Use of Crohn's Disease Exclusion Diet on Top of Standard Therapy Versus Standard Therapy Alone in Unstable Pediatric Crohn's Disease Patients.

Study Overview
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Brief Summary
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This research is a multicenter French randomized and single blinded phase III clinical trial evaluating two treatment strategies among Crohn's disease (CD) patients. The main objective is to assess if the addition of Crohn's Disease Exclusion Diet (CDED) to ongoing standard medication is superior to reduce the rate of relapses over 12 months compared to standard medication alone in children/adolescents with unstable CD responding with remission after a 2-months course of CDED

Detailed Description
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Crohn's disease is a recurrent inflammatory disorder. Current treatment strategies aim reducing intestinal (and systemic) inflammation based on the use of Immunomodulators (IM) and biologics (B). However, some patients, particularly in the pediatric age group do not respond with remission to standard therapy and approximately 30% of patients lose response to efficient therapy. There is a clear unmet need for new treatment strategies. In addition, patients and families have a high degree of reluctance to use IM/B as life-long medication, particularly due to potential side effects including cancer, lymphomas, serious infections or drug-related immune diseases. This is of particular importance for children/adolescents with CD, potentially exposed over many decades to various IM/B. Experimental and epidemiological data indicate that the western life style and particularly modern food play a key role in the development of CD, probably via alteration of the intestinal barrier function and/or enforcing the intestinal dysbiosis. Based on these data and the observation that exclusive enteral nutrition is highly efficacious in inducing remission in active CD, nutritional therapies are more and more in the focus for the development of new treatment approaches. The main objective is to assess if the addition of CDED to ongoing standard medication is superior to reduce the rate of relapses over 12 months compared to standard medication alone in children/adolescents with unstable CD responding with remission after a 2-months course of CDED. To achieve this objective, eligible patients with active CD will participate to this study for a 13 months period. After a screening period, the patients will have a 2 months run-in phase where they will follow the CDED protocol, but continue their maintenance therapy, with the exception of corticosteroid that have to be tapered and stopped at the end of the 2 months. Then, the patients responding to CDED during run-in will be randomized at M2 to one of the two treatment arms (CDED/Modulen™IBD® or Unrestricted food access) and will have 4 follow-up visits (M4, M6, M9 and M12)

Official Title
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Randomized Trial for Unstable Pediatric Crohn's Disease Patients Comparing the Use of Crohn's Disease Exclusion Diet (CDED) on Top of Standard Therapy Versus Standard Therapy Alone.

Conditions
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Crohn's Disease

Intervention / Treatment
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* Dietary Supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy
* Dietary Supplement: Phase2 and 3 :


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Child/Adolescent aged 6-17 years with a confirmed diagnosis of CD (for at least 3 months) with an active disease (defined as: wPCDAI >12.5 or CRP > 2 times upper limit or calprotectin levels >250µg/g if available) despite anti-inflammatory (5-ASA and derivates), corticosteroids, immunomodulator (thiopurines or methotrexate) and/or biologic therapy (anti-TNF, anti-integrin anti-IL23 antibodies) For girls of childbearing age: a negative pregnancy test, and use of an effective method of contraception (abstinence, oral contraceptives, intra-uterine device, diaphragm with spermicide and condom) Patient willing to comply with daily intake of an exclusion diet Informed and signed consent of parents Patient affiliated to social security (or health insurance) Exclusion Criteria: Active perianal fistulizing disease Internal fistula or evidence of un-drained and un-controlled abscess/phlegmon Patient who require CD-related surgical therapy Patient with known allergy to cow milk's proteins Patient incapable to follow CDED for a prolonged period Pregnancy, breastfeeding Patient already included in an interventional study

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 17 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: CDED/Modulen™IBD®<br>Strategy combining CD exclusion diet plus Modulen™IBD® on top of ongoing maintenance therapy. | Dietary Supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy<br>* from D0 until M2: Phase 1 (2 months run-in phase with CDED protocol + maintenance therapy, with the exception of corticosteroid that have to be tapered and stopped until M2.)<br>Dietary Supplement: Phase2 and 3 :<br>* from M2 until M4 CDED phase 2 (introduction of a selected number of additional food). From M4 until end of the study CDED phase 3 (enlargement of number of additional foods and allowance of some initially excluded foods).<br>* Other names: CDED/Modulen™IBD® + Maintenance therapy;|
| Active Comparator: Unrestricted food access<br>Stop CDED and Modulen™IBD®, but continue maintenance therapy with unrestricted food access. | Dietary Supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy<br>* from D0 until M2: Phase 1 (2 months run-in phase with CDED protocol + maintenance therapy, with the exception of corticosteroid that have to be tapered and stopped until M2.)<br>|
| Other: Not randomized<br>Patient not in remission at M2 or refusing randomisation | Dietary Supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy<br>* from D0 until M2: Phase 1 (2 months run-in phase with CDED protocol + maintenance therapy, with the exception of corticosteroid that have to be tapered and stopped until M2.)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse from randomization until M12 | Relapse is defined as weighted Paediatric Crohn's disease activity index (wPCDAI) >40 points and/or CRP >2 times over upper limit (in the absence of any obvious infections sign) or if at two consecutive visits (within 2-8 weeks) the wPCDAI is >12,5 but less 40 and/or CRP >1,5 but less 2 times over upper limit (in the absence of any obvious infections sign) or if the patient required additional CD-specific medication/surgery in the interval. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change of wPCDAI from baseline to M2 |  | 2 months | 
| Change of fecal calprotectin values from baseline to M2 |  | 2 months | 
| Clinical remission at M2 | Defined as wPCDAI ≤12.5 and normal CRP (≤1.5 fold upper normal range) | 2 months | 
| Deep remission at M2 | Defined as wPCDAI ≤12.5 and normal CRP within normal lab range) and normal fecal calprotectin ((<250µg/g) | 2 months | 
| Physician global assessment (PGA) from baseline to M2 | Crohn's Disease activity assessed as remission - weak - moderate - severe | 2 months | 
| Mucosal healing at M2 | absence of any ulcerations (including aphthae) | 2 months | 
| Endoscopic response at M2 | Decrease of Crohn's Disease Endoscopic Index Score (CDEIS) ≥ 50% from baseline | 2 months | 
| Change of MRI from baseline to M2 | Simplified Magnetic Resonance Index of Activity (MARIA) for Crohn's Disease score from baseline to M2 | 2 months | 
| CDED tolerance rate at M2 | serious and non serious adverse events | 2 months | 
| CDED compliance rate at M2 |  | 2 months | 
| Change of intestinal microbiome composition from baseline to M2 |  | 2 months | 
| Clinical remission | Defined as wPCDAI ≤12.5 and normal CRP (≤1.5 fold upper normal range) | At 4 months, 6 months, 9 months and 12 months | 
| Deep remission | Defined as wPCDAI ≤12.5 and normal CRP (within normal lab range) and normal fecal calprotectin (<250µg/g) | At 4 months, 6 months, 9 months and 12 months | 
| Relapse | Defined as wPCDAI >40 points and/or CRP >2 times over upper limit (in the absence of any obvious infections sign) or if at two consecutive visits (within 2-8 weeks) the wPCDAI is >12,5 but less 40 and/or CRP >1,5 but less 2 times over upper limit (in the absence of any obvious infections sign) or if the patient required additional CD-specific medication/surgery in the interval | At 4 months, 6 months, 9 months and 12 months | 
| Physician global assessment (PGA) | Crohn's Disease activity assessed as remission - weak - moderate - severe | At 4 months, 6 months, 9 months and 12 months | 
| Mucosal Healing at M12 | Absence of any ulcerations (including aphthae) | 12 months | 
| Endoscopic response at M12 | Decrease of Crohn's Disease Endoscopic Index Score (CDEIS) ≥ 50% from baseline | 12 months | 
| Change of MRI from M2 to M12 | Simplified Magnetic Resonance Index of Activity (MARIA) for Crohn's Disease score from M2 to M12 | 12 months | 
| CDED tolerance rate at M12 | Serious and non serious adverse events | 12 months | 
| CDED compliance rate at M12 |  | 12 months | 
| Change of Intestinal microbiome composition |  | At 4 months, 6 months, 9 months, 12 months | 
| Change of quality of life IMPACT-3 from inclusion until 12 months | IMPACT-3 questionnaire of 35 closed questions - scale ranging from 1 to 5 for all answers - higher score suggesting better quality of life | At baseline, 2 months, 4 months, 6 months, 9 months, 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Crohn's disease, Recurrent inflammatory disorder, Immunomodulators, Biologics, Exclusive Enteral Nutrition, Crohn's disease exclusion diet (CDED), Modulen™IBD®