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Ertugliflozin As Monotherapy and in Dual Therapy for Treating Type 2 Diabetes [ID1158]

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Ertugliflozin As Monotherapy and in Dual Therapy for Treating Type 2 Diabetes [ID1158] Single Technology Appraisal Ertugliflozin as monotherapy and in dual therapy for treating type 2 diabetes [ID1158] Committee Papers © National Institute for Health and Care Excellence [2019]. All rights reserved. See Notice of Rights. The content in this publication is owned by multiple parties and may not be re-used without the permission of the relevant copyright owner. NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE SINGLE TECHNOLOGY APPRAISAL Ertugliflozin as monotherapy and in dual therapy for treating type 2 diabetes [ID1158] Contents: 1. Technical Briefing Document 2. Company submission from Merck Sharpe and Dohme Company submission errata 3. Clarification letters NICE request to the company for clarification on their submission Company response to NICE’s request for clarification 4. Expert personal perspectives from: Professor John Wilding, Clinical expert nominated by Royal College of Physicians and Association of British Clinical Diabetologists Professor Stephen Bain, Clinical expert nominated by Merck Sharpe and Dohme 5. Evidence Review Group report prepared by Warwick Evidence 6. Evidence Review group – factual accuracy check Any information supplied to NICE which has been marked as confidential, has been redacted. All personal information has also been redacted. © National Institute for Health and Care Excellence [2019]. All rights reserved. See Notice of Rights. The content in this publication is owned by multiple parties and may not be re-used without the permission of the relevant copyright owner. 1 CONFIDENTIAL National Institute for Health and Care Excellence Pre-meeting briefing – Fulvestrant for untreated hormone-receptor positive locally advanced or metastatic breast cancer Issue date: [August 2017] 2 CONFIDENTIAL Source: Company submission document B, section 31.2, table 2 p10; NICE TAs 390, 288, 315 and 336; electronic medicines compendium (eMC) [https://www.medicines.org.uk/emc accessed October 2018] 3 Source: Company submission document B, section 3.1 p20, section 3.2.1 table 11 p21, section 3.3.3, table 16, p39 The all subjects as treated (ASaT) population was used for summarising baseline characteristics. The ASaT consisted of all randomised patients who took at least one dose of study medication. Patients were diagnosed according to the American Diabetes Association (ADA) guidelines AEs included urinary tract infections, genital infections and malignancies 4 Abbreviations: LS, least squares; SE, standard error; W= week; PBO, placebo Source: Company submission document B, section 3.6.1, figure 5, p49 and table 21, p50 The full analysis set (FAS) population was used for the primary and secondary efficacy outcomes, which included all randomised patients who took at least one dose of study medication and had at least one measurement of the outcome variable (baseline or post-baseline) A constrained longitudinal data analysis (cLDA) model was used that included terms for treatment (categorical), time, the treatment by time interaction, AHA status at study entry (binary: yes/no), and baseline eGFR (continuous). An unstructured covariance matrix was used to model the correlation among repeated measurements. The Kenward-Roger adjustment was used with restricted (or residual) maximum likelihood (REML) to support appropriate statistical inference. Sensitivity analyses were performed to assess the robustness of the primary model. 5 Abbreviations: cLDA, constrained longitudinal data analysis; LS, least squares; SE, standard error; W= week; FAS, full analysis set Source: Company submission document B, section 3.6.1, figures 6-8, pp51-53 6 Abbreviations: AE, adverse event; SAE, Serious adverse event; UTIs, urinary tract infections Source: Company submission document B, section 3.10.2, table 47, p87 The all subjects as treated (ASaT) population was used for the safety analysis. The ASaT consisted of all randomised patients who took at least one dose of study medication Patients were prescribed with glycaemic rescue therapy in the form of open-label metformin when exceeding the following thresholds: • FPG >15.0 mmol/L after randomisation up to week 6 • FPG>13.3 mmol/L after week 6 and up to week 12 • FPG>11.1 mmol/L after week 12 and up to week 26 Investigator determined whether events were related to the study drug Symptomatic hypoglycaemia = Event with clinical symptoms reported 7 by the investigator as hypoglycaemia 7 Abbreviations: SITA, sitagliptin; LINA, linagliptin; SLR, systematic literature review Source: Company submission document B, section 3.9.1 figure 13, p64 8 CONFIDENTIAL 9 Source: ERG report, section 3.3 p14 10 Source: ERG report, section 3.3 p14 11 Abbreviations: eGFR, estimated glomerular filtration rate; tx, treatment Source: ERG report, section 3.4, pp15-17, table 2 Monotherapy trial designs are similar ERG thought the following trials were less suitable comparators: • Roden 2013 trial of empagliflozin because it was done mainly in Asians, with a lower baseline BMI (28kg/m2) • Ferrannini trial of dapagliflozin because it recruited a slightly younger population (mean age 50.6 years on dapagliflozin 10 mg/day versus 56.8 years on ertugliflozin 5 mg/day) and shorter duration of diabetes (about 6 months versus over 5 years in VERTIS MONO), and there was a larger drop in HbA1c on placebo (reduction 0.25%) 12 Source: ERG report, section 3.4, pp15-17, table 2 13 Source: Company submission document B, section 3.1 p20, section 3.2 tables 12-13 pp2225, section 3.3.1, pp30-35, section 3.3.2 table 15 pp36-37, table 16, p39 The all subjects as treated (ASaT) population was used for summarising baseline characteristics. The ASaT consisted of all randomised patients who took at least one dose of study medication. Patients were diagnosed according to the American Diabetes Association (ADA) guidelines The safety and tolerability of ertugliflozin was evaluated through the assessment of pre-specified adverse events (AEs) following a tiered approach. Tier 1 AEs were AEs of special interest such as genital mycotic infections, UTIs, symptomatic hypoglycaemia and hypovolemia. AEs that were not pre-specified as Tier 1 endpoints were classified as belonging to Tier 2 or Tier 3, based on the number of events observed 14 Abbreviations: LS, least squares; SE, standard error; W= week; PBO, placebo Source: Company submission document B, section 3.6.2 figure 9 p54 and table 22, p55 The full analysis set (FAS) population was used for the primary and secondary efficacy outcomes, which included all randomised patients who took at least one dose of study medication and had at least one measurement of the outcome variable (baseline or post-baseline) 15 Abbreviations: cLDA, constrained longitudinal data analysis; LS, least squares; SE, standard error; W= week; FAS, full analysis set Source: Company submission document B, section 3.6.2, figures 10-12, pp55-57 16 Abbreviations: cLDA, constrained longitudinal data analysis; LS, least squares; SE, standard error; W= week; FAS, full analysis set; Tx, treatment Source: Company submission document B, section 3.6.3, tables 23-27, pp57-59 17 Abbreviations: AE, adverse event; SAE, Serious adverse event; UTIs, urinary tract infections Source: Company submission document B, section 3.10.2, table 47, p87 The all subjects as treated (ASaT) population was used for the safety analysis. The ASaT consisted of all randomised patients who took at least one dose of study medication Patients in both trials were prescribed with glycaemic rescue therapy in the form of open-label glimepiride or basal insulin when exceeding the following thresholds: • FPG > 270 mg/dL after randomisation up to week 6 • FPG > 240 mg/dL after week 6 through week 12 • FPG > 200 mg/dL after week 12 through week 26 Investigator determined whether events were related to the study drug Symptomatic hypoglycaemia = Event with clinical symptoms reported 18 by the investigator as hypoglycaemia 18 Abbreviations: SITA, sitagliptin; LINA, linagliptin; SLR, systematic literature review Source: Company submission document B, section 3.9.1 p61 and figure 14, p64 19 CONFIDENTIAL 20 Source: ERG report, section 3.2 p12 and 3.3 p14 21 Source: ERG report, section 3.4 table 3 pp17-19 ERG thought Haring 2013 (empagliflozin) a less suitable comparator because the ethnic mix in Bailey was more comparable with VERTIS MET 22 Source: ERG report, section 3.4 table 3 pp17-19 23 24 25 26 27 28 29 30 NATIONAL INSTITUTE FOR HEALTH AND CARE EXCELLENCE Fast track appraisal: cost-comparison case Ertugliflozin monotherapy and dual therapy for treating type 2 diabetes mellitus [ID1158] [ACIC] Document B Company evidence submission 18th July 2018 File name Version Contains Date confidential information Yes 18th July 2018 Ertugliflozin monotherapy and dual therapy for treating type 2 diabetes mellitus © MSD (2018). All rights reserved Page 1 of 102 Contents Tables and figures ................................................................................................................ 3 Appendices ........................................................................................................................... 5 Abbreviations ........................................................................................................................ 6 B.1 Decision problem, description of the technology and clinical care pathway ..................... 8 B.1.1. Decision problem ................................................................................................. 8 B.1.2. Description of the technology being appraised .................................................
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