Estimating Differences in the Comparison of Outcomes in Clinical Trials for Ulcerative Colitis Patients using Patient-Level Data and Aggregated Data Network Meta-Analysis

Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Estimating Differences in the Comparison of Outcomes in Clinical Trials for Ulcerative Colitis Patients using Patient-Level Data and Aggregated Data Network Meta-Analysis
Vivli Data Request: 8377
Funding Source: None
Potential Conflicts of Interest: Neeraj Narula holds a McMaster University Department of Medicine Internal Career Award. Neeraj Narula has received honoraria from Janssen, Abbvie, Takeda, Pfizer, Merck, Lupin and Ferring. None of the listed conflicts of interest are aware of or are involved in this research

Summary of the Proposed Research:

Ulcerative colitis (UC) is a chronic inflammatory bowel disorder that disrupts the normal functioning of the colon. Patients with UC encounter periods of asymptomatic remission and symptomatic relapse, including symptoms such as diarrhea, abdominal cramping, and rectal bleeding. The many therapeutics that exist for UC should exhibit efficacy and safety, and these outcomes are assessed often in placebo-controlled clinical trials. Analyzing and comparing clinical outcomes between these trials can inform clinical decisions on the basis of comparing and ranking the effectiveness offered by UC therapeutics.

Infliximab, adalimumab and vedolizumab have shown to be effective biologic therapeutic options for patients with moderate-to-severe UC, suggesting success in ability to maintain clinical remission in placebo-controlled trials, including ACT 1 (NCT00036439) and ACT 2 (NCT00096655), ULTRA 1 (NCT00385736) and ULTRA 2 (NCT00408629), and GEMINI 1 (NCT00783718). The head-to-head VARSITY trial (NCT02497469) depicted vedolizumab was more effective in comparison to adalimumab, in achieving clinical remission in moderate-to-severe UC patients. Golimumab is another therapeutic for treatment of moderate-to-severe active UC and has demonstrated efficacy and safety in the placebo-controlled study PURSUIT (NCT00488631). Induction and maintenance therapy in patients with moderate-to-severe UC has been depicted with ustekinumab on the strength of the UNIFI placebo-controlled trials (NCT02407236). More recently, small molecule biologics such as tofacitinib have recently evolved as an effective therapeutic on the strength of data from the placebo-controlled OCTAVE trials (NCT01465763).

The Mayo Score is commonly used as an indicator of disease severity in UC patients. It ranges from 0 (normal or inactive disease) to 12 (severe disease). The four sub-scores rank several patient-reported indicators of disease such as stool frequency, rectal bleeding, endoscopic observations, and physician’s global assessment. Sub-scores are ranked from 0 (normal) to 3 (severe disease). The partial Mayo Score excludes the endoscopic subscore, and ranges from 0-9. Clinical response and clinical remission are two common primary and secondary endpoints in clinical trials.

Though a meta-analysis can investigate estimations of one effect between two treatments, the potential of a network meta-analysis offers more than one estimate involved in measuring the effects between multiple treatments simultaneously. An aggregate network meta-analysis and an individual patient level meta-analysis can both yield estimates of the effects between clinical trials. However, the advantage of IPD meta-analyses can enhance the quality and information available in studies, by allowing us to adjust for differences in patient-level covariates. This can allow us to conduct more reliable, precise, and informative estimations on ranking interventions and inform clinical-based decisions in the realm of UC disease. While meta-analyses have been extensively performed in inflammatory bowel disease research, what is not entirely certain is whether the use of individual patient-level data makes a difference in the estimates obtained from network meta-analyses. Burr et.al. recently performed a network meta-analysis to compare the efficacy of biologic and small molecule therapeutics utilized in UC treatment, ranking upadacitinib as most effective in achieving clinical remission, and infliximab ranking superior in achieving endoscopic improvement. Bonovas et.al. performed a systematic review investigating the efficacy of biologics such as tofacitinib, infliximab, adalimumab, golimumab and vedolizumab, suggesting infliximab was superior in attaining clinical response and endoscopic improvement. An updated network-meta-analysis conducted by Singh et.al. discovered infliximab was ranked first in clinical remission and endoscopic improvement.

Although previous network meta-analyses have compared current biologics in respect to their ability to induce and maintain clinical response and remission, many have not explored treatment effect estimates using individual patient-level data.

The primary objective of this study is to evaluate whether differences exist in the estimations of clinical outcomes between two types of network meta-analyses. This will be facilitated by comparing a network-meta-analysis using individual patient-level data and an aggregated network meta-analysis using risk estimates from previously published clinical trial data.

Patient-level data from ULTRA 1, ULTRA 2, GEMINI 1, VARSITY and OCTAVE 1 is being requested from Vivli. Patient-level data from ACT 1, ACT 2, PURSUIT and UNIFI is being requested from the YODA project.

Requested Studies:

A Randomized, Double-Blind, Double-Dummy, Multicenter, Active-Controlled Study to Evaluate the Efficacy and Safety of Vedolizumab IV Compared to Adalimumab SC in Subjects With Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT02497469
Sponsor ID: MLN0002-3026

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Protocol to Evaluate the Safety and Efficacy of Ustekinumab Induction and Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT02407236
Sponsor ID: CR106920

A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis
Data Contributor: Pfizer
Study ID: NCT01465763
Sponsor ID: A3921094

A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by MLN0002 in Patients With Moderate to Severe Ulcerative Colitis
Data Contributor: Takeda
Study ID: NCT00783718
Sponsor ID: C13006

A Phase 3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Maintenance Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00488631
Sponsor ID: CR014179

A Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction and Maintenance of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: AbbVie
Study ID: NCT00408629
Sponsor ID: M06-827

A Multicenter, Randomized, Double-blind Placebo-controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab for the Induction of Clinical Remission in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: AbbVie
Study ID: NCT00385736
Sponsor ID: M06-826

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00096655
Sponsor ID: CR004783