Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Endoscopic Disease Severity and Patient Reported Outcomes in Crohn’s Disease
Vivli Data Request: 6496
Funding Source: None
Potential Conflicts of Interest: None
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. CD affects any area of the gastrointestinal tract but is more common in the ileum and colon. Symptoms of CD include abdominal pain, diarrhea, fever, fatigue and weight loss, which are considered as part of disease assessment. The Crohn’s Disease Activity Index (CDAI) is a tool that combines laboratory values, findings from physical examination, and three patient-reported outcomes (PROs): abdominal pain, number of daily soft/liquid stools and general well-being.
PRO-based endpoints are now required for clinical trials for CD in place of CDAI-based endpoints. However, several studies have identified a disconnect between the CDAI, PROs and objective measures of disease such as endoscopy. Endoscopic remission (ER) remains an important goal of treatment in CD. Recent post-hoc analyses have suggested that PROs at baseline and after the induction phase of treatment are not associated with one-year ER. Further, it has been shown that ulcer size and location at baseline play an integral role in the ability to achieve one-year ER.
In the context of these findings, there is a need to better understand how ulcer size at baseline and post-induction impact the ability to achieve one-year ER. The proposed study aims to analyze data from the UNITI-1, UNITI-2, and IM-UNITI trials (provided by the YODA Project) and the EXTEND trial (provided by Vivli).
Statistical Analysis Plan:
Data from EXTEND, UNITI-1, UNITI-2 and IM-UNITI are being requested. Data from three time points will be acquired: baseline, end of induction (week 8 in UNITI and week 12 in EXTEND) and week 52.
UNITI-1 and UNITI-2 were phase three induction studies with a duration of 8 weeks in which patients were randomized to weight-based ustekinumab, standard dose ustekinumab, or placebo. Patients who responded to induction therapy were re-randomized to placebo or ustekinumab every 8 or 12 weeks in the maintenance phase of the study, IM-UNITI, which continued for an additional 44 weeks for a total study duration of 52 weeks. Participants in the endoscopic substudy underwent colonoscopies at baseline, week 8 (end of induction) and week 52 (one-year).
Participants in EXTEND were treated with adalimumab induction therapy for four weeks and subsequently were randomized to adalimumab every other week or placebo for an additional 48 weeks, for a total study duration of 52 weeks. Endoscopies were performed at baseline, week 12 (end of induction) and week 52 (one-year). In both UNITI and EXTEND, all endoscopies were centrally read.
For this analysis, participants with baseline and post-induction endoscopic and PRO assessments will be included. For the main analysis, a complete case analysis of all participants will be done. In separate sensitivity analyses, those who crossed over between treatments (e.g. adalimumab and placebo, ustekinumab and placebo) will be excluded. Additionally, participants will be analyzed on an intention-to-treat basis; as such, participants with missing outcome data will be assumed to not have achieved the outcome of interest.
Baseline summary statistics of the patient population will be provided. While participants from all trials requested will be grouped for the main analysis, baseline characteristics for each trial population will also be evaluated. A variable that categorizes participants based on trial will be included in the model. Continuous variables will be presented as means and standard deviations and dichotomous variables as proportions/percentages. Logistic regression will be performed to model the relationship between the independent and dependent variables. Unadjusted and adjusted odds ratios, 95% confidence intervals and associated p-values will be provided. To address the issue of multiple hypotheses testing, the threshold for statistical significance will be set to 0.01 instead of the conventional 0.05. Disease duration and treatment allocation are known confounders of endoscopic healing, which will be adjusted for in multivariate logistic regression.
Data from YODA will be transferred to the Vivli secure platform for analysis. Data will be analyzed using Stata, which is available on the Vivli secure platform.
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)
Sponsor: 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)
Sponsor: 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
Sponsor: Johnson & Johnson
Study ID: NCT01369355
Sponsor ID: CR018421
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
Study ID: NCT00348283
Sponsor ID: M05-769
Cara Pray, MD, Emily C L Wong, BHSc, Achuthan Aruljothy, MDCM, Parambir S Dulai, MD, John K Marshall, MD, MSc, Walter Reinisch, MD, PhD, Neeraj Narula, MD, MPH, Ulcer Size After Induction Therapy Performs Better Than Symptom Assessment for Prediction of One Year Endoscopic Remission in Crohn’s Disease: A Post Hoc Analysis, Inflammatory Bowel Diseases, 2022;, izac210, doi: 10.1093/ibd/izac210