Lead Investigator: Vipul Jairath, University of Western Ontario
Title of Proposal Research: Efficacy of medical therapies for ulcerative colitis according to disease distribution: An individual patient data meta-analysis of randomized controlled trials
Vivli Data Request: 7854
Funding Source: None
Potential Conflicts of Interest: Dr. Jairath reports: Consulting fees from AbbVie, Alimentiv Inc, Arena pharmaceuticals, Asahi Kasei Pharma, Asieris, Astra Zeneca, Bristol Myers Squibb, Celltrion, Eli Lilly, Ferring, Flagship Pioneering, Fresenius Kabi, Galapagos, GlaxoSmithKline, Genentech, Gilead, Janssen, Merck, Mylan, Pandion, Pendopharm, Pfizer, Protagonist, Reistone Biopharma, Roche, Sandoz, Second Genome,Takeda, Teva, Topivert, Ventyx, Vividion
Speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, Fresenius Kabi
Financial Salary Support from the John and Susan McDonald Endowed Chair at Western University, London, Ontario, Canada
These conflicts of interest will be disclosed when the research is presented and published.
Dr. Singh reports: Institutional research grants from AbbVie (completed 2020), Janssen (completed 2020) and Pfizer (active).
Personal fees from Pfizer for ad hoc grant review.
Summary of the Proposed Research:
Inflammatory bowel disease (IBD) is a common condition that causes chronic inflammation to the gastrointestinal (GI) tract, impacting 6.8 million people around the world. The two types of IBD include ulcerative colitis (UC) and Crohn’s Disease (CD). In CD, inflammation occurs in any part of the GI tract, affecting multiple layers of the colon. The inflamed areas are not continuous and may appear next to areas with healthy tissue. In UC, inflammation occurs in the colon and rectum, typically only affecting the outer layer of the colon. The inflamed areas are continuous and starts at the rectum, spreading proximally into the colon.
UC can be categorized according to where in the colon the inflammation occurs. Left-sided colitis is where the inflammation starts at the anus and extends to approximately to affect one-third of the colon, whereas extensive colitis is where the inflammation extends further to affect the entire colon. Previous studies have shown that disease in UC patients in only the rectum and the S-shaped part of the lower large intestine is found in 30%-50% of patients, left-sided colitis found in 20%-30%, and inflammation of the entire colon is found in approximately 20%. The Montreal classification categorizes disease distribution in UC by extent of disease as follows: (E1) Ulcerative proctitis; (E2) Left sided UC ; (E3) Extensive. Differing distribution of disease may present with differing burden of symptoms and a differential response to treatment, neither of which have been well studied. For example, patients with UC only affecting the last portion of their colon could be more likely to experience bleeding and urgency. Given that patients with UC have different disease distributions, it is important to assess whether disease distribution impacts the efficacy of the new drug being studied. However, when clinical trials are performed to assess the efficacy of a medication, there are no restrictions on disease distribution as an entry criteria, apart from the exclusion of patients with isolated inflammation of the lining of the rectum.
In this study, we want to look at whether the disease distribution of patients enrolled in clinical trials of moderate to severe UC, impacts the treatment effects of the trial intervention. We are specifically interested in whether the treatment effect varies by patients with left sided colitis, compared to patients with extensive colitis. By identifying the impact of disease distribution on treatment efficacy, it may help improve the design of future clinical trials as any differential effect may result in stratification of patients by disease distribution. It may also help to inform treatment recommendations for patients depending upon their disease distribution.
Statistical Analysis Plan:
Appropriate descriptive statistics will be presented for demographic and baseline characteristics for both the entire study sample and according to each study treatment arm (active or placebo) across different disease distributions (extensive disease vs. left sided disease).
We will analyze individual level data using the modified Poisson regression to quantify modification of new drug effects by disease distribution on the risk ratio scale (Zou 2004). Study-specific estimates and the 95% two-sided confidence intervals will be obtained for outcomes of interest (clinical, histologic, and endoscopic remission and response).To obtain overall estimates and 95% confidence intervals of all studies, we will apply the extended modified Poisson regression model (Zou et al., 2013) with studies being considered as clusters. The same analysis will be performed for the other secondary binary outcomes, including
endoscopic and histologic response/remission.
For the secondary outcomes including individual symptoms of rectal frequency and stool bleeding, the regression model for counts will be used, while binary data will be analyzed using the modified Poisson regression. To handle the potential over-dispersion of the data, negative binomial regression models will be used and the results will be presented in terms of rate ratios and 95% confidence intervals. In order to assess both the CRP and FCP levels and change in the CRP and FCP levels from baseline (Week 0) to primary endpoint assessment, log-transformed endpoint CRP and FCP will be analyzed using regression model with independent variables including baseline CRP/FCP and treatment indicators, as well as other patients’ characteristics as appropriate.
Lastly, to assess the additional endpoints including the baseline (Week 0) and primary endpoint assessment visits for the MCS, each subcomponent of the MCS, change in the total MCS score and change in each subcomponent of the MCS, Geboes score, change in the Geboes score, RHI score, and change in the RHI score, linear regression models will be used with covariates including baseline outcomes, treatment groups and other characteristics as appropriate.
Each model will have independent variables including drug, disease distribution, and their interaction. The focus of this project is the coefficient estimation for the interaction term. Primary estimates will be the ratio of treatment effects on left-sided colitis to that of extensive colitis.
Software Used:
SAS
Requested Studies:
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 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: NCT01458951
Sponsor ID: A3921095
A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Intravenously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00488774
Sponsor ID: CR014188
A Phase 2/3 Multicenter, Randomized, Placebo-controlled, Double-blind Study to Evaluate the Safety and Efficacy of Golimumab Induction Therapy, Administered Subcutaneously, in Subjects With Moderately to Severely Active Ulcerative Colitis
Data Contributor: Johnson & Johnson
Study ID: NCT00487539
Sponsor ID: CR014176
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
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: NCT00036439
Sponsor ID: CR004777
A Phase 3 Randomized, Double-Blind, Placebo-Controlled Study, With a Vedolizumab IV Reference Arm, to Evaluate the Efficacy and Safety of Vedolizumab Subcutaneous as Maintenance Therapy in Subjects With Moderately to Severely Active Ulcerative Colitis Who Achieved Clinical Response Following Open-Label Vedolizumab Intravenous Therapy
Data Contributor: Takeda
Study ID: NCT02611830
Sponsor ID: MLN0002SC-3027
A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As A Maintenance Therapy In Subjects With Ulcerative Colitis
Data Contributor: Pfizer
Study ID: NCT01458574
Sponsor ID: A3921096
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 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 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 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
Public Disclosures:
Vuyyuru, S.K., Ma, C., Nguyen, T.M., Zou, G., Peyrin-Biroulet, L., Danese, S., Dulai, P., Narula, N., Singh, S. and Jairath, V., 2024. Differential efficacy of medical therapies for ulcerative colitis according to disease extent: patient-level analysis from multiple randomized controlled trials. eClinicalMedicine, 72. Doi : 10.1016/j.eclinm.2024.102621