7) 18 (7.1) 3 (12.5) 1 (2.2) 4 (5.7) Patients with evaluable endoscopy data d 104 185 289 29 54 83 Patients with eligible SES- CD score or ulcerations, e n (%) 97 (93.3) 155 (83.8) 252 (87.2) 24 (82.8) 46 (85.2) 70 (84.3) SES-CD, Mean (SD) 12.3 (7.61) 14.2 (8.10) 13.5 (7.95) 15.7 (8.31) 15.2 (8.16) 15.4 (8.15) Median (IQ range) 12.0 (6.0; 16.0) 12.0 (8.0; 19.0) 12.0 (8.0; 18.0) 12.5 (9.5; 24.0) 14.0 (8.0; 22.0) 13.0 (9.0; 23.0) Endoscopic disease severity (total SES-CD score at baseline of induction), n (%) Mild (3-6) 27 (27.8) 23 (14.8) 50 (19.8) 2 (8.3) 7 (15.2) 9 (12.9) Moderate (7 -16) 46 (47.4) 80 (51.6) 126 (50.0) 13 (54.2) 20 (43.5) 33 (47.1) Severe (>16) ACCEPTED24 (24.7) 52 (33.5) 76 (30.2) 9 (37.5) 19 (41.3) 28 (40.0) ACCEPTED MANUSCRIPT
Table 1: Demography, disease characteristics, and endoscopic information at baseline of induction; randomized patients with eligible SES-CD score or ulcerations at induction baseline UNITI-1 and UNITI-2 IM-UNITI Placebo Ustekinumab a Total Placebo Ustekinumab b Total (N=97) (N=155) (N=252) (N=24) (N=46) (N=70)
Patients who had ulcerations at baseline of induction, n (%); score, mean (SD) 97 155 252 24 46 70 Ileum only 27 (27.8) 42 (27.1) 69 (27.4) 5 (20.8) 10 (21.7) 15 (21.4) Ileum SES -CD score 5.9 (2.81) 6.9 (2.51) 6.5 (2.66) ND ND ND Colon only f 36 (37.1) 48 (31.0) 84 (33.3) 7 (29.2) 17 (37.0) 24 (34.3) Colon f SES-CD score 12.5 (6.72) 15.7 (7.36) 14.3 (7.23) ND ND ND Ileum and colon f 34 (35.1) 65 (41.9) 99 (39.3) 12 (50.0) 19 (41.3) 31 (44.3) Ileum SES -CD score 6.1 (2.39) 6.2 (2.32) 6.1 (2.33) ND ND ND Colon f SES-CD score 11.2 (7.37) 11.5 (7.91) 11.4 (7.70) ND ND ND a. Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b. Ustekinumab 90 mg SC q12w and 90mg SC q8w combined. c. Current or past. d. Patients with at least 1 segment that could be evaluated at baseline. e. Baseline SES-CD score ≥3, excluding the contribution of the narrowing component score. f. Colon includes right colon, transverse colon, left colon, and rectum.
Key: CDAI, Crohn’s disease; CRP, C-reactive protein; GI, gastrointestinal; IQ, interquartile; ND, not done SES-CD, Simplified Endoscopic Disease Severity Score for Crohn’s disease; SD, standard deviation; q8w, every 8 weeks; q12w, every 12 weeks.
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UNITI-1 and UNITI-2
Placebo Ustekinumab combineda,b (n = 380) (n = 912) Enrolled in substudy Enrolled in substudy (n = 124) (n = 210) Evaluable datac Evaluable datac (n = 104) (n = 185) Evaluable SES-CDd or ulceration Evaluable SES-CDd or ulceration (n = 97) (n = 155)
Completed Week 8 Completed Week 8 (n = 97) (n = 155)
IM-UNITI 1281 Enrolled
397 Randomized 884 Nonrandomized
Placebo SC Ustekinumab combinede IV Placebo Responders: IV Nonresponders: (n = 133) (n = 264) Placebo SC Ustekinumab SC Enrolled in substudy Enrolled in substudy (n = 120) (n = 746) (n = 32) (n = 63) Enrolled in substudy Enrolled in substudy Evaluable datac Evaluable datac (n = 37) (n = 93) (n = 29) (n = 54) MANUSCRIPTEvaluable datac Evaluable datac Evaluable SES-CDd Evaluable SES-CDc (n = 31) (n = 82) or ulceration or ulceration Evaluable SES-CDd Evaluable SES-CDd (n = 24) (n = 46) or ulceration or ulceration (n = 27) (n = 75)
Discontinued study Discontinued study before Week 44 before Week 44 Discontinued study Discontinued study (n = 1) (n = 7) before Week 44 before Week 44 (n = 1) (n = 3) 1 LFU 1 LFU 0 W/D consent 5 W/D consent 0 LFU 0 LFU 0 Death 0 Death 1 W/D consent 3 W/D consent 0 Other 1 Other 0 Death 0 Death 0 Other 0 Other
Completed through Completed through Completed through Completed through Week 44 Week 44 Week 44 Week 44 (n = 23) (n = 39) (n = 26) (n = 72) ACCEPTED 1776_v2 a. Ustekinumab doses approximating 6 mg/kg: 260 mg (weight ≤ 55 kg), 390 mg (weight > 55 kg and ≤ 85 kg), 520 mg (weight > 85 kg). b. Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. c. Patients with at least 1 segment that could be evaluated at baseline. d. Baseline SES-CD score ≥ 3, excluding the contribution of the narrowing component score. e. Ustekinumab 90 mg SC q12w and 90 mg SC q8w combined. Key: SES-CD Simpli ed Endoscopic Severity Score for Crohn’s disease; SC, subcutaneous; IV, intravenous; LFU – lost to follow-up; W/D – withdrew; q8w, every 8 weeks; q12w, every 12 weeks ACCEPTED MANUSCRIPT
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ACCEPTED ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
SUPPLEMENTAL APPENDIX
Analysis to Evaluate the Meaningfulness of Endoscopic Improvement (Reduction from Baseline in SES-
CD Score of ≥3) ...... 3
Figure S1. Clinically-meaningful endoscopic improvement ( ≥3-point reduction in SES-CD score) at
Week 8 by average trough serum ustekinumab concentration quartile at Week 8; treated
patients with eligible SES-CD scores at induction baseline ...... 5
Figure S2: Endoscopic response (50% decrease in SES-CD) (A) or endoscopic remission (SES-CD <2)
(B) at Week 44 by serum ustekinumab concentration quartile at Week 44; all endoscopy
substudy patients with SES-CD >3 at induction baseline ...... 6
Table S1: Baseline demographics and disease characteristics ...... 7
Table S2: Concomitant medications for Crohn's disease and TNF-antagonist history at baseline;
randomized patients with eligible SES-CD score or ulcerations at induction baseline ...... 8 MANUSCRIPT Table S3: Baseline demographics and disease characteristics; patients enrolled in the IM-UNITI study
with eligible SES-CD score or ulcerations at induction baseline ...... 9
Table S4: Change from baseline in SES-CD score at Week 8 by dose; randomized patients with
eligible SES-CD score at induction baseline ...... 13
Table S5: Change from baseline in SES-CD score at Week 8 (sensitivity analysis: observed data);
randomized patients with eligible SES-CD score at induction baseline ...... 14
Table S6: ChangeACCEPTED from baseline in SES-CD score at Week 8 (sensitivity analysis: observed case); randomized patients with eligible SES-CD score at induction baseline ...... 15
Table S7: Change from baseline in SES-CD score at Week 8 by individual study; randomized patients
with eligible SES-CD score at induction baseline ...... 16
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Table S8: Change from baseline in SES-CD score at Week 8 by segment; randomized patients who
were treated with ustekinumab in induction and had eligible SES-CD score at induction
baseline ...... 17
Table S9: Number of patients with at least 3 points reduction from baseline in SES-CD score at Week
8 by induction dose; randomized patients with eligible SES-CD score at induction baseline18
Table S10: Number of patients in endoscopic response at Week 8 by induction dose; randomized
patients with eligible SES-CD score at induction baseline ...... 19
Table S11: Number of patients in endoscopic remission at Week 8 by induction dose; randomized
patients with eligible SES-CD score at induction baseline ...... 20
Table S12: Number of patients in mucosal healing at Week 8 by induction dose; randomized patients
with ulcerations at induction baseline ...... 21 MANUSCRIPT Table S13: Number of patients in mucosal healing at Week 8 (sensitivity analysis: observed data);
randomized patients with ulcerations at induction baseline ...... 22
Table S14: Number of patients in mucosal healing at Week 8 (sensitivity analysis: observed case);
randomized patients with ulcerations at induction baseline ...... 23
Table S15: Change from baseline of the induction study in SES-CD score at Week 44; randomized
patients in IM-UNITI with eligible SES-CD score at baseline of induction ...... 24
Table S16: EndoscopyACCEPTED assessments in IM-UNITI; nonrandomized patients with eligible SES-CD score or ulceration at induction baseline ...... 25
Post hoc Pooled Randomized Nonrandomized Maintenance Population ...... 26
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SUPPLEMENTAL APPENDIX
Analysis to Evaluate the Meaningfulness of Endoscopic Improvement (Reduction from Baseline in
SES-CD Score of ≥3)
A majority of studies that have incorporated SES-CD scoring have defined the severity of endoscopic disease activity as follows: total scores of 0-2 for remission, 3-6 for mild inflammation, 7-16 for moderate inflammation, and >16 for severe inflammation. 1 A reduction from induction baseline in SES-CD score of
≥3 points was therefore anticipated to lead to the achievement of endoscopic disease improvement by 1 category in many patients, and therefore would likely meet the threshold for a clinically meaningful improvement. For example, patients with a baseline SES-CD score of 7 that improved to a post-treatment
SES-CD score of 4 would have improved from moderate to mild endoscopic disease severity. Likewise, patients improving from 3-6 to ≤3 would have improvements towards mild disease/ remission. The
Authors acknowledge that a clinically meaningful improvement in patients who have severe endoscopic disease activity (>16) at baseline would be more challenging to quantify based on this logic. MANUSCRIPT A post-hoc exploratory analysis was conducted to evaluate the meaningfulness of improvement in SES-
CD by ≥3 points by examining the relationship between this endoscopic endpoint change in clinical outcomes such as clinical response (reduction from induction baseline in the CDAI score of ≥100 points), clinical remission (a CDAI score of <150 points), IBDQ response (increase from induction baseline ≥16 points), normalized CRP among patients with abnormal CRP at induction baseline, and normalized fecal calprotectin among patients with abnormal fecal calprotectin at induction baseline (Table).
1. Moskovitz DN, DapernoACCEPTED M, Van Assche GA, et al. Defining and validating cut-off’s for the Simple Endoscopic Score for Crohn’s Disease. Gastroenterology 2007;132(4Suppl2):S1097
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SUPPLEMENTAL APPENDIX
Table: Summary of Clinical Endpoints at Designated Analysis Timepoints by Change from Baseline in SES-CD Score at Week 8; Randomized Patients with Eligible SES-CD Score at Baseline from the UNITI-1 and UNITI-2 Studies Analysis set: Randomized patients with eligible SES-CD <3 ≥3 score at baseline from the UNITI -1 and UNITI -2 studies response a 149 103 Week 8 N 149 103 Patients in clinical response, n (%) d,e 50 (33.6) 52 (50.5) Patients in clinical remission, n (%) d,e 29 (19.5) 32 (31.1) N 148 102 Patients with ≥ 16 -point improvement in IBDQ, n (%) d,f 67 (45.3) 66 (64.7) No. of patients with abnormal CRP ( ≥3 mg/L) at baseline 111 81 Patients with normalized CRP (<3 mg/L), n (%) d,g 14 (12.6) 21 (25.9) Week 6 No. of patients with abnormal fecal calprotectin (>250 mg/kg) at baseline 85 61 Patients with normalized fecal calprotectin ( ≤250 mg/kg), n (%) d,h 13 (15.3) 21 (34.4) a. Placebo and Ustekinumab are combined. b. Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline score carried forward. MANUSCRIPT c. Patients with missing segments at the designated analysis timepoint had their baseline score for the missing segment(s) carried forward. d. Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had prohibited concomitant medication changes are considered not to be in clinical response or clinical remission. e. Patients who had insufficient data to calculate the CDAI score at the designated analysis timepoint are considered not to be in clinical response or clinical remission. f. Patients who had insufficient data to calculate the IBDQ score at the designated analysis timepoint were considered not to have a ≥16-point improvement. g. Patients who did not have a CRP reading at Week 8 had their last value carried forward. h. Patients who did not have a Fecal calprotectin reading at Week 6 had their last value carried forward.
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SUPPLEMENTAL APPENDIX
Figure S1: Clinically-meaningful endoscopic improvement ( ≥3-point reduction in SES-CD Score) at
Week 8 by average trough serum ustekinumab concentration quartile at Week 8; treated
patients with eligible SES-CD scores at induction baseline
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Figure S2: Endoscopic response (50% decrease in SES-CD) (A) or endoscopic remission (SES-CD <2)
(B) at Week 44 by serum ustekinumab concentration quartile at Week 44; all endoscopy
substudy patients with SES-CD >3 at induction baseline
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SUPPLEMENTAL APPENDIX
Table S1: Baseline demographics and disease characteristics
UNITI-1a UNITI-2 a Endoscopic Substudy b Characteristic (N=741) (N=628) (N=252) Disease duration, c yrs 10.14 6.40 8.46 IQR (5.6, 16.7) (2.2, 13.1) (3.8; 15.8) Involved area, % Ileum only 13.9 23.3 19.1 Colon only 16.8 19.8 17.9 Ileum and colon 68.6 56.6 62.9 Proximal GI tract 21.1 15.2 13.9 Perianal 43.4 28.4 31.9 CDAI score c 317.0 292.5 311.0 IQR (274.0, 360.0) (257.0, 341.0) (260.5, 357.0) IBDQ score c 120.0 121.0 116.5 IQR (98.0, 138.0) (98.0, 146.0) (97.0, 135.0) CRP, c mg/L 9.88 8.05 8.35 IQR (3.5, 24.4) (3.3, 20.3) (3.4, 23.2) a. All patients randomized in the induction studies. MANUSCRIPT b. Patients enrolled in the induction studies with eligible SES-CD score or ulcerations at baseline of induction . c. Median values.
Key: CDAI, Crohn’s disease activity index; CRP, C-reactive protein; GI, gastrointestinal; IBDQ, inflammatory bowel disease questionnaire; IQR, interquartile range; SES-CD, simplified endoscopy severity score for Crohn’s disease.
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Table S2: Concomitant medications for Crohn's disease and TNF-antagonist history at baseline; randomized patients with eligible SES-CD score or ulcerations at induction baseline Placebo Ustekinumab a Total (N=97) (N=155) (N=252) Patients with ≥1 concomitant medications, n (%) 72 (74.2) 113 (72.9) 185 (73.4) Immunomodulatory drugs, n (%) 31 (32.0) 45 (29.0) 76 (30.2) 6-Mercaptopurine/Azathioprine 25 (25.8) 36 (23.2) 61 (24.2) Methotrexate 6 (6.2) 9 (5.8) 15 (6.0) Aminosalicylates, n (%) 33 (34.0) 45 (29.0) 78 (31.0) Antibiotics, n (%) 6 (6.2) 12 (7.7) 18 (7.1) Corticosteroids (including budesonide), n (%) 40 (41.2) 63 (40.6) 103 (40.9) Corticosteroids P.Eq dose(excluding budesonide) (mg/day) N 30 52 82 Mean (SD) 17.1 (9.42) 19.5 (9.83) 18.6 (9.70) Median 15.0 20.0 20.0 IQ range (10.0; 20.0) (10.0; 27.5) (10.0; 25.0) Range (5; 40) (5; 40) (5; 40)
Budesonide dose (mg/day) N 10 MANUSCRIPT11 21 Mean (SD) 7.2 (2.53) 7.4 (2.06) 7.3 (2.24) Median 9.0 9.0 9.0 IQ range (6.0; 9.0) (6.0; 9.0) (6.0; 9.0) Range (3; 9) (3; 9) (3; 9)
TNF antagonist history b TNF antagonist naive 29 (29.9) 65 (41.9) 94 (37.3) TNF antagonist exposed 68 (70.1) 90 (58.1) 158 (62.7) TNF antagonist failure c 41 (42.3) 66 (42.6) 107 (42.5) TNF antagonist experienced (not failed) c 27 (27.8) 24 (15.5) 51 (20.2) a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Denominator is the number of patients in the analysis set. c Per study entry criteria. Key: IQ, interquartile; P.Eq, prednisone equivalent; SES-CD, Simplified endoscopy severity score for Crohn’s disease; SD, standard deviation; TNF, tumor nectosis factor. ACCEPTED
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Table S3: Baseline demographics and disease characteristics; patients enrolled in the IM-UNITI study with eligible SES-CD score or ulcerations at induction baseline Placebo UST 90 mg q12w UST 90 mg q8w PBO IV to UST IV to UST IV to UST IV to PBO IV to UST IV to nonrandomized randomized nonrandomized randomized nonrandomized randomized UST 90 mg SC UST 90 mg SC UST 90 mg SC UST 90 mg PBO SC a PBO SC b Pooled q12w c q12w d Pooled q8w e SC q8wf Pooled (N=27) (N=24) (N=51) (N=30) (N=17 (N=47) (N=45) (N=29) (N=74) Age (years) Mean (SD) 36.9 (10.97) 40.5 (12.10) 38.6 (11.54) 40.7 (14.13) 35.8 (11.66) 38.9 (13.37) 39.3 (11.54) 41.6 (15.65) 40.2 (13.25) Median 35.0 39.0 38.0 39.0 32.0 38.0 38.0 35.0 37.0 IQ range (29.0; 43.0) (31.0; 49.0) (31.0; 45.0) (27.0; 49.0) (26.0; 45.0) (27.0; 48.0) (31.0; 47.0) (30.0; 53.0) (31.0; 50.0) Range (19; 65) (23; 62) (19; 65) (21; 72) (19; 59) (19; 72) (18; 65) (18; 72) (18; 72) Sex, n(%) Male 17 (63.0) 12 (50.0) 29 (56.9) 15 (50.0) 9 (52.9) 24 (51.1) 20 (44.4) 8 (27.6) 28 (37.8) Race, n (%) White 21 (77.8) 16 (66.7) 37 (72.5) 24 (80.0) 12 (70.6) 36 (76.6) 40 (88.9) 25 (86.2) 65 (87.8) Black or African 2 (7.4) 3 (12.5) 5 (9.8) 1 (3.3) 1 (5.9) 2 (4.3) 2 (4.4) 0 2 (2.7) American Asian 1 (3.7) 3 (12.5) 4 (7.8) 4 (13.3) 2 (11.8) 6 (12.8) 0 2 (6.9) 2 (2.7) Other 3 (11.1) 0 3 (5.9) 1 (3.3) MANUSCRIPT2 (11.8) 3 (6.4) 1 (2.2) 1 (3.4) 2 (2.7) Not Reported 0 2 (8.3) 2 (3.9) 0 0 0 1 (2.2) 1 (3.4) 2 (2.7) Weight (kg) N 24 22 46 29 16 45 44 29 73 Mean (SD) 75.1 (14.26) 72.4 (15.51) 73.8 (14.76) 74.7 (18.33) 75.6 (18.75) 75.0 (18.27) 73.3 (20.33) 72.2 (15.37) 72.8 (18.41) Median 73.7 76.3 74.7 74.3 75.6 74.3 68.3 72.3 69.0 IQ range (63.2;89.2) (57.0;86.0) (61.5;87.0) (61.0;82.6) (61.2;86.6) (61.00;85.00) (57.8;90.1) (62.6;81.5) (58.1;85.9) Range (54.3;102.0) (44.0; 98.0) (44.0;102.0) (50.0;133.3) (49.6;110.7) (49.6;133.3) (43.0;108.0) (44.2;107.0) (43.0;108.0)
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Table S3: Baseline demographics and disease characteristics; patients enrolled in the IM-UNITI study with eligible SES-CD score or ulcerations at induction baseline Placebo UST 90 mg q12w UST 90 mg q8w PBO IV to UST IV to UST IV to UST IV to PBO IV to UST IV to nonrandomized randomized nonrandomized randomized nonrandomized randomized UST 90 mg SC UST 90 mg SC UST 90 mg SC UST 90 mg PBO SC a PBO SC b Pooled q12w c q12w d Pooled q8w e SC q8wf Pooled (N=27) (N=24) (N=51) (N=30) (N=17 (N=47) (N=45) (N=29) (N=74) Crohn’s Disease duration (yrs) Mean (SD) 8.7 (7.18) 12.1 (10.31) 10.3 (8.87) 11.9 (10.50) 10.8 (11.13) 11.5 (10.62) 11.9 (9.16) 9.5 (9.13) 11.0 (9.16) Median 8.6 8.6 8.6 8.6 6.2 7.8 10.4 7.6 9.2 IQ range (1.9;13.0) (5.1; 15.9) (3.4; 13.2) (5.2; 13.0) (3.9; 12.7) (4.6; 13.0) (3.1; 18.3) (1.6; 13.8) (2.8; 17.6) Range (0.6; 28.5) (1.6; 42.7) (0.6; 42.7) (0.7; 46.1) (0.8; 40.1) (0.7; 46.1) (0.7; 40.1) (0.4; 36.0) (0.4; 40.1) Involved GI areas, n (%) N 27 24 51 30 17 47 44 29 73 Ileum only 2 (7.4) 2 (8.3) 4 (7.8) 10 (33.3) 0 10 (21.3) 12 (27.3) 6 (20.7) 18 (24.7) Colon only 10 (37.0) 5 (20.8) 15 (29.4) 4 (13.3) 2 (11.8) 6 (12.8) 3 (6.8) 6 (20.7) 9 (12.3) Ileum and colon 15 (55.6) 17 (70.8) 32 (62.7) 16 (53.3) 15 (88.2) 31 (66.0) 29 (65.9) 17 (58.6) 46 (63.0) Proximal gastrointestinal tract 3 (11.1) 4 (16.7) 7 (13.7) 6 (20.0) 5 (29.4) 11 (23.4) 4 (9.1) 3 (10.3) 7 (9.6) Perianal 6 (22.2) 8 (33.3) 14 (27.5) 10 (33.3)MANUSCRIPT 5 (29.4) 15 (31.9) 18 (40.9) 7 (24.1) 25 (34.2) CDAI score Mean (SD) 305.3 (62.57) 329.2 (64.52) 316.5 (63.99) 296.8 (54.25) 319.8 (73.19) 305.1(61.99) 321.0 (62.55) 316.4 (60.75) 319.2 (61.47) Median 301.0 340.5 317.0 302.0 321.0 310.0 312.0 314.0 312.0 IQ range (246.0;347.0) (268.0;368.0) (256.0;360.0) (254.0;333.0) (252.0;381.0) (252.0; 340.0) (273.0;375.0) (267.0;351.0) (268.0;365.0) Range (223; 456) (218; 452) (218; 456) (198; 414) (217; 429) (198; 429) (208; 460) (220; 436) (208; 460) CRP (mg/L) Mean (SD) 15.6 (35.03) 12.9 (11.67) 14.3 (26.50) 9.1 (9.27) 28.7 (29.63) 16.2 (21.22) 13.8 (20.52) 24.2 (31.46) 17.9 (25.68) Median 3.8 9.8 5.9 6.8 14.5 8.1 6.8 9.1 7.5 IQ range (1.7; 17.3) (3.0; 18.6) (1.9; 18.4) (1.4; 12.9) (8.0; 51.3) (4.7; 19.8) (2.9; 15.3) (5.4; 29.1) (3.3; 23.6) Range (0.3; 180.0) (0.3; 39.4) (0.3; 180.0) (0.1; 40.6) (2.9; 106.0) (0.1; 106.0) (0.1; 121.0) (1.0; 136.0) (0.1; 136.0)
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Table S3: Baseline demographics and disease characteristics; patients enrolled in the IM-UNITI study with eligible SES-CD score or ulcerations at induction baseline Placebo UST 90 mg q12w UST 90 mg q8w PBO IV to UST IV to UST IV to UST IV to PBO IV to UST IV to nonrandomized randomized nonrandomized randomized nonrandomized randomized UST 90 mg SC UST 90 mg SC UST 90 mg SC UST 90 mg PBO SC a PBO SC b Pooled q12w c q12w d Pooled q8w e SC q8wf Pooled (N=27) (N=24) (N=51) (N=30) (N=17 (N=47) (N=45) (N=29) (N=74) Crohn's Disease Complications, n (%) Intra-abdominal abscess (Past) 3 (11.1) 3 (12.5) 6 (11.8) 2 (6.7) 2 (11.8) 4 (8.5) 3 (6.7) 3 (10.3) 6 (8.1) Sinus tracts / perforation g 3 (11.1) 3 (12.5) 6 (11.8) 0 0 0 2 (4.4) 2 (6.9) 4 (5.4) Fistula g 8 (29.6) 9 (37.5) 17 (33.3) 11 (36.7) 5 (29.4) 16 (34.0) 17 (37.8) 8 (27.6) 25 (33.8) Current 2 (7.4) 3 (12.5) 5 (9.8) 6 (20.0) 3 (17.6) 9 (19.1) 7 (15.6) 1 (3.4) 8 (10.8) Bowel Stricturing g 5 (18.5) 12 (50.0) 17 (33.3) 11 (36.7) 2 (11.8) 13 (27.7) 18 (40.0) 5 (17.2) 23 (31.1) Current 1 (3.7) 3 (12.5) 4 (7.8) 1 (3.3) 0 1 (2.1) 4 (8.9) 1 (3.4) 5 (6.8) SES-CD Mean (SD) 12.9 (8.35) 15.7 (8.31) 14.2 (8.37) 11.8 (7.30) 14.1 (8.94) 12.6 (7.92) 13.0 (8.38) 15.8 (7.77) 14.1 (8.21) Median 12.0 12.5 12.0 10.5 13.0 11.0 10.0 15.0 12.0 IQ range (4.0; 20.0) (9.5; 24.0) (8.0; 21.0) (6.0; 16.0) (7.0; 18.0) (6.0; 17.0) (8.0; 15.0) (9.0; 23.0) (8.0; 19.0) Range (3; 33) (3; 32) (3; 33) (3; 29) MANUSCRIPT(3; 33) (3; 33) (3; 38) (4; 30) (3; 38) Patients with ≥1 concomitant medications, n (%) Immunomodulatory drugs 10 (37.0) 6 (25.0) 16 (31.4) 10 (33.3) 7 (41.2) 17 (36.2) 10 (22.2) 8 (27.6) 18 (24.3) 6-MP/AZA 9 (33.3) 5 (20.8) 14 (27.5) 9 (30.0) 5 (29.4) 14 (29.8) 9 (20.0) 6 (20.7) 15 (20.3) MTX 1 (3.7) 1 (4.2) 2 (3.9) 1 (3.3) 2 (11.8) 3 (6.4) 1 (2.2) 2 (6.9) 3 (4.1) Aminosalicylates 12 (44.4) 10 (41.7) 22 (43.1) 13 (43.3) 5 (29.4) 18 (38.3) 14 (31.1) 9 (31.0) 23 (31.1) Antibiotics 1 (3.7) 1 (4.2) 2 (3.9) 3 (10.0) 2 (11.8) 5 (10.6) 5 (11.1) 1 (3.4) 6 (8.1) Corticosteroids (including budesonide), n (%) 14 (51.9) 10 (41.7) 24 (47.1) 12 (40.0) 6 (35.3) 18 (38.3) 21 (46.7) 12 (41.4) 33 (44.6) Corticosteroids P.Eq dose(excluding budesonide)(mg/day) N 10 8 18 8 5 13 19 9 28 Mean (SD) 19.8 (10.57) 21.3 (6.94) 20.4 (8.92) 15.0 (8.86) 22.0 (10.95) 17.7 (9.92) 18.8 (10.88) 13.9 (9.28) 17.2 (10.48) Median 17.5 20.0 20.0 15.0 20.0 20.0 20.0 10.0 15.0 IQ range (10.0; 30.0) (17.5; 27.5)ACCEPTED (15.0; 30.0) (7.5; 20.0) (20.0; 20.0) (10.0; 20.0) (10.0; 30.0) (5.0; 20.0) (10.0; 22.5) Range (8; 40) (10; 30) (8; 40) (5; 30) (10; 40) (5; 40) (5; 40) (5; 30) (5; 40)
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Table S3: Baseline demographics and disease characteristics; patients enrolled in the IM-UNITI study with eligible SES-CD score or ulcerations at induction baseline Placebo UST 90 mg q12w UST 90 mg q8w PBO IV to UST IV to UST IV to UST IV to PBO IV to UST IV to nonrandomized randomized nonrandomized randomized nonrandomized randomized UST 90 mg SC UST 90 mg SC UST 90 mg SC UST 90 mg PBO SC a PBO SC b Pooled q12w c q12w d Pooled q8w e SC q8wf Pooled (N=27) (N=24) (N=51) (N=30) (N=17 (N=47) (N=45) (N=29) (N=74) Budesonide dose (mg/day) N 4 2 6 4 1 5 2 3 5 Mean (SD) 6.8 (2.87) 6.0 (0.00) 6.5 (2.26) 8.3 (1.50) 9.0 (-) 8.4 (1.34) 7.5 (2.12) 9.0 (0.00) 8.4 (1.34) Median 7.5 6.0 6.0 9.0 9.0 9.0 7.5 9.0 9.0 IQ range (4.5; 9.0) (6.0; 6.0) (6.0; 9.0) (7.5; 9.0) (9.0; 9.0) (9.0; 9.0) (6.0; 9.0) (9.0; 9.0) (9.0; 9.0) Range (3; 9) (6; 6) (3; 9) (6; 9) (9; 9) (6; 9) (6; 9) (9; 9) (6; 9) TNF antagonist history, h n (%) TNF antagonist naive 12 (44.4) 11 (45.8) 23 (45.1) 10 (33.3) 9 (52.9) 19 (40.4) 17 (37.8) 15 (51.7) 32 (43.2) TNF antagonist exposed 15 (55.6) 13 (54.2) 28 (54.9) 20 (66.7) 8 (47.1) 28 (59.6) 28 (62.2) 14 (48.3) 42 (56.8) TNF antagonist failure i 8 (29.6) 8 (33.3) 16 (31.4) 13 (43.3) 5 (29.4) 18 (38.3) 22 (48.9) 9 (31.0) 31 (41.9) TNF antagonist MANUSCRIPT experienced (not failed) i 7 (25.9) 5 (20.8) 12 (23.5) 7 (23.3) 3 (17.6) 10 (21.3) 6 (13.3) 5 (17.2) 11 (14.9) a. Nonrandomized patients who were responders to placebo IV induction and received placebo SC in maintenance. b. Patients who were responders to ustekinumab IV induction and randomized to placebo SC in maintenance. c. Nonrandomized patients who were not responders to placebo IV induction and received ustekinumab 130 mg IV at Week 0 of maintenance, achieved clinical response at Week 8 of maintenance, and received maintenance therapy with ustekinumab 90 mg SC q12w. d. Patients who were responders to ustekinumab IV induction and randomized to ustekinumab 90 mg SC q12w. e. Nonrandomized patients who were not responders to ustekinumab IV induction and received ustekinumab 90 mg SC at Week 0 of maintenance, achieved clinical response at Week 8 of maintenance, and received maintenance therapy with ustekinumab 90 mg SC q8w. f. Patients who were responders to ustekinumab IV induction and randomized to ustekinumab 90 mg SC q8w. g. Current or past. h Denominator is the number of patients in analysis set. i Per study entry criteria. Key: IQ, interquartile; IV, intravenous; PBO, placebo; SC, subcutaneous; SES-CD, Simplified endoscopy severity score for Crohn’s disease; SD, standard deviation; TNF, tumor necrosis factor; q8w, every 8 weeks; q12w, every 12 ACCEPTEDweeks; UST ustekinumab
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Table S4: Change from baseline in SES-CD score at Week 8 by dose; randomized patients with eligible SES-CD score at induction baseline Ustekinumab Placebo 130 mg 6 mg/kg Combined Analysis set: Randomized patients with eligible SES-CD score at baseline from the UNITI-1 and UNITI-2 97 72 83 155
Baseline N 97 72 83 155 Mean (SD) 12.3 (7.61) 15.3 (8.71) 13.2 (7.45) 14.2 (8.10) Median 12.0 14.0 11.0 12.0 IQ range (6.0; 16.0) (8.0; 21.5) (8.0; 17.0) (8.0; 19.0) Range (3; 39) (3; 38) (3; 39) (3; 39)
Change from baseline
Week 8 b,c MANUSCRIPT N 97 72 83 155 Mean (SD) -0.7 (4.97) -2.5 (6.15) -3.0 (5.26) -2.8 (5.68) Median 0.0 -1.0 -2.0 -2.0 IQ range (-3.0; 1.0) (-5.0; 0.0) (-5.0; 0.0) (-5.0; 0.0) Range (-14; 16) (-22; 15) (-22; 5) (-22; 15) p-value 0.096 0.009 0.012 a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward. c Patients with missing segments at the designated analysis timepoint had their baseline score for the missing segment(s) carried forward.
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Table S5: Change from baseline in SES-CD score at Week 8 (sensitivity analysis: observed data); randomized patients with eligible SES-CD score at induction baseline Placebo Ustekinumab a Analysis set: Randomized patients with eligible SES-CD score at baseline from the UNITI-1 and UNITI-2 97 155
Baseline N 97 155 Mean (SD) 12.3 (7.61) 14.2 (8.10) Median 12.0 12.0 IQ range (6.0; 16.0) (8.0; 19.0) Range (3; 39) (3; 39)
Change from baseline MANUSCRIPT Week 8 b,c Nd 80 124 Mean (SD) -1.5 (5.92) -3.8 (6.30) Median -0.5 -4.0 IQ range (-4.5; 2.0) (-7.0; 0.0) Range (-21; 17) (-22; 15) P-value .014 a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward. c SES-CD score at the designated analysis timepoint was based on all observed segments scored at that visit. d Patients who had no data for any segment at the designated analysis timepoint were excluded. Patients who had a treatment failure prior to the designated analysis timepoint had their baseline value carried forward, regardless of whether they had data.
Key: IQ, interquartile; SES-CD, Simplified endoscopy severity score for Crohn’s disease; SD, standard deviation ACCEPTED
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Table S6: Change from baseline in SES-CD score at Week 8 (sensitivity analysis: observed case) ; randomized patients with eligible SES-CD score at induction baseline Placebo Ustekinumab a Analysis set: Randomized patients with eligible SES-CD score at baseline from the UNITI-1 and UNITI-2 studies 97 155
Baseline N 97 155 Mean (SD) 12.3 (7.61) 14.2 (8.10) Median 12.0 12.0 IQ range (6.0; 16.0) (8.0; 19.0) Range (3; 39) (3; 39)
Change from baseline
Week 8 b Nc 72 109 Mean (SD) -1.5 (5.00) -3.9 (6.09) Median 0.0 -4.0 IQ range (-4.0; 1.5) MANUSCRIPT(-6.0; 0.0) Range (-14; 10) (-22; 15) P-value .013
a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward. c Based on segments scored at baseline only, patients who had a segment not being evaluated or missing at the designated analysis timepoint were excluded. Patients who had a treatment failure prior to the designated analysis timepoint had their baseline value carried forward, regardless of whether they had data for those segments. : IQ, interquartile; SES-CD, Simplified endoscopy severity score for Crohn’s disease; SD, standard deviation
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Table S7: Change from baseline in SES-CD score at Week 8 by individual study; randomized patients with eligible SES-CD score at induction baseline UNITI-1 UNITI-2 Placebo Ustekinumab a Placebo Ustekinumab a Analysis set: Randomized patients with eligible SES-CD score at baseline from the UNITI-1 and UNITI-2 41 66 56 89
Baseline N 41 66 56 89 Mean (SD) 12.3 (6.68) 14.6 (8.25) 12.4 (8.28) 13.9 (8.03) Median 10.0 12.0 12.0 12.0 IQ range (7.0; 16.0) (9.0; 21.0) (5.5; 16.5) (8.0; 18.0) Range (3; 26) (3; 38) (3; 39) (3; 39)
Change from baseline
Week 8 b,c N 41 66 56 89 Mean (SD) 0.2 (3.24) -2.3MANUSCRIPT (5.22) -1.4 (5.85) -3.1 (6.00) Median 0.0 -1.0 0.0 -3.0 IQ range (0.0; 1.0) (-5.0; 0.0) (-5.5; 1.0) (-6.0; 0.0) Range (-9; 10) (-22; 13) (-14; 16) (-22; 15) p-value 0.010 0.234 a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward. c Patients with missing segments at the designated analysis timepoint had their baseline score for the missing segment(s) carried forward.
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Table S8: Change from baseline in SES-CD score at Week 8 by segment; randomized patients who were treated with ustekinumab in induction and had eligible SES-CD score at induction baseline Ileum a Right Colon a Transverse Colon a Left Colon a Rectum a Total a Presence and size of ulcers N 139 141 144 151 154 155 Mean (SD) -0.2 (0.86) -0.2 (0.83) -0.2 (0.85) -0.4 (0.91) -0.1 (0.85) -1.0 (2.38)
Extent of ulcerated surface N 139 141 144 151 154 155 Mean (SD) -0.2 (0.58) -0.1 (0.53) -0.1 (0.54) -0.2 (0.59) -0.1 (0.55) -0.7 (1.58)
Extent of affected surface N 139 141 144 151 154 155 Mean (SD) -0.2 (0.88) -0.2 (0.74) -0.2 (0.69) -0.3 (0.71) -0.1 (0.69) -1.0 (1.91) MANUSCRIPT Presence and type of narrowings N 139 141 144 151 154 155 Mean (SD) 0.0 (1.04) 0.0 (0.72) 0.0 (0.08) 0.0 (0.18) 0.0 (0.00) -0.1 (1.22)
Total N NAP NAP NAP NAP NAP 155 Mean (SD) -2.8 (5.68) a. Include all patients with a non-missing baseline score in the corresponding column. Patients who, prior to Week 8, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward. Patients with missing segments at Week 8 had their baseline score for the missing segment(s) carried forward. Key: SES-CD, Simplified Endoscopic Disease Severity Score for Crohn’s Disease; NAP, not applicable; SD, standard deviation. ACCEPTED
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Table S9: Number of patients with at least 3 points reduction from baseline in SES-CD score at Week 8 by induction dose; randomized patients with eligible SES-CD score at induction baseline Ustekinumab
Placebo 130 mg 6 mg/kg
Analysis set: Randomized patients with eligible SES-CD score at baseline 97 72 83
Week 8
N 97 72 83
Patients with ≥3 points reduction from baseline in SES-CD score a,b 29 (29.9%) 33 (45.8%) 41 (49.4%)
P -value .034 .007 a Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline score carried forward. MANUSCRIPT b Patients with missing segments at the designated analysis timepoint had their baseline score for the missing segment(s) carried forward Key:SES-CD, Simplified endoscopy severity score for Crohn’s disease.
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Table S10: Number of patients in endoscopic response at Week 8 by induction dose; randomized patients with eligible SES-CD score at induction baseline Ustekinumab
Placebo 130 mg 6 mg/kg
Analysis set: Randomized patients with eligible SES-CD score at baseline 97 72 83
Week 8
N 97 72 83
Patients in endoscopic response a,b 13 (13.4%) 14 (19.4%) 18 (21.7%)
P -value .289 .142 a Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline score carried forward. b Patients with missing segments at the designated analysis timepoint had their baselineMANUSCRIPT score for the missing segment(s) carried forward. Key: : SES-CD, Simplified endoscopy severity score for Crohn’s disease.
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Table S11: Number of patients in endoscopic remission at Week 8 by induction dose; randomized patients with eligible SES-CD score at induction baseline Ustekinumab
Placebo 130 mg 6 mg/kg
Analysis set: Randomized patients with eligible SES-CD score at baseline 97 72 83
Week 8
N 97 72 83
Patients in endoscopic remission a,b 4 (4.1%) 5 (6.9%) 7 (8.4%) P-value MANUSCRIPT.498 .350 a Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline score carried forward. b Patients with missing segments at the designated analysis timepoint had their baseline score for the missing segment(s) carried forward. Key: -CD, Simplified endoscopy severity score for Crohn’s disease.
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Table S12: Number of patients in mucosal healing at Week 8 by induction dose; randomized patients with ulcerations at induction baseline Ustekinumab
Placebo 130 mg 6 mg/kg
Analysis set: Randomized patients with ulcerations at baseline from the UNITI-1 and UNITI-2 studies 97 72 83
Week 8
N 97 72 83
Patients in mucosal healing a,b 4 (4.1%) 6 (8.3%) 8 (9.6%)
P-value .328 .230
a Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy, or had an initiation of specified prohibited medication were considered as not achieving mucosal healing. b Patients with missing segments at the designated analysis timepoint had their ulceration status at baseline for the missing segment(s) carried forward.
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Table S13: Number of patients in mucosal healing at Week 8 (sensitivity analysis: observed data); randomized patients with ulcerations at induction baseline Placebo Ustekinumab a
Analysis set: Randomized patients with ulcerations at baseline from the UNITI-1 and UNITI-2 studies 97 155
Week 8
N b 80 124
Patients in mucosal healing c,d 7 (8.8%) 16 (12.9%)
P-value .360
a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Patients who had no data for any segment at the designated analysis timepoint were excluded. Patients who had a treatment failure prior to the designated analysis timepoint were considered as not achieving mucosal healing, regardless of whether they had data. c Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy, or had an initiation of specified prohibited medication were considered as not achieving mucosal healing. d Mucosal healing at the designated analysis timepoint was based on all observed segments evaluated at that visit.
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Table S14: Number of patients in mucosal healing at Week 8 (sensitivity analysis: observed case); randomized patients with ulcerations at induction baseline Placebo Ustekinumab a
Analysis set: Randomized patients with ulcerations at baseline from the UNITI-1 and UNITI-2 studies 97 155
Week 8
N b 72 109
Patients in mucosal healing c,d 4 (5.6%) 13 (11.9%)
P-value .150
a Ustekinumab 130 mg and tiered ustekinumab doses approximating 6 mg/kg combined. b Based on segments scored at baseline only, patients who had a segment not being evaluated or missing at the designated analysis timepoint were excluded. Patients who had a treatment failure prior to the designated analysis timepoint were considered as not achieving mucosal healing, regardless of whether they had data for those segments. c Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy, or had an initiation of specified prohibited medication were considered as not achieving mucosal healing. d Mucosal healing at the designated analysis timepoint was based on all observed segments evaluated at that visit.
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Table S15: Change from baseline of the induction study in SES-CD score at Week 44; randomized patients in IM-UNITI with eligible SES-CD score at baseline of induction Ustekinumab Placebo 90 mg q12w 90 mg q8w Combined a Analysis set: Randomized patients in IM-UNITI with eligible SES-CD score at baseline of induction 24 17 29 46
Baseline of induction N 24 17 29 46 Mean (SD) 15.7 (8.31) 14.1 (8.94) 15.8 (7.77) 15.2 (8.16) Median 12.5 13.0 15,0 14.0 IQ range (9.5; 24.0) (7.0; 18.0) (9.0; 23.0) (8.0; 22.0) Range (3; 32) (3; 33) (4; 30) (3; 33)
Change from baseline of induction
Week 0 of maintenance b,c N 24 MANUSCRIPT17 29 46 Mean (SD) -3.4 (7.85) -2.8 (3.98) -4.1 (5.23) -3.6 (4.80) Median -1.5 -2.0 -3.0 -3.0 IQ range (-8.5; 1.5) (-6.0; 0.0) (-7.0; 0.0) (-7.0; 0.0) Range (-22; 12) (-10; 5) (-22; 2) (-22; 5)
Week 44 of maintenance b,c N 24 17 29 46 Mean (SD) -1.9 (4.06) -1.6 (2.83) -3.1 (4.11) -2.5 (3.73) Median 0.0 0.0 -1.0 0.0 IQ range (-2.5; 0.0) (-3.0; 0.0) (-5.0; 0.0) (-4.0; 0.0) Range (-14; 2) (-9; 0) (-13; 0) (-13; 0) p-value 0.637 0.107 0.176 a Ustekinumab 90 mg SC q12w and 90mg SC q8w combined. b Patients who, priorACCEPTED to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy, had an initiation of specified prohibited medication, or had a loss of response during maintenance had their induction baseline score carried forward. c Patients with missing segments at the designated analysis timepoint had their induction baseline score for the missing segment(s) carried forward.
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Table S16: Endoscopy assessments in IM-UNITI; nonrandomized patients with eligible SES-CD score or ulceration at induction baseline Placebo a Ustekinumab b
(N=27) (N=75) SES-CD
Baseline of induction Mean (SD) 12.9 (8.35) 12.5 (7.94) Median 12.0 10.0 IQ range (4.0; 20.0) (7.0; 16.0) Range (3; 33) (3; 38)
Change from baseline c,d Week 8 of induction (ie, Week 0 of maintenance) Mean (SD) -2.5 (6.43) -1.1 (5.48) Median -3.0 0.0 IQ range (-7.0; 0.0) (-4.0; 2.0) Range (-14; 16) (-19; 13)
Week 44 Mean (SD) -2.0 (6.20) -3.1 (6.35) Median 0.0 0.0 IQ range (-3.0; 0.0) (-6.0; 0.0) Range (-22; 9) (-34; 7)
Mucosal Healing, n (%) c,d,e 4 (14.8) 16 (21.3) a. Patients who received placebo induction and then received placebo SC on entry into the maintenance study. MANUSCRIPT b. Patients who received ustekinumab 130 mg IV or 90 mg SC at Week 0 of maintenance, achieved clinical response at Week 8 of maintenance, and received maintenance therapy with ustekinumab 90 mg SC q12w or 90 mg SC q8w. c. Patients who, prior to the designated analysis timepoint, had a Crohn’s Disease-related surgery due to lack of efficacy or had an initiation of specified prohibited medication had their baseline value carried forward or were considered to not have mucosal healing. d. Patients with missing segments at the designated analysis timepoint had their baseline score or ulceration status at baseline for the missing segment(s) carried forward. e. Complete absence of ulcers in patients with ulcers at baseline.
Key: IQ, interquartile; IV, intravenous; SC, subcutaneous; SD, standard deviation; SES-CD, simplified endoscopic severity score for Crohn’s disease; q8w, every 8 weeks; q12w, every 12 weeks.
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Pooled Randomized and Nonrandomized Maintenance Population
To increase power for the endoscopic analyses, ad-hoc analyses of the pooled randomized and non-randomized populations were performed. This was justified because of the similar baseline demographics and disease characteristics, and efficacy at Week 44 to ustekinumab therapy of the two populations. 1 The change in SES-CD from induction baseline and rates of all the endpoints were higher in the ustekinumab treated patients compared to placebo, with greater effects being consistently seen with the 90 mg q8w dose (Table, Figure).
1. Feagan BG, Sandborn WJ , Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn’s disease. N Engl J Med 2016; 375:1946-60.
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Table: Summary of change from baseline of the induction study in SES-CD score through week 44; patients enrolled in iM-UNITI with eligible SES-CD score at baseline of induction Ustekinumab Placebo a 90 mg q12w b 90 mg q8w c Analysis set: Randomized patients in IM-UNITI with eligible SES-CD score at baseline of induction 51 47 74 Baseline of induction N 51 47 74 Mean (SD) 14.2 (8.37) 12.6 (7.92) 14.1 (8.21) Median 12.0 11.0 12.0 IQ range (8.0; 21.0) (6.0; 17.0) (8.0; 19.0) Range (3; 33) (3; 33) (3; 38) Change from baseline of induction d,e Week 0 of maintenance N 51 47 74 Mean (SD) -2.9 (7.07) -0.5 (4.70) -3.0 (5.54) Median -3.0 MANUSCRIPT0.0 -3.0 IQ range (-7.0; 0.0) (-3.0; 2.0) (-6.0; 0.0) Range (-22; 16) (-13; 10) (-22; 13) Week 44 of maintenance N 51 47 74 Mean (SD) -2.0 (5.25) -1.5 (4.22) -3.8 (6.02) Median 0.0 0.0 -1.5 IQ range (-3.0; 0.0) (-3.0; 0.0) (-7.0; 0.0) Range (-22; 9) (-21; 6) (-34; 7) p-value 0.758 0.054 a Includes: nonrandomized patients who were responders to placebo IV induction and received placebo SC in maintenance; patients who were responders to ustekinumab IV induction and randomized to placebo SC in maintenance. b Includes: patients who were responders to ustekinumab IV induction and randomized to ustekinumab 90 mg SC q12w in maintenance; as well as nonrandomized patients who were not responders to placebo IV induction and received ustekinumab 130 mg IV at Week 0 of maintenance, achieved clinical response at Week 8 of maintenance, and received maintenance therapy with ustekinumab 90 mg SC q12w. c Includes: patients who were responders to ustekinumab IV induction and randomized to ustekinumab 90 mg SC q8w in maintenance; as well as nonrandomizedACCEPTED patients who were not responders to ustekinumab IV induction and received 90 mg SC at Week 0 of maintenance, achieved clinical response at Week 8 of maintenance, and received maintenance therapy with ustekinumab 90 mg SC q8w. d Patients who, prior to the designated analysis timepoint, had a Crohn's disease-related surgery due to lack of efficacy, had an initiation of specified prohibited medication, or had a loss of response during maintenance had their induction baseline score carried forward. e Patients with missing segments at the designated analysis timepoint had their induction baseline score for the missing segment(s) carried forward.
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ACCEPTED MANUSCRIPT Target Journal: Gastroenterology Rutgeerts P
Figure. Endoscopic endpoints at Week 44 in pooled randomized and nonrandomized
maintenance population; enrolled patients in the IM-UNITI study with eligible
SES-CD scores or ulcerations at induction baseline
MANUSCRIPT Key: SES-CD, Simplified Endoscopic Disease Severity Score for Crohn’s disease; q8w, every 8 weeks; q12w, every 12 weeks.
Note: Combined ustekinumab group includes the ustekinumab 90 mg q8w and 90 mg q12w groups.
ACCEPTED
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