Medical Treatment Versus Surgery in Stricturing Small Bowel Crohn's Disease

Study Overview
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Brief Summary
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The objective of the SMART trial is to compare a combination therapy using azathioprine and subcutaneous infliximab versus ileocecal resection in patients with symptomatic small bowel Crohn's disease.

Detailed Description
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Crohn's disease (CD) is a chronic, disabling and destructive inflammatory bowel disease (IBD) leading to progressive and cumulative bowel damage, including fistulas and strictures. Strictures are defined as intestinal luminal narrowing and can lead to obstructive symptoms in the medium-to-long term. Symptomatic strictures significantly impair patient's quality of life by the presence of obstructive symptoms such as abdominal pain, nausea, vomiting, abdominal distension, and dietary restrictions leading to malnutrition. Strictures can appear anywhere in the gastrointestinal tract, but affect most commonly the terminal ileum. Epidemiological studies indicate that more than 40% of patients with ileal CD will develop strictures. However, treatment strategies are not well-defined in this indication. Most patients undergo surgery but recent observations indicate that a medical treatment by anti-TNF may be considered in stricturing CD. The European Crohn's Colitis Organization recommends that ileocecal CD with obstructive symptoms, but no significant evidence of active inflammation, should be treated by surgery. However, the lack of inflammation is difficult to demonstrate and does not predict the extent of fibrosis, and inflammation and fibrosis are often associated. Thus, there is a need for better defining therapeutic strategies. The objective of the SMART trial is to compare for the first time medical versus surgical approaches in stricturing CD. Indeed, up to date, no randomized controlled trial has been conducted to compare medical treatment alone versus surgery in patients with symptomatic stricturing CD. The hypothesis is that medical treatment by a combination therapy using infliximab and azathioprine is non-inferior to surgical resection in terms of health-related quality of life (HRQoL) at 1 year, with the advantage of being conservative as regards the high rates of post-operative recurrence with the subsequent risk of small bowel syndrome, as well as highly more acceptable by patients, especially since infliximab is now available as a biosimilar in a subcutaneous formulation, which should also improve the cost-effectiveness of the medical strategy.

Official Title
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SyMptomAtic Stricturing Small Bowel CRohn's Disease - Medical Treatment Versus Surgery, a Prospective, Multi-centre, Randomized, Non-inferiority Trial

Conditions
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Crohn Disease

Intervention / Treatment
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* Drug: Azathioprine + infliximab
* Procedure: Intestinal resection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18 and 70 years Male or female Documented small bowel CD with intestinal stricture(s) identified on CT, MRI or endoscopy, AND responsible for obstructive symptoms CREOLE score > 2 Exclusion Criteria: Adults under guardianship, safeguard justice or trusteeship Pregnant or breastfeeding female Acute bowel obstruction requiring urgent surgical intervention Suspected or confirmed gastrointestinal perforation Concurrent active perianal sepsis Internal fistulizing disease in association with strictures Colonic stenosis and/or colonic active disease at screening endoscopy Contra-indication to surgery, general anesthesia, anti-TNF, thiopurines Use of corticosteroids (prednisolone > 20 mg daily or equivalent) within 4 weeks prior to visit V0 Treatment with any biologics within 8 weeks before visit V0 Presence of a stoma HIV/HCV/HBV infection

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Medical treatment<br>Combination therapy with subcutaneous infliximab and azathioprine | Drug: Azathioprine + infliximab<br>* Combination therapy using 2-2.5 mg/kg oral azathioprine plus subcutaneous infliximab<br>* Other names: Imurel, Remsima;|
| Active Comparator: Surgery<br>Intestinal resection | Procedure: Intestinal resection<br>* Ileocolonic or small bowel resection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IBD (inflammatory bowel disease) - related quality of life | Mean total inflammatory bowel disease questionnaire (IBDQ - Inflammatory Bowel Disease Questionnaire ) score. The total score ranges from 32 to 224, the higher the score the better the quality of life. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| IBD (inflammatory bowel disease) -related quality of life | Mean total inflammatory bowel disease questionnaire (IBDQ - Inflammatory Bowel Disease Questionnaire ) score. The total score ranges from 32 to 224, the higher the score the better the quality of life. | 1, 3, 6, 9, 18 and 24 months | 
| Endoscopic remission | Proportion of patients achieving endoscopic remission at month 6 (SES-CD < 2 in case of medical treatment or Rutgeerts score < i,2 in case of resection) | 6 months | 
| Obstructive symptoms | Mean total score of CDOS (CROHN'S DISEASE OBSTRUCTIVE SCORE ) Scale frome 0 to 6. 0 is the best outcome. | 1, 3, 6, 9, 12, 18 and 24 months | 
| Clinical activity | Mean total score of CDAI (CROHN'S DISEASE ACTIVITY INDEX ) Scale from 0 to 1100. 0 is the best outcome. | 1, 3, 6, 9, 12, 18 and 24 months | 
| inflammatory biomarkers (fecal calprotectin) | Mean values of fecal calprotectin | 1, 6, 12, 18 and 24 months | 
| inflammatory biomarkers ( C-reactive protein [CRP]) | Mean values of CRP | 1, 6, 12, 18 and 24 months | 
| imaging parameters | Proportion of patients with an improvement in wall thickening, contrast enhancement, T2-signal increase, diffusion weighted-signal increase and length of pathological segment at month 12 as compared to screening imaging (MRI) by physician global assessment | 12 months | 
| treatment failures | Proportion of patients without any treatment failures | 12 and 24 months | 
| patient-reported outcomes (disability) | Mean total score of IBD-DI (INFLAMMATORY BOWEL DISEASE DISABILITY INDEX ) Score from 0 to 100. 0 is the best outcome (no disability) | 1, 3, 6, 9, 12, 18 and 24 months | 
| patient-reported outcomes (work productivity) | Mean total score of WPAI (WORK PRODUCTIVITY AND ACTIVITY IMPAIRMENT QUESTIONNAIRE) In percentage from 0 to 100. | 1, 3, 6, 9, 12, 18 and 24 months | 
| patient-reported outcomes (fatigue) | Mean total score of FACIT-F (Functional Assessment of Chronic Illness Therapy ) scores from 0 to 52, with higher scores corresponding to less fatigue | 1, 3, 6, 9, 12, 18 and 24 months | 
| patient-reported outcomes (body image) | Mean total score of body image questionnaire Ranges from 0 to 30 and can be calculated by summing up the 10 items. A higher score means a higher level of body image disturbance | 1, 3, 6, 9, 12, 18 and 24 months | 
| patient-reported outcomes (generic quality-of-life) | Mean total score of SF-36 (QUESTIONNAIRE SHORT FORM 36 HEALTH SURVEY ) Score ranging from 0 to 100. A low score reflects a perception of poor health, loss of function, presence of pain. A high score reflects a perception of good health, absence of functional deficit and pain | 1, 3, 6, 9, 12, 18 and 24 months | 
| patient-reported outcomes (anxiety/depression) | Mean total score of HAD (Hospital Anxiety and Depression scale) 14 items rated from 0 to 3. Seven questions relate to anxiety (total A) and seven others to the depressive dimension (total D), thus allowing two scores (maximum score for each score = 21). Minimum : 0. The best outcome is 0. | 1, 3, 6, 9, 12, 18 and 24 months | 
| Patient's acceptability -patients refusing to be included | Number of screened patients refusing to be included | 24 months | 
| patient's acceptability - The reason | The reason for refusing | 24 months | 
| intervention-related adverse events | Proportion of patients with intervention (drug or surgery) -related adverse events during the study | 24 months | 
| efficiency of medical treatment compared to surgery as assessed by a cost-utility analysis performed from a collective perspective | Incremental cost-utility ratio (cost per Quality-Adjusted Life-Years, QALYs) from a collective perspective | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, stricture, resection, infliximab, azathioprine