This study of patients with Crohn’s disease from the SONIC trial (Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease; ClinicalTrials.gov, NCT00094458) aims to evaluate the association of baseline endoscopic ulcerations (size, depth and location), disease activity, as measured by CD endoscopic index of severity (CDEIS) or Simple Endoscopic Score-CD (SES-CD), with the achievement of EH and CR at week 26.
Our hypothesis is that CD patients who are biologic and immunodulator naïve with baseline larger ulcer sizes and extensive inflammation are less likely to achieve EH and CR, regardless of treatment with either combination therapy, infliximab or azathioprine monotherapy at week 26.
Current and future medical therapies in Crohn’s disease (CD) need to demonstrate efficacy in achieving mucosal healing1. However, there is insufficient information regarding what degree of ulceration and inflammation affects endoscopic healing (EH) and clinical remission (CR).
This study aims to evaluate the association of baseline mucosal lesions and disease activity with the achievement of EH and CR at week 26.
SONIC was a multicentre, randomised, double-blinded trial that randomized patients to infliximab, azathioprine, or combination therapy and evaluated corticosteroid-free CR at week 26. This post hoc analysis will assess the likelihood of achieving EH and CR at week 26 based on baseline endoscopic inflammation present.
Moderate-to-severe CD patients who are naive to immunomodulators and biologics, and had poor response to conventional therapies were eligible.
Main Outcome Measure(s)
The primary outcome measures will be EH, CR and corticosteroid-free CR at week 26. Baseline mucosal lesion features and inflammation will be assessed using endoscopic scoring systems.
A multivariate logistic regression analysis will be used to examine the relationship between baseline endoscopic extent of disease and ability to achieve week 26 EH and CR. Known confounding factors for achieving endoscopic healing, such as treatment allocation and disease duration, will be adjusted for.
Crohn’s disease is a progressive, relapsing and remitting disease due to chronic transmural inflammation which can lead to complications such as strictures, fistulas, and abscess formation2. Current medical therapies and prospective therapies have adopted a ‘treat-to-target’ approach with the primary target being an ability to achieve EH, defined as an absence of ulcers on endoscopy1. EH in inflammatory bowel disease has become an important measure of treatment efficacy and a prognostic indicator of long-term adverse outcomes, such as hospitalizations and surgeries 3-5. However, there is currently insufficient information as to what degree of ulceration and inflammation of mucosal lesions across the different colonic segments and ileum affects EH and CR. This has clinical implications in moderate-to-severe CD as it determines if baseline characteristics and location of mucosal lesions, extent of inflammation are negative predictors of EH and CR.
Data Source: Eligibility criteria and the SONIC (Study of Biologic and Immunomodulator Naïve Patients in Crohn’s Disease) study design were previously published in the clinical trial(ClinicalTrials.gov number: NCT00094458).
Inclusion Criteria: Patients eligible will be at least 21 years of age and have had CD for least 6 weeks, with moderate-to-severe disease activity (i.e. Crohn’s Disease Activity Index [CDAI] score 220-450 points). These patients will be either corticosteroid-dependent, being considered for a second course of systemic corticosteroids within 12 months, or will have had no response to either mesalamine (≥ 2.4 g/d) or budesonide (≥ 6 mg/d) after at least 4 weeks of treatment.
Exclusion Criteria: Patients who are ineligible include those with previous treatment to 6-mercaptopurine, methotrexate, or anti-TNF biologic agents. Previous abdominal surgery in the previous 6 months, symptomatic stricture, abscess, short gut, or ostomy. Patients with granulomatous infection, including tuberculosis, active infection with human immunodeficiency virus, hepatitis B or C, or opportunistic infection in the prior 6 months, multiple sclerosis or malignancy were excluded.
Endoscopic healing of the bowel has become a goal of treatment for patients with Crohn’s disease. Clinical trials conducted in Crohn’s disease for new therapies need to demonstrate the ability to heal the mucosa. However, nothing is known about the impact of lesion size and distribution on the ability to achieve endoscopic healing. This study proposes to look at the SONIC (Study of Biologic and Immunomodulator Naive Patients in Crohn's Disease; ClinicalTrials.gov, NCT00094458) database and determine whether patients who have more extensive inflammation at baseline and larger ulcer sizes are less likely to achieve endoscopic healing.
Anticipated Project Start Date: To be started within the first week of database approval and acquisition in September 2019.
Analysis Completion Date: Research proposal to be finalized with data collection and analysis. Estimated data of completion will be November 2019.
Manuscript Draft Date: Manuscript draft estimated to be completed in December 2019 – January 2020.
Manuscript Submission Date: January – February 2020
Date Results Reported to YODA: March - April 2020
The dissemination of results, which may include but are not limited to abstracts and manuscripts will be reported to the YODA Project at the time of submission.
Anticipated products include abstracts, which will be published or shared during scientific meetings, including Canadian Digestive Diseases Week, Digestive Disease Week, and European Crohn’s and Colitis Organisation. Additionally, a manuscript is expected to be completed for the research project and will be submitted for publication. Potential journals for submission include Clinical Gastroenterology and Hepatology, Journal of Crohn’s and Colitis, Inflammatory Bowel Diseases, and Digestive Diseases and Sciences. The dissemination of results, which may include but are not limited to abstracts, manuscripts, preprints, posters, and slide decks will be shared with the YODA Project at the time of submission.
Target audiences include clinicians and researchers interested in the advancement of the inflammatory bowel disease diagnostics and management.
1. Bouguen G, Levesque BG, Feagan BG, Kavanaugh A, Peyrin–Biroulet L, Colombel JF, Hanauer SB, Sandborn WJ. Treat to target: a proposed new paradigm for the management of Crohn's disease. Clinical Gastroenterology and Hepatology. 2015 Jun 1;13(6):1042-50.
2. Rieder F, Zimmermann EM, Remzi FH, Sandborn WJ. Crohn’s disease complicated by strictures: a systematic review. Gut. 2013;62:1072-1084.
3. Rutgeerts P, Diamond RH, Bala M, Olson A, Lichtenstein GR, Bao W, Patel K, Wolf DC, Safdi M, Colombel JF, Lashner B. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn's disease. Gastrointestinal endoscopy. 2006 Mar 1;63(3):433-42.
4. Frøslie KF, Jahnsen J, Moum BA, Vatn MH, IBSEN Group. Mucosal healing in inflammatory bowel disease: results from a Norwegian population-based cohort. Gastroenterology. 2007 Aug 1;133(2):412-22.
5. Schnitzler F, Fidder H, Ferrante M, Noman M, Arijs I, Van Assche G, Hoffman I, Van Steen K, Vermeire S, Rutgeerts P. Mucosal healing predicts long‐term outcome of maintenance therapy with infliximab in Crohn's disease. Inflammatory bowel diseases. 2009 Sep;15(9):1295-301.
6. Best, W., Becktel, J., Singleton, J. et al. Development of a Crohns disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology. 1976; 70: 439–444
7. Mary JY, Modigliani R. Development and validation of an endoscopic index of the severity for Crohn’s disease: a prospective multicentre study. Groupe d’Etudes Therapeutiques des Affections Inflammatoires du Tube Digestif [GETAID]. Gut 1989;30:983–9.
8. Daperno M, D’Haens G, Van Assche G, et al. Development and validation of a new, simplified endoscopic activity score for Crohn’s disease: the SES-CD. Gastrointest Endosc 2004;60:505–12.
In SONIC, patients underwent a colonoscopy at baseline prior to randomization to treatment and mucosal ulcerations were detected in 325 patients. At week 26, of patients with mucosal ulcerations on baseline colonoscopy, a repeat colonoscopy was performed to determine EH. One of the main outcome measures will be EH at week 26. EH was defined as the absence of mucosal ulceration at week 26 in patients who had confirmed ulceration at baseline.
Additionally, CR at 26 will be an outcome measure defined as a Crohn’s Disease Activity Index (CDAI) score < 1506. Corticosteroid-free CR at week 26 will be measured as well, which is defined as CDAI score <150, budesonide <6mg/day, and no systemic corticosteroids in prior 3 weeks.
To establish the baseline mucosal lesion characteristics and extent of inflammation of disease activity, multiple scoring systems derived from endoscopy (Crohn’s Disease Endoscopic Index of Severity [CDEIS]7 and Simple Endoscopic Score for Crohn’s Disease [SES-CD]8) will be used. Further description of CDEIS and SES-CD will be outlined below in ‘other variables of interest.’
The CDEIS scores six endoscopic variables [presence of deep ulcers, superficial ulcers, nonulcerated stenosis, and ulcerated stenosis; proportion of ulcerated surfaces; and surface involved by disease] that are assessed in each of five ileocolonic segments [rectum, sigmoid/left colon, transverse colon, right colon, and ileum] 7.
The SES-CD is a simple scoring system based on four endoscopic variables [presence and size of ulcers, proportion of surface covered by ulcers, proportion of affected surface, and presence and severity of stenosis] measured in the same five ileocolonic segments as the CDEIS8.
Continuous variables will be presented as means (and standard deviations [SD] or as medians and interquartile ranges [IQR]) if the distribution is skewed, and categorical or binary variables will be presented as proportions or percentages. Descriptive statistics will be used to summarize baseline demographics, disease characteristics and outcome parameters of CD patients with baseline mucosal lesions at screening colonoscopy. Proportions of patients achieving EH, CR, and corticosteroid-free CR will be compared between treatments with the use of the Fisher’s exact test.
Known baseline disease factors significantly associated with the different composite remission outcomes (i.e. EH, CR, and corticosteroid-free CR) at week 26 such as treatment allocation and disease duration will be included within a multivariate logistic regression analysis to help adjust for potential confounding factors.
Approved investigators will be granted access to participant-level data sets via a remote, secure, password-protected data sharing platform. All work on the data must take place within the secure platform. The platform will be easily accessible to researchers, and ongoing system monitoring and support will be available. Within the platform, researchers will have access to the following analytical tools: Stata, R, RStudio, and Open Office. If needed, researchers will be able to upload additional data sets to the secure platform, if the researcher has the rights/license to do so.