Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Dominant Patient Reported Outcomes on Predicting Mucosal Healing in Crohn’s Disease
Vivli Data Request: 7077
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. 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. 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. For example, PRO-2 remission is an endpoint that considers abdominal pain and number of daily soft/liquid stools. However, several studies have identified a disconnect between the CDAI, PROs and objective measures of disease such as endoscopy. Mucosal healing (MH) 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 MH. However, PROs are subjective to each patient, and it is hypothesized that improvement in the most severe (dominant) PRO may have a prognostic role. The primary objective of this study is to evaluate if dominant PROs at baseline, and their improvement at the end of induction therapy, can predict longer term clinical and endoscopic outcomes at week 52.
Statistical Analysis Plan:
Descriptive statistics will be used to summarize baseline characteristics (e.g. disease activity and patient demographics) as well as outcomes among patients with baseline endoscopic disease activity. Dichotomous variables will be presented as proportions or percentages. Continuous variables will be reported as means with standard deviations or medians with interquartile ranges.
Severe AP is defined as a score of 3, on a scale of 0=none, 1=mild, 2=moderate and 3=severe. As no defined cut-off for severely elevated SF exists, a cut-off of ≥4 will be used to define severely elevated SF as this has been shown to correlate with elevated CDAI scores (9,10). At baseline, the most severe score for AP or SF will be defined as the dominant PRO. Participants with severe AP and SF will be classified as achieving dominant PRO resolution if both AP and SF have been resolved. Participants with missing outcome data will be analyzed on an intention-to-treat basis (e.g. those with missing endoscopic data at week 52 will be assumed to not have achieved MH).
Multivariable logistic regression models will be used to assess the relationship between baseline and post-induction PROs and outcomes of interest. Adjustment for known confounders, including treatment allocation, disease duration, presence of stricture at baseline and concomitant corticosteroid use, will be performed. Planned exploratory analyses will stratify patients based on MM-SES-CD category, SES-CD category, and other factors that are known predictors for the outcomes of interest (e.g. prior anti-TNF failure, disease location, disease duration). Sensitivity analyses will be conducted with alternative definitions of dominant PRO resolution (e.g. those with severely elevated AP and SF at baseline will have achieved resolution if either AP or SF is resolved). Results will be presented as odds ratios with 95% confidence intervals and associated p-values. To maintain independence between studies, a variable that categorizes participants based on trial will be included in the model. Data will be analyzed using Stata.
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 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
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
Public Disclosure:
- Wong, EC, Dulai, PS, Marshall, JK, Jairath, V, Reinisch, W, Narula, N. Resolution of dominant patient-reported outcome at end of induction predicts clinical and endoscopic remission in Crohn’s disease. Aliment Pharmacol Ther. 2022; 00: 1– 9. doi: 10.1111/apt.16805
- N Narula, C Pray, E Wong, J F Colombel, J Marshall, M Daperno, W Reinisch, P Dulai, DOP16 Categorizing endoscopic severity of Crohn’s Disease using the Modified Multiplier SES-CD (MM-SES-CD), Journal of Crohn’s and Colitis, Volume 16, Issue Supplement_1, January 2022, Pages i065–i066, doi: 10.1093/ecco-jcc/jjab232.055
- Neeraj Narula, Cara Pray, Emily C L Wong, Jean-Frederic Colombel, John K Marshall, Marco Daperno, Walter Reinisch, Parambir S Dulai. Categorising Endoscopic Severity of Crohn’s Disease Using the Modified Multiplier SES-CD [MM-SES-CD]. Journal of Crohn’s and Colitis, 2022;, jjac018,. doi: 10.1093/ecco-jcc/jjac018