Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal

Crohn Disease Clinical Trial

— MIRACLE  

Official title:

Fecal Microbiota Transplantation in Crohn's Disease as Relay After Anti-TNF Withdrawal

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04997733
• Other study ID #: APHP190183
• Secondary ID: 2019-003816-29
• Status: Recruiting
• Phase: Phase 3
• Start date: September 22, 2021
• Est. completion date: July 22, 2027

Study information

• Verified date: October 2023
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Harry SOKOL, PU-PH
• Phone: 01 49 28 31 62
• Email: harry.sokol[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Crohn's disease (CD) is a chronic inflammatory bowel disease. CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts. The purpose of this study is to evaluate de clinical efficacy of the fecal microbiota transplantation (FMT) as a maintenance treatment following anti-TNF agent withdrawal in CD's patient.

Description:

Crohn's disease (CD) is a chronic inflammatory bowel disease affecting approximately 120000 patients in France, mostly at young age, and altering their quality of life. Immunosuppressive treatments in CD are expensive and associated with potentially severe complications. Alternative treatment strategies are thus required. This is particularly the case for CD patients in remission under anti-TNF agents for which no specific recommendation are available. CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota in predisposed hosts. Fecal microbiota transplantation (FMT) is currently recommended for treating recurrent Clostridium difficile infection. Although the pathogenesis involved in CD differs, FMT is a potential therapeutic strategy that could restore the appropriate host-microbiota crosstalk by transferring a healthy microbiota in a CD patient. However, as the gut microbiota is dramatically altered by intestinal inflammation, transferring a massive amount of microbes in an inflamed gut with epithelial barrier disruption might be a suboptimal strategy and could even have detrimental effects by allowing bacterial translocation. Results of randomized controlled trial (RCT) in CD are lacking to date. We performed a pilot RCT (NCT02097797), evaluating the impact of a single FMT in 18 CD patients who achieved remission by corticosteroid treatment. A higher rate of steroid free clinical remission was observed in the FMT arm at 24 weeks (57.1% vs 33.3% in FMT and control arm respectively). CD Endoscopic Index of Severity was also improved at 6 weeks in FMT (median 8.5 vs 3.5 p=0.03) but not in sham group (median 2.4 vs 2.7 p=0.8). Moreover, the only 2 patients who early relapsed in the FMT group were those who did not show any engraftment of donor microbiota at week 6. These promising data, currently submitted for publication, suggest that using FMT as a maintenance treatment in CD can be effective. However, these promising findings need to be confirmed by a Phase III RCT.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 150
• Est. completion date: July 22, 2027
• Est. primary completion date: May 22, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 74 Years

Eligibility

Inclusion Criteria for patients :

• Age = 18 years and < 75 years
• Crohn's disease (according to the Lennard-Jones criteria) for at least 6 months
• Patient in steroid-free clinical remission for at least 6 months under anti-TNF agent (no clinical evidence of flare nor change in Crohn's disease specific treatment (anti-TNF, immunosuppressive, …) within 6 months before inclusion) and CDAI <150 the week before inclusion) and willing to withdraw anti-TNF treatment
• Female of child-bearing age with an active contraception and this during at least the period of treatment (week 52)
• Patient with health insurance
• Informed Written consent

Inclusion Criteria for healthy volunteer donor :

• Age = 18 years and < 50 years
• 17 kg/m² < body mass index < 30 kg/m²
• Regular bowel movement defined as at least 1 stool every other day and maximum 2 stools per day
• Subject with health insurance (AME excepted)
• Informed written consent

Exclusion Criteria for patients :

• Crohn's Disease complication requiring surgical treatment
• Contraindication to colonoscopy or anesthesia
• Pregnancy or breastfeeding during the study (Cf. Addendum 4)
• Diagnosis of Crohn's disease restricted to the upper gastrointestinal tract (oesophagus, stomach, duodenum, jejunum)
• Patient with active perineal disease (defined as evidence of perineal abscess or active draining fistula or presence of seton or presence of perineal ulceration)
• History of more than one small bowel resection or small intestine resection > 1 meter
• Current stoma (Ileostomy or a colostomy) or stoma in the last 6 months or any other intra-abdominal surgery within 3 months prior to inclusion
• Participation in any other interventional study
• Patient under legal protection

Exclusion Criteria for healthy volunteer donor :

• For details, please see protocol

Related Conditions & MeSH terms

• Crohn Disease

Intervention

Drug:
• Fecal Microbiota Transplantation (FMT)
The colonoscopy for FMT will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either FMT (frozen preparation of 50g of stools in 300ml of saline (NaCl 0.9%), (FMT vehicle in the terminal ileum or the colon. At W12 and W24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain 0.8g of stools by visit).
• Sham-transplantation (placebo)
The colonoscopy for sham-transplantation will be planned between 7 and 14 days after the last adalimumab or sub-cutaneous infliximab administration and 6 weeks +/- 7 days after the last intravenous infliximab administration, 14 and 28 days following the last sub-cutaneous golimumab administration. After colon cleansing using polyethylene glycol, the patient will have a colonoscopy under general anesthesia. The patient will then receive either sham transplantation (frozen preparation of NaCl 0.9% with 10% glycerol) in the terminal ileum or the colon. At S12 and S24 after first colonoscopy, the patient receives treatment by capsule (15 capsules contain placebo).

Locations

Country	Name	City	State
France	Gastroenterology Department of Saint Antoine Hospital	Paris

Sponsors (3)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris	CRB-HUEP, Institut National de la Santé Et de la Recherche Médicale, France

Country where clinical trial is conducted

France, 

References & Publications (34)

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* Note: There are 34 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Mucosal healing	Proportion of endoscopic remission (SES-CD =2) at week 52 (V8) and change (in %) in endoscopic score (SES-CD) between week 0 (V2) and 52 (V8)	52 weeks after FMT or sham-transplantation
Other	Clinical remission	Clinical remission defined by a CDAI < 150 at week 52	52 weeks after FMT or sham-transplantation
Other	Endoscopic remission	Endoscopic remission defined by a SES-CD = 2 at week 52	52 weeks after FMT or sham-transplantation
Other	Changes in inflammation 1	Measures of inflammation: blood cell count	6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
Other	Changes in inflammation 2	Measures of inflammation: C reactive protein (CRP) level	6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
Other	Changes in inflammation 3	Measures of inflammation: fecal calprotectin	6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
Other	Changes in intestinal microbiota composition	Microbiota composition and diversity using 16s sequencing technology	6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation
Primary	Evaluate the clinical efficacy of FMT versus sham transplantation as a maintenance treatment following anti-TNF agent withdrawal in patients with Crohn's disease in steroid-free clinical remission for at least 6 months under anti-TNF agent	Clinical remission (defined by a Crohn's disease activity index (CDAI) <150) at week 52 (V8) without any flare between week 0 (colonoscopy (V2)) and week 52 (V8). Flare is defined by a CDAI (Addendum 2) above 250 or between 150 points and 250 points with a 70-point increase from baseline over 2 consecutive weeks and the need	52 weeks after FMT or sham-transplantation
Secondary	Relapse free survival	Relapse free survival rate from week 0 (V2) to week 52 (V8)	52 weeks after FMT or sham-transplantation

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