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

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

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.

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

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)

Crohn's disease, Recurrent inflammatory disorder, Immunomodulators, Biologics, Exclusive Enteral Nutrition, Crohn's disease exclusion diet (CDED), Modulen™IBD®

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.)

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).

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.

Defined as wPCDAI ≤12.5 and normal CRP within normal lab range) and normal fecal calprotectin ((<250µg/g)

Simplified Magnetic Resonance Index of Activity (MARIA) for Crohn's Disease score from baseline to M2

Defined as wPCDAI ≤12.5 and normal CRP (within normal lab range) and normal fecal calprotectin (<250µg/g)

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

IMPACT-3 questionnaire of 35 closed questions - scale ranging from 1 to 5 for all answers - higher score suggesting better quality of life

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

Ruemmele FM, Veres G, Kolho KL, Griffiths A, Levine A, Escher JC, Amil Dias J, Barabino A, Braegger CP, Bronsky J, Buderus S, Martin-de-Carpi J, De Ridder L, Fagerberg UL, Hugot JP, Kierkus J, Kolacek S, Koletzko S, Lionetti P, Miele E, Navas Lopez VM, Paerregaard A, Russell RK, Serban DE, Shaoul R, Van Rheenen P, Veereman G, Weiss B, Wilson D, Dignass A, Eliakim A, Winter H, Turner D; European Crohn's and Colitis Organisation; European Society of Pediatric Gastroenterology, Hepatology and Nutrition. Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease. J Crohns Colitis. 2014 Oct;8(10):1179-207. doi: 10.1016/j.crohns.2014.04.005. Epub 2014 Jun 6.

Wynands J, Belbouab R, Candon S, Talbotec C, Mougenot JF, Chatenoud L, Schmitz J, Cezard JP, Goulet O, Hugot JP, Ruemmele FM. 12-month follow-up after successful infliximab therapy in pediatric crohn disease. J Pediatr Gastroenterol Nutr. 2008 Mar;46(3):293-8. doi: 10.1097/MPG.0b013e31815604cd.

Pigneur B, Lepage P, Mondot S, Schmitz J, Goulet O, Dore J, Ruemmele FM. Mucosal Healing and Bacterial Composition in Response to Enteral Nutrition Vs Steroid-based Induction Therapy-A Randomised Prospective Clinical Trial in Children With Crohn's Disease. J Crohns Colitis. 2019 Jul 25;13(7):846-855. doi: 10.1093/ecco-jcc/jjy207.

Levine A, Wine E, Assa A, Sigall Boneh R, Shaoul R, Kori M, Cohen S, Peleg S, Shamaly H, On A, Millman P, Abramas L, Ziv-Baran T, Grant S, Abitbol G, Dunn KA, Bielawski JP, Van Limbergen J. Crohn's Disease Exclusion Diet Plus Partial Enteral Nutrition Induces Sustained Remission in a Randomized Controlled Trial. Gastroenterology. 2019 Aug;157(2):440-450.e8. doi: 10.1053/j.gastro.2019.04.021. Epub 2019 Jun 4.

Levine A, Sigall Boneh R, Wine E. Evolving role of diet in the pathogenesis and treatment of inflammatory bowel diseases. Gut. 2018 Sep;67(9):1726-1738. doi: 10.1136/gutjnl-2017-315866. Epub 2018 May 18.