Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Histologic Predictors of Endoscopic Healing in Crohn’s Disease
Vivli Data Request: 6041
Funding Source: None
Potential Conflicts of Interest: None
Summary of the Proposed Research:
Crohn’s disease (CD) is an inflammatory bowel disease that can affect any part of the gastrointestinal tract and is characterized by periods of relapse and remission. Unfortunately, patients with CD often experience disease progression, including fistulas, strictures, and symptoms including worsening abdominal pain and/or diarrhea.
The Crohn’s Disease Activity Index (CDAI) is a widely used tool in clinical trials for CD as primary endpoints, namely clinical remission (CR) and response. While the CDAI has demonstrated drug efficacy through these endpoints, histologic endpoints are lacking. Several studies have identified a disconnect between patient reported symptoms and endoscopic evidence of disease, which may be attributed to the presence of comorbid gastrointestinal disorders.
Treatment goals have evolved to include endoscopic-based endpoints, using tools such as the Crohn’s Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for CD (SES-CD). However, evidence of histologic inflammation is present in approximately one third of patients achieving endoscopic healing. Therefore, the relationship between clinical, histologic and endoscopic measures of CD activity require further investigation. The Global Histology Activity Score (GHAS) is a widely used tool that grades biopsies of the ileum and colonic segments (collected at baseline, week 12 and 54 in EXTEND). Therefore, regional and global GHAS can be separated and compared.
Recently, the efficacy of ustekinumab on histologic improvement in CD patients have been explored, using data from the phase 3 induction and maintenance UNITI trials (ClinicalTrials.gov NCT01369329, NCT01369342, and NCT01369355). However, to date, no study has investigated the relationship between baseline histologic disease activity and ability to attain endoscopic healing in CD.
The primary objective of this study is to evaluate the association between baseline histologic characteristics and endoscopic measures of disease activity at week 54 using data from the EXTEND trial. The secondary objectives of this study include assessing alternative definitions of mucosal healing (SES-CD of 0 and/or absence of mucosal ulcerations) and endoscopic response (SES-CD reduction at least 50% from baseline) at week 12 and 54. Planned exploratory analyses with immunohistochemistry may be done. Logistic regression will be used and models will be adjusted for confounders, such as disease duration, treatment allocation, concomitant corticosteroid use and concomitant immunomodulator use.
Statistical Analysis Plan:
The EXTEND study is being requested as it is one of few studies that captures clinical, histologic and endoscopic data at common time points (i.e. baseline, week 12 and 54). Participants in EXTEND with baseline GHAS scores will be included in the analysis as everyone enrolled in EXTEND received active treatment (i.e. adalimumab) at baseline until week 4, when randomization to adalimumab or placebo occurred. Patients had the opportunity to enter the open-label phase of the study starting at week 8 (i.e. receive adalimumab) if patients experience disease progression or had no response during the double-blind phase. Treatment allocation at week 4 and/or upon open-label entry will be adjusted for in the multivariate analyses, in addition to concomitant immunomodulator use and concomitant corticosteroid use.
Summary statistics of the eight GHAS parameters will be done to determine data availability. If the proportion of missing data for a subscore exceeds 50%, the GHAS parameter will be removed for the analysis and overall score. If the proportion of missing data for a subscore is between 25-50%, the subscore will be included in the main analysis, and a sensitivity analysis will be done excluding the subscore. If the proportion of missing data is less than 25%, the subscore will be included in the analysis. Regardless, missing data and any modification to the GHAS score will be clearly described in publication of the results.
Baseline GHAS will be treated as a continuous variable as well as categorial (i.e. by segment and GHAS subscore). Global and regional GHAS will be assessed. Logistic regression will be used to model the likelihood of achieving the outcomes of interest. Backward stepwise selection will be used, with threshold for inclusion set to 0.10. To address potential confounding factors, an adjusted multivariate model will include baseline factors which are found to be significant on univariate analyses, in addition to disease duration and treatment allocation.
Continuous variables will be presented as means (and standard deviations [SD] or as medians and interquartile ranges [IQR]). Binary variables will be presented as proportions or percentages. Descriptive statistics will be used to summarize baseline demographics, disease characteristics and outcome parameters of included patients.
Data will be analyzed using Stata, which is available on the Vivli secure platform.
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
Emily C L Wong, BHSc, Arif Yusuf, MD, Jagoda Pokryszka, MD, Parambir S Dulai, MD, Jean-Frederic Colombel, MD, John K Marshall, MD, MSc, Walter Reinisch, MD, PhD, Neeraj Narula, MD, MPH. Increased Expression of Interleukin-13 Receptor in Ileum Associated With Nonresponse to Adalimumab in Ileal Crohn’s Disease. Inflammatory Bowel Diseases. 2022, izac157. doi: 10.1093/ibd/izac157, doi: 10.1093/ibd/izac208