Comparative Effectiveness of Vedolizumab vs. Infliximab in Ulcerative Colitis

Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Comparative Effectiveness of Vedolizumab vs. Infliximab in Ulcerative Colitis
Vivli Data Request: 6064
Funding Source: None
Potential Conflicts of Interest: None

Summary of the Proposed Research:

Ulcerative colitis (UC) is an inflammatory bowel disease that affects the large intestine and is characterized by diarrhea, rectal bleeding, abdominal pain, urgency, and tenesmus (Tenesmus is the feeling of incomplete evacuation of stool). Patients with severe UC and/or corticosteroid-refractory disease are candidates for biologic monoclonal antibody treatments.

Vedolizumab and infliximab are two biologic therapies that have demonstrated efficacy in achieving and maintaining remission through several pivotal placebo-controlled trials, including ACT 1 (NCT00036439), ACT 2 (NCT00096655), and GEMINI 1 (NCT00783718). Recently, the VARSITY trial used an active-comparator approach to demonstrate the superiority of vedolizumab to adalimumab among patients with moderate to severe UC. However, network meta-analyses have suggested superiority of infliximab over adalimumab as a first-line biologic treatment in UC patients. There are no head-to-head trials comparing vedolizumab and infliximab.

Given the routine use of vedolizumab and infliximab as a treatment for UC, head-to-head comparisons are needed to better understand the positioning of vedolizumab as a treatment for biologic-naïve UC patients.

The Mayo Score is a tool that is used to determine UC disease activity and is comprised of four patient-reported and endoscopic parameters: stool frequency, rectal bleeding, endoscopic findings, and physician’s global assessment. Each parameter is scored from 0 to 3, with higher scores indicating greater disease severity. The total Mayo Score ranges from 0 to 12, while the partial Mayo Score excludes the endoscopic subscore and thus ranges from 0 to 9. While Mayo Scores have been widely used in clinical trials for UC as primary endpoints, mucosal healing (determined by endoscopy) remains an important target of treatment as well.

The primary objective of this study is to compare the efficacy of vedolizumab and infliximab to achieve post-induction (week 6) clinical remission and one year mucosal healing as determined by the Mayo Score. The secondary objectives of this study include clinical remission at one year, mucosal healing at post-induction (week 6). Additionally, clinical response, reduction in markers of disease activity (e.g. fecal calprotectin, C-reactive protein), and reduction in histologic measures of disease activity at post-induction (week 6) and one year will be analyzed.

Data from GEMINI 1 and VARSITY, which is being requested from Vivli, will be pooled to obtain a cohort of biologic-naïve UC patients treated with vedolizumab. Biologic-naïve patients treated with infliximab in ACT 1 and ACT 2 which is being requested from the Yale University Open Data Access (YODA) Project, will be pooled to comprise the infliximab cohort.

Statistical Analysis Plan

In GEMINI 1, 746 patients were randomized to vedolizumab, of which 388 were biologic-naïve. In VARSITY, 385 patients were randomized to vedolizumab, of which 305 were biologic-naïve. All patients who received infliximab in ACT 1 (n=243, 121 received 5mg/kg infliximab and 122 received 10mg/kg infliximab) and ACT 2 (n=241, 121 received 5mg/kg infliximab and 120 received 10mg/kg infliximab) were biologic-naïve. Therefore, the eligible study population includes 484 (243 from ACT 1 and 241 from ACT 2) in the infliximab cohort and 693 (388 from GEMINI 1 and 305 from VARSITY) in the vedolizumab cohort. Data from these trials are being requested as common time points were used. Mayo Scores were captured at two common time points of interest (week 6 and one year) in GEMINI 1, VARSITY, ACT 1 and ACT 2.

Patients with missing outcome data (e.g. one year Mayo Score) will be excluded from the primary analysis. A separate intention-to-treat analysis will be conducted where patients with missing data will be assumed to not have achieved the outcomes of interest.

Logistic regression will used to assess the treatment effect on the outcome of interest. Univariate analyses will be conducted to identify associations between covariates and the outcome of interest, and any variables with a p-value < 0.10 will be included in the multivariate model.

In addition, propensity score matching on a one-to-one basis using k-nearest neighbor without replacement will be performed. The propensity score represents the conditional probability of receiving vedolizumab or infliximab, given the observed co-variates.8 The propensity scores will be estimated using a nonparsimonious logistic regression model that will consider baseline covariates. The treatment group will be regressed on these baseline covariates. Subsequently, graphs of the propensity scores for participants treated in both studies will be compared to assess the region of common support. This assesses the propensity score distributions between both groups and identifies the region of common support (overlap).

Continuous variables will be presented as means (and standard deviations [SD] or as medians and interquartile ranges [IQR]), if the data is skewed. Binary variables will be presented as proportions or percentages. Descriptive statistics will be used to summarize baseline demographics, disease characteristics and outcome parameters of included patients. Differences between groups will be compared using the Mann-Whitney U test or chi-squared test. Data will be analyzed using Stata, which is available on the Vivli and YODA Project secure platform.

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
Sponsor: Takeda
Study ID: NCT02497469
Sponsor ID: MLN0002-3026

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
Sponsor: Takeda
Study ID: NCT00783718
Sponsor ID: C13006

A Randomized, Placebo-controlled, Double-blind Trial to Evaluate the Safety and Efficacy of Infliximab in Patients With Active Ulcerative Colitis
Sponsor: Johnson & Johnson
Study ID: NCT00036439
Sponsor ID: CR004777

Public Disclosure:

Narula N, Wong ECL, Marshall JK, Colombel JF, Dulai PS, Reinisch W. Comparative Efficacy for Infliximab Vs Vedolizumab in Biologic Naive Ulcerative Colitis. Clin Gastroenterol Hepatol. 2021 Jul 28:S1542-3565(21)00820-X. doi: 10.1016/j.cgh.2021.07.038 PMID: 34329776.