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

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

Study Overview

• Status: Recruiting
• Conditions: Crohn's Disease
• Intervention / Treatment: Dietary supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy; Dietary supplement: Phase2 and 3 :

Detailed Description

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)

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Franck Ruemmele, MD, PhD; Phone Number: +33 (0)1 44 49 25 16; Email: frank.ruemmele@aphp.fr
• Study Contact Backup: Name: Prissile Bakouboula, PhD; Phone Number: +33 (0)1 71 19 64 94; Email: prissile.bakouboula@aphp.fr

Study Locations

• France
  • Bron, France, 69677
    • Recruiting
    • Hôpital Femme mère enfant, CHU Lyon - Service Hépato-gastroentérologie et Nutrition pédiatrique
    • Contact: Rémi Duclaux-Loras, MD, PhD; Phone Number: +33-4-72-35-70-50; Email: remi.duclaux-loras@chu-lyon.fr
  • Caen, France, 14033
    • Recruiting
    • CHU Caen Normandie - Service de Gastroentérologie pédiatrique
    • Contact: Claire Dupont-Lucas, MD, PhD; Phone Number: +33-2-31-27-25-94; Email: dupont-c@chu-caen.fr
  • Marseille, France, 13385
    • Recruiting
    • Hôpital de la Timone, AP-HM - Service de Gastroentérologie pédiatrique
    • Contact: Céline Roman, MD, PhD; Phone Number: +33-4-91-38-83-83; Email: celine.roman@ap-hm.fr
  • Paris, France, 75015
    • Recruiting
    • Hôpital Necker-Enfants malades - Service de Gastroentérologie pédiatrique
    • Contact: Franck Ruemmele, MD, PhD; Phone Number: +33 (0)1 44 49 25 16; Email: frank.ruemmele@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: CDED/Modulen™IBD®; Strategy combining CD exclusion diet plus Modulen™IBD® on top of ongoing maintenance therapy.	Dietary supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy; 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.); Dietary supplement: Phase2 and 3 : 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).; Other Names: CDED/Modulen™IBD® + Maintenance therapy
Active Comparator: Unrestricted food access; Stop CDED and Modulen™IBD®, but continue maintenance therapy with unrestricted food access.	Dietary supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy; 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.)
Other: Not randomized; Patient not in remission at M2 or refusing randomisation	Dietary supplement: Phase1 : CDED/Modulen™IBD® + Maintenance therapy; 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.)

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Collaborators: URC-CIC Paris Descartes Necker Cochin; MICALIS Institute
• Investigators: Principal Investigator: Franck Ruemmele, MD, PhD, Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• 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.
• 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, 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.

Study record dates

Study Major Dates

• Study Start (Actual): September 26, 2022
• Primary Completion (Anticipated): November 1, 2026
• Study Completion (Anticipated): November 1, 2026

Study Registration Dates

• First Submitted: February 26, 2021
• First Submitted That Met QC Criteria: February 26, 2021
• First Posted (Actual): March 2, 2021

Study Record Updates

• Last Update Posted (Actual): November 1, 2022
• Last Update Submitted That Met QC Criteria: October 31, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Keywords: Crohn's disease; Biologics; Immunomodulators; Exclusive Enteral Nutrition; Recurrent inflammatory disorder; Crohn's disease exclusion diet (CDED); Modulen™IBD®
• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Inflammatory Bowel Diseases; Crohn Disease
• Other Study ID Numbers: APHP200010; 2020-A02569-30 (Other Identifier: ID-RCB)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No