Exclusion Diet vs corticosteroIds in patientS With activE Crohn's Disease

Study Overview
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Brief Summary
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Crohn's disease exclusion diet (CDED) is a whole-food diet coupled with partial enteral nutrition. The main objective of this trial is to assess whether CDED is superior to corticosteroids, in terms of endoscopic response, in patients active CD. The primary endpoint is endoscopic response at week 16, without corticosteroids or further therapeutic intervention, assessed by a centralized, anonymous and blinded, double lecture panel of panenteric PillCam Crohn's Capsule. This is a multicentre, open-label, comparative, randomized, 2:1, controlled, single-blind, superiority trial. Patients included are aged 16 to 70 years, have mild to moderate, luminal, active CD, and have active endoscopic lesions. Eighty patients will be randomized between CDED (n=56) and corticosteroids (n=24) in centres in France, Israel and the Netherlands.

Official Title
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Prospective rAndomized Controlled tRial of Crohn's diseAse Exclusion Diet vs corticosteroIds in patientS With activE Crohn's Disease - PARADISE

Conditions
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Crohn Disease

Intervention / Treatment
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* Dietary Supplement: Crohn's disease exclusion diet (CDED)
* Drug: Oral prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 16 to 70 years, With mild to moderate, luminal, active CD, defined by a CDAI of 150 to 350, Involving the small bowel, and/or the colon Not treated with corticosteroids at baseline Patent small bowel as assessed by the patency capsule Active endoscopic lesions, as defined by Lewis score ≥ 225 in the small bowel and/or SES-CD≥ 4 in the colon. The eligibility of the patient will be determined by the site investigator and a central reader. Informed consent to participate in this study. In patients from France and Israel who are aged less than 18: parents' informed consent to participate in this study (parents' agreement is not required in patients aged 16 to 18 in the Netherlands) Affiliation to social security or any health insurance Exclusion Criteria: Inability to follow the CDED during 16 weeks. Prior intolerance to corticosteroids. Ongoing infections, evolving virus diseases. Live vaccines. Psychotic state not controlled by treatment. Arthritis or uveitis as main presenting symptoms. Patients with severe and/or predominant rectal or perianal disease. Heavy smokers (more than 10 cigarettes per day). Infliximab, adalimumab, methotrexate or azathioprine initiated less than 3 months before inclusion in this trial. Vedolizumab, ustekinumab initiated less than 6 months before inclusion in this trial. Change in methotrexate, azathioprine, infliximab, adalimumab, vedolizumab or ustekinumab dosage less than 3 months before inclusion. Pregnant or lactating women. Patients already included in a biomedical research other than an observational study (e.g. registry, cohort, biobank). Severe pubertal delay (Tanner 1 or Tanner 2) and/or height velocity z-score < 2.5 and/or Bone mineral density z-score (hip or lumbar spine) <2.5. Persons deprived of their liberty by a judicial or administrative decision, persons subject to psychiatric care under sections L.3212-1 et L.3213-1 and persons admitted to a health or social institution for purposes other than research (L.1121-6)

Ages Eligible for Study
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Minimum Age: 16 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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Crohn's disease exclusion diet (CDED)<br>16-week course of Crohn's disease exclusion diet (CDED) and Partial Enteral Nutrition. | Dietary Supplement: Crohn's disease exclusion diet (CDED)<br>* 16-week course of CDED+Partial Enteral Nutrition. During the first 6 weeks (phase 1 of CDED), patients will be prescribed the CDED and oral Modulen 1 liter (1000kcal) daily. Between week 6 and 16 (phase 2 of CDED), patients will be prescribed CDED and oral Modulen (500 mL).<br>|
| Active Comparator: Steroids<br>oral prednisolone at an initial dose of 40 to 60 mg/day. | Drug: Oral prednisolone<br>* oral prednisolone at an initial dose of 40 to 60 mg/day (or 1 mg/kg for those patients who weigh less than 40 kg), with a fixed, tapering regimen such that patients should be off steroids by the last day of week 12. Increases in steroid dose during tapering of corticosteroids is allowed but if the patient receives steroids (other than hydrocortisone for adrenal insufficiency) after week 12, he/she is in failure.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endoscopic response W16 | The primary endpoint is the endoscopic response at week 16, assessed by Panenteric capsule (PillCam Crohn's capsule) using centralized, anonymous and blinded reading of PCC. The response is defined as a single binary endpoint according to the initial strata of the patient: Small bowel Crohn's diseAse (CD) : decrease of the Lewis score of at least 50% compared to baseline values Colonic CD : decrease of SES-CD of at least 50% compared to baseline values Small bowel and colonic CD : decrease of the Lewis score of at least 50% AND decrease of SES-CD of at least 50% compared to baseline values. Lewis score : Gralnek IM, Defranchis R, et al. Development of a capsule endoscopy scoring index for small bowel mucosal inflammatory change. Aliment Pharmacol Ther 2008; 27: 146-154. SES-CD : Daperno M, D'Haens G, et al . Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointest Endosc 2004; 60 (4): 505-512. | Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Clinical remission | Crohn's disease activity index (CDAI) <150. CDAI will be measured by the investigator on the basis of prospective questionnaires filled in by patients during the week preceding each visit. Best, William R., Jack M. Becktel, John W. Singleton, and Fred Kern Jr. Development of a Crohn's disease activity index: National Cooperative Crohn's Disease Study. Gastroenterology 70, no. 3 (1976): 439-444. | Week 16 and Week 48 | 
| Rate of Clinical response | Decrease of at least 70 points in Crohn's disease activity index (CDAI) compare to CDAI baseline. | Week 16 and Week 48 | 
| Rate of Need for further therapeutic intervention | Need for further therapeutic intervention (i.e., steroids, immunosuppressants, new biologic or surgery) between week 13 and 48 | Week 48 | 
| Decrease of fecal calprotectin concentration | Decrease of fecal calprotectin of at least 50% compared to baseline at week 16 and 48 | Week 16 and Week 48 | 
| Rate of Fecal calprotectin below thresholds | Fecal calprotectin of less than 250 μg/g, less than 100 μg/g and less than 50 μg/g at week 16. | Week 16 | 
| Rate of normal CRP concentration | CRP serum level <5 mg/L. | Week 16 and Week 48 | 
| Rate of Endoscopic remission | Endoscopic remission as defined as Lewis score <135 in the small bowel and/or Simple Endoscopic Score for Crohn Disease (SES-CD) <4 in the colon, without further therapeutic intervention (surgery, biologics or dietary intervention) at week 16. Dias de Castro, F., Pedro Boal Carvalho, Sara Monteiro, Bruno Rosa, João Firmino-Machado, Maria João Moreira, and José Cotter. Lewis score-prognostic value in patients with isolated small bowel Crohn's disease. Journal of Crohn's and Colitis 9, no. 12 (2015): 1146-1151. Daperno, Marco, Geert D'Haens, Gert Van Assche, Filip Baert, Philippe Bulois, Vincent Maunoury, Raffaello Sostegni et al. Development and validation of a new, simplified endoscopic activity score for Crohn's disease: the SES-CD. Gastrointestinal endoscopy 60, no. 4 (2004): 505-512. | Week 16 | 
| Rate of Endoscopic response | Endoscopic response and remission graded by Eliakim score at week 16. Eliakim, Rami, et al. A novel PillCam Crohn's capsule score (Eliakim score) for quantification of mucosal inflammation in Crohn's disease. United European gastroenterology journal 8.5 (2020): 544-551. | Week 16 | 
| Gut microbiota composition | Gut microbiota composition at week 6 and week 16. The endpoint consist in the rate of the diffrent microorganisms present in the gut. | Week 6 and Week 16 | 
| Value of adherence by Medication Adherence Report Scale | Medication Adherence Report Scale (MARS) at week 1, 9 and 16. Chan, Amy Hai Yan, Rob Horne, Matthew Hankins, and Claudia Chisari. The medication adherence report scale: a measurement tool for eliciting patients' reports of nonadherence. British Journal of Clinical Pharmacology 86, no. 7 (2020): 1281-1288. | Week 1, Week 9 and Week 16 | 
| Rate of adherence using food diaries | Adherence evaluate as binuary outcome evaluated using food diaries at week 1, 9 and 16 | Week 1, Week 9 and Week 16 | 
| Value of Quality of life | Quality of life will be assessed by short inflammatory bowel disease questionnaire (IBDQ) at week 3, 6 and 16. Irvine, E. J., Q. Zhou, and A. K. Thompson. The Short Inflammatory Bowel Disease Questionnaire: A Quality of Life Instrument for Community Physicians Managing Inflammatory Bowel Disease. American Journal of Gastroenterology (Springer Nature) 91.8 (1996). | Week 3, Week 6 and Week 16 | 
| Value Work | Work productivity and activity will be assessed by thework productivity and activity impairment questionnaire (WPAI) at 6 and 16. Reilly, Margaret C., Arthur S. Zbrozek, and Ellen M. Dukes. The validity and reproducibility of a work productivity and activity impairment instrument. Pharmacoeconomics 4.5 (1993): 353-365. | Week 6 and Week 16 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn Disease, Diet, Corticosteroids