Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Comparative Effectiveness of Biologics for Endoscopic Healing of the Ileum and Colon in Crohn’s Disease
Vivli Data Request: 7387
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:
Crohn’s disease (CD) is a type of inflammatory bowel disease that is characterized by periods of relapse and remission and affects nearly 300,000 Canadians. CD affects any area of the gastrointestinal tract but is more common in the ileum and colon. Healing of ulcers is an important treatment target in CD, and is defined as endoscopic healing (EH). The Simple Endoscopic Score for CD (SES-CD) is a validated tool used to quantify mucosal inflammation in CD via endoscopy and is used to define EH. Biologics are medications used to treat patients with moderate to severe CD. To obtain regulatory approval, biologics must demonstrate the ability to heal ulcers in clinical trials of CD. Biologics approved for CD include adalimumab, ustekinumab, infliximab, and vedolizumab. Previous studies have demonstrated EH is not linear across the segments of the colon and the ileum and may be more difficult to achieve in the ileum and rectum. However, the comparative effectiveness of approved biologics for CD for achieving segment-specific EH has not been reported. The primary objective of this study is to compare the efficacy of four approved biologics for CD on endoscopic healing of the ileum and individual segments of the colon at week 52.
Statistical Analysis Plan:
Descriptive statistics will be used to summarize baseline characteristics (e.g. distribution of endoscopic disease and patient demographics) as well as outcomes. Dichotomous variables will be presented as proportions or percentages. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges.
The SES-CD is an endoscopic scoring tool used in clinical trials to quantify endoscopic burden in CD. Each of the five ileocolonic segments are scored using four parameters, which are each scored from a scale of 0-3, for a total segment SES-CD score totalling 0-12. The primary outcome (segment SES-CD of 0) will be determined based on the total segment SES-CD score. Additionally, one of the parameters of the SES-CD measures the size of ulcers (0: none, 1: small, 2: large , 3: very large). The secondary outcome (absence of mucosal ulcerations) will be determined based on this parameter. Participants with missing outcome data will be analyzed on an intention-to-treat basis (e.g. those with missing endoscopic data at one year will be assumed to not have achieved endoscopic healing (EH)). As this is a pooled analysis, a categorical variable will be used to identify the trial.
Multivariable logistic regression models will be used to assess the relationship between treatments and segment EH at one year. Adjustment for known confounders, including disease duration, concomitant corticosteroid use, and prior anti-tumor necrosis alpha failure will be performed. Additionally, other socio-demographic factors that may influence the outcome will be assessed on univariate analysis, and those with a p < 0.05 will be included in the multivariable regression models. Planned exploratory analyses will stratify patients based on previous biologic exposure among other factors that are known predictors for the outcomes of interest. Sensitivity analyses will be conducted with alternative definitions of endoscopic healing (absence of mucosal ulcerations). Results will be presented as odds ratios with 95% confidence intervals and associated p-values. Data will be analyzed using Stata.
Requested Studies:
An Open-Label Phase 3b Study to Assess Mucosal Healing in Subjects With Moderately to Severely Active Crohn’s Disease Treated With Vedolizumab IV
Data Contributor: Takeda
Study ID: NCT02425111
Sponsor ID: MLN0002-3028
A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study of the Human Anti-TNF Monoclonal Antibody Adalimumab Endoscopy Trial to Evaluate the Effects on Mucosal Healing in Subjects With Crohn’s Disease Involving the Colon
Data Contributor: AbbVie
Study ID: NCT00348283
Sponsor ID: M05-769
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, 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 Maintenance Therapy in Subjects With Moderately to Severely Active Crohn’s Disease
Data Contributor: Johnson & Johnson
Study ID: NCT01369355
Sponsor ID: CR018421
Public Disclosure:
Narula, Neeraj; Wong, Emily C.L.; Dulai, Parambir S.; Marshall, John K.; Jairath, Vipul; Reinisch, Walter. Comparative Effectiveness of Biologics for Endoscopic Healing of the Ileum and Colon in Crohn’s Disease. The American Journal of Gastroenterology: April 15, 2022 – Volume – Issue – 10.14309/ajg.0000000000001795. doi: 10.14309/ajg.0000000000001795