Lead Investigator: Neeraj Narula, Hamilton Health Sciences
Title of Proposal Research: Modified Multiplier SES-CD (MM-SES-CD) on Predicting Endoscopic Remission in Crohn’s Disease
Vivli Data Request: 6642
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 is a type of inflammatory bowel disease characterized by periods of relapse and remission. Disease severity is assessed by endoscopy and is important to inform treatment decision-making. For example, patients with more severe disease (e.g. large bleeding ulcers in the colon) may require more advanced therapies to help heal the colon. Gastroenterologists often use scoring tools to help them quantify disease severity. One such tool is the Simple Endoscopic Score for Crohn’s disease (SES-CD). This tool scores the ileum, right colon, transverse colon, descending colon and rectum on four parameters: size of ulcers, extent of ulcers, surface affected by ulcers and any narrowings observed throughout the ileum and colon.
An important goal of treatment in Crohn’s disease is mucosal healing (MH). MH is a term used to describe healing of the ileum and colon. MH can be defined in many ways, including absence of ulcers in the ileum and colon, SES-CD score less than 3 and SES-CD score of 0. In clinical trials, patients often undergo endoscopy after the induction period of therapy (e.g. week 8-12) and at one year to assess if MH was achieved.
The SES-CD assumes each of these four parameters across all ileocolonic segments are equally important for predicting MH. However, there is growing evidence to suggest some components of the SES-CD are more important for predicting who will achieve MH in the future. As published in Gut, the Modified Multiplier SES-CD (MM-SES-CD) is a novel tool that differentially weights components of the SES-CD to reflect the relative importance of each baseline parameter on disease prognosis at one year. However, it is unknown what short-term reduction in MM-SES-CD can reliably predict long-term healing.
The primary objective of this study is to determine the minimally clinically important reduction in MM-SES-CD from baseline to post-induction endoscopy that can predict MH at week 52. Week 52 will be used as the endpoint as it was used as the endpoint in the initial MM-SES-CD publication. After further validation, this reduction in MM-SES-CD can potentially be used as a target cut-off of endoscopic response.
Patients with Crohn’s disease may benefit from this study as the MM-SES-CD can help them understand how likely they are to achieve healing in the future based on their improvement in MM-SES-CD score. This may help patients and clinicians in deciding if their therapy is helping them achieve healing, or if an earlier switch in therapy is warranted. In the future, patients may also benefit from alternative stratification criteria in clinical trials based on evidence generated from this study on the MM-SES-CD.
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.
Possible cut-off values at the end of induction (i.e. week 8 or 12) will be evaluated for predicting MH and CSFREM at week 52, which includes: mucosal healing (absence of ulcerations), absolute value of MM-SES-CD ranging from < 50 to < 1 points, absolute value of SES-CD ranging from < 10 to < 1 points, absolute decrease in MM-SES-CD from baseline ranging from 0 to 50 points (only among those with a baseline value higher than the cut-off), absolute decrease in SES-CD from baseline ranging from 0 to 10 points (only among those with a baseline value higher than the cut-off), relative change in SES-CD from baseline (0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%) and relative change in MM-SES-CD from baseline (0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%). 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). A variable that categorizes participants based on trial will be included in the model.
The accuracy of the various cut-offs will be evaluated using the area under the curve (AUC) of the receiver operative characteristic (ROC) and defined as poor (AUC: 0.5–0.7), fair (0.7–0.8), good (0.8–0.9) and excellent (0.9–1.0). AUCs will be compared using the concept of generalized U-statistics, as described by DeLong et al.(5) Sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and associated 95% confidence intervals will also be calculated. Cut-offs with an AUC of at least 0.70 will be considered and the optimal cut-off will be selected among those with a high PLR and low NLR. Bootstrap resampling on 10,000 samples will be done to validate the chosen cut-off.
Sensitivity analyses will be conducted on subpopulations (e.g. participants on active treatment only and participants who did not cross-over to a different treatment arm during the trial). To account for multiple hypotheses testing, the statistical significance level will be set at 0.025. Data will be analyzed using Stata.
Requested Studies:
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
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 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
Multicenter, Randomized, Double-Blind, Active Controlled Trial Comparing REMICADE (Infliximab) and REMICADE Plus Azathioprine to Azathioprine in the Treatment of Patients With Crohn’s Disease Naive to Both Immunomodulators and Biologic Therapy
Data Contributor: Johnson & Johnson
Study ID: NCT00094458
Sponsor ID: CR004804
Public Disclosures:
- Neeraj Narula, Emily C L Wong, Jean-Frederic Colombel, William J Sandborn, Marc Ferrante, John K Marshall, Walter Reinisch, Parambir S Dulai, Early Reduction in MM-SES-CD Score After Initiation of Biologic Therapy is Highly Specific for 1-year Endoscopic Remission in Moderate to Severe Crohn’s Disease, Journal of Crohn’s and Colitis, Volume 16, Issue 4, April 2022, Pages 616–624.Doi:10.1093/ecco-jcc/jjab183.
- C Galts, N Narula, E Wong, W Reinisch. A116 OPTIMIZING CROHN’S DISEASE ENDOSCOPIC SCORING OPERATING CHARACTERISTICS TO ASSIST WITH THE ADVENT OF ARTIFICIAL INTELLIGENCE. Journal of the Canadian Association of Gastroenterology, Volume 6, Issue Supplement_1, March 2023, Page 63. doi:10.1093/jcag/gwac036.116