Lead Investigator: Vipul Jairath, University of Western Ontario
Title of Proposal Research: Impact of concomitant baseline medication on efficacy of biologics and small molecules for Inflammatory Bowel Disease
Vivli Data Request: 7850
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, and Vividion.
Speaker’s fees from, Abbvie, Ferring, Galapagos, Janssen Pfizer Shire, Takeda, and 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 condition that causes chronic inflammation to the gastrointestinal (GI) tract. The two types of IBD include ulcerative colitis (UC) and Crohn’s Disease (CD). In UC, inflammation occurs in the colon and rectum, mainly affecting the inner lining of the colon. For CD, inflammation occurs in any part of the GI tract from mouth to anus, affecting multiple layers of the small intestinal and colon. IBD is a common disease, with 6.8 million people around the world who suffer from it (Global Burden of Disease Inflammatory Bowel Disease Collaborators, 2020). There is currently no cure for IBD, however there are several types of medications that can be used to treat the disease including aminosalicylates, corticosteroids, immunomodulators, antibiotics, biologic therapies and small molecule drugs.
Given that patients with IBD may be on a variety of different medications to help manage their condition, it is important to understand whether the medications a patient is currently taking at the start of a trial modifies the efficacy of the new drug being studied (Feuerstein et al., 2020; Bressler et al., 2015). For example, we would be interested in whether the new drug is more or less effective for patients on steroids at the start of a study, compared to patients not on steroids. This is important to establish as the results could influence how we interpret the results of clinical trials and how clinicians use treatments in routine practice, such as prescribing the drug to most effective groups of patients. The results will also guide the design of future clinical trials. Published clinical trials usually do not present effect modification of new drug by baseline medications. Such results can only be obtained through access to patient level data from clinical trials.
In this study, we want to specifically look at whether the use of concomitant steroids, aminosalicylates (5ASA), immunosuppressants (azathioprine, methotrexate), protein pump inhibitors (PPI), histamine receptor agonists (H2RA), antibiotics, cholesterol lowering drugs, anti-hypertensive agents, drugs for management of diabetes, antidepressants, or opioid use at baseline in patients with IBD, impacts the efficacy of the investigational drug (Lu et al., 2021; Macer et al., 2017; Niccum et al., 2021).
In addition to baseline medications, we plan to assess impact of racial differences in the efficacy of drugs. Historically, IBD has been predominantly studied in White population than patients from other racial backgrounds. There is limited evidence on the impact of race/ethnicity on differences in clinical response, especially amongst Asians and Hispanics, which are reflecting an increase in disease incidence. The treatment response and utilization of advanced biological agents vary amongst different racio-ethnic backgrounds. This difference has been implicated to arise from socioeconomic factors and access to specialist gastroenterologists. While non-modifiable factors like genetic and demographic variables cannot be changed, the effect of modifiable factors such as healthcare access and environmental factors can be abridged. Previous studies have shown response rates by Infliximab, a biological agent, differ between black and white patients despite adjusting for income, demographic and disease characteristics. This suggests that factors other than socioeconomic differences also impact treatment results across different races/ethnicities. It is crucial to investigate other factors influencing this disparity in treatment response and hospitalization rate after balancing the access to specialist healthcare resources, socioeconomic and financial factors through clinical trials. The different advanced biological agents have distinct mechanism of action than the previously cited biologic agent, Infliximab, which may also influence difference in treatment response. The proposed study will assess the impact of racial-ethnic differences on treatment efficacy and safety in IBD across diverse medication options. This will provide an opportunity to better understand the differential outcomes across races and select appropriate treatment tailored to the individual.
By identifying the impact of racio-ethnic differences and the medications used at baseline, it may help improve the design of future studies as well as help guide treatment decisions for patients with IBD.
We will further assess the analysis in age groups (< 60 years and ≥ 60 years age) to study the impact of advanced age. The highly efficacious agents also pose a risk of serious adverse events which can have poorer outcomes in elderly because of multiple co-morbidities and a weakened immune system. The data for less than 60 years age is often limited in a single trial and combination of multiple trials will facilitate enough sample size for this population in a trial setting.
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 baseline medications (yes/no).
In order to assess our primary outcome (clinical response/remission), we will analyze individual level data using the modified Poisson regression to quantify modification of new drug effects by baseline medications 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 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, infections and serious adverse events.
For the secondary outcomes including 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.
The additional endpoints for UC trials include: 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. The additional endpoints for CD trials include: the baseline (Week 0) and primary endpoint assessment visits for the CDAI, each subcomponent of the CDAI, change in the total CDAI score, PRO2 score, change in the PRO2 score, SES-CD score, CDEIS score, each subcomponent of the SES-CD/CDEIS score, change in the SES-CD/CDEIS, change in each of the sub-component of the SES-CD/CDEIS, total, colonic, and ileal Global Histologic Disease Activity Score (GHAS), and change in the total, colonic, and ileal GHAS. To assess the additional endpoints for the UC and CD trials, appropriate regression methods for continuous data will be used. All analyses will be adjusted for other patient characteristics including age, sex, and disease duration. Results will be reported in terms of treatment effects (mean differences in scores) for patients used baseline medications and those did not use baseline medications, as well as difference in treatment effects between the two groups. Two-sided 95% confidence intervals and associated p-values will be presented.
Each model will have independent variables including drug, baseline medication, and their interaction. The focus of this project is the coefficient estimation for the interaction term.
Software used: RStudio
Requested Studies:
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn’s Disease (UNITI-2)
Data Contributor: Johnson & Johnson
Study ID: NCT01369342
Sponsor ID: CR018418
A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, Multicenter Study to Evaluate the Safety and Efficacy of Ustekinumab Induction Therapy in Subjects With Moderately to Severely Active Crohn’s Disease Who Have Failed or Are Intolerant to TNF Antagonist Therapy (UNITI-1)
Data Contributor: Johnson & Johnson
Study ID: NCT01369329
Sponsor ID: CR018415
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction of Clinical Response and Remission by Vedolizumab in Patients With Moderate to Severe Crohn’s Disease
Data Contributor: Takeda
Study ID: NCT01224171
Sponsor ID: C13011
Phase IIIb, Multinational, Randomized, Double-blind, Placebo-controlled Trial to Assess the Efficacy and Safety of Certolizumab Pegol, a Pegylated Fab’ Fragment of a Humanized Anti-Tumor Necrosis Factor(TNF)-Alpha Monoclonal Antibody, Administered in Subjects With Moderately to Severely Active Crohn’s Disease.
Data Contributor: UCB
Study ID: NCT00552058
Sponsor ID: C87085
ACCENT I – A Randomized, Double-blind, Placebo-controlled Trial of Anti-TNFa Chimeric Monoclonal Antibody (Infliximab, Remicade) in the Long-term Treatment of Patients With Moderately to Severely Active Crohn’s Disease
Data Contributor: Johnson & Johnson
Study ID: NCT00207662
Sponsor ID: CR004771
A Phase 3, Randomized, Placebo-Controlled, Blinded, Multicenter Study of the Induction and Maintenance of Clinical Response and Remission by Vedolizumab (MLN0002) in Patients With Moderate to Severe Crohn’s Disease
Data Contributor: Takeda
Study ID: NCT00783692
Sponsor ID: C13007
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, 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:
Ahuja, D., Zou, G., Solitano, V., Syal, G., Lee, H.H., Ma, C., Jairath, V. and Singh, S., 2024. No Impact of Concomitant Medications on Efficacy and Safety of Biologics and Small Molecules for Ulcerative Colitis. Clinical Gastroenterology and Hepatology. Doi: 10.1016/j.cgh.2024.08.040