Crohn Disease
Conditions
Keywords
Crohn disease, Inflammatory bowel disease, Fecal microbiota transplantation
Brief 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.
Detailed 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.
Interventions
DRUGFecal 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).
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).
Sponsors
CRB-HUEP
Institut National de la Santé Et de la Recherche Médicale, France
Assistance Publique - Hôpitaux de Paris
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 74 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 52 weeks after FMT or sham-transplantation | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Relapse free survival | 52 weeks after FMT or sham-transplantation | Relapse free survival rate from week 0 (V2) to week 52 (V8) |
Other
| Measure | Time frame | Description |
|---|---|---|
| Endoscopic remission | 52 weeks after FMT or sham-transplantation | Endoscopic remission defined by a SES-CD ≤ 2 at week 52 |
| Changes in inflammation 1 | 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation | Measures of inflammation: blood cell count |
| Mucosal healing | 52 weeks after FMT or sham-transplantation | 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) |
| Changes in inflammation 3 | 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation | Measures of inflammation: fecal calprotectin |
| Changes in intestinal microbiota composition | 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation | Microbiota composition and diversity using 16s sequencing technology |
| Changes in inflammation 2 | 6, 12, 24, 36, 48 and 52 weeks after TMF or sham-transplantation | Measures of inflammation: C reactive protein (CRP) level |
| Clinical remission | 52 weeks after FMT or sham-transplantation | Clinical remission defined by a CDAI \< 150 at week 52 |
Countries
France
Contacts
Primary ContactHarry SOKOL, PU-PH
Backup ContactLaurent BEAUGERIE, PU-PH
Outcome results
None listed