Clinical trial NCT02097797: Impact of the Fecal Flora Transplantation on Crohn's Disease
Official title: Impact of Fecal transPlantAtion on MiCrobotia and hosT in Crohn's Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Crohn's Disease
Keywords: Inflammatory bowel disease
Crohn's disease
microbiota
fecal transplantation
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: ANRS, Emerging Infectious Diseases
name: Pierre and Marie Curie University
name: Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement
First posted: 2014-03-27
Enrollment: 24
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Crohn's disease is a chronic and relapsing inflammatory bowel disease. Many data show that the intestinal flora is involved in the disease and it has been show that patients with Crohn's disease exhibit an abnormal fecal flora that might play a role in inflammation. The purpose of this study is to determine the effect of the fecal flora transplantation on Crohn's disease.

Detailed description: Introduction : Crohn's disease (CD) is an relapsing inflammatory bowel disease relatively frequent. Its prevalence is about 1 for 700 in France, affecting predominantly young adults. Its treatment is based on immunosuppressants that might be associated with potentially severe complications such as infection and cancers. Moreover, these treatments are expensive. The gut microbiota being involved in the disease pathogenesis, it can be considered as a potential therapeutic target.

CD pathogenesis remains poorly understood but involves an inappropriate immune response toward an unbalanced gut microbiota (called dysbiosis) in predisposed hosts. The complete replacement of a dysbiotic microbiota by a "healthy" one is thus an attractive strategy. Fecal transplantation (FT) has been used with success for a long time in the context of Clostridium difficile.

Hypothesis : Fecal transplantation allow the replacement of a dysbiotic microbiota by a " healthy " one with favorable impact on CD evolution.

Primary endpoint : In CD patient with colonic or ileo-colonic involvement put in remission with corticosteroids, Evaluate if FT can modify a dysbiotic fecal microbiota to be closer of the one of a healthy donor.

Methodology

For the Receiver :

Once corticoid-induced remission will be achieved, the patient will be included and randomised to receive either FT or sham transplantation during a colonoscopy. The patient will be evaluated at week 2, 6, 10, 14, 18 and 24. At week 6, a colonoscopy will be performed.

For the Donor :

Donors will be recruited by poster advertising. When a receiver will be included, 3 donors will be contacted to attend an inclusion visit including physical examination as well as blood and stool screening for pathogen. The 3 donors will then come the day of the FT to donate their stool.

Eligibility criteria: Receiver

Inclusion Criteria:

* Age \> 18 years and \< 70 years
* Crohn's disease with colonic or ileo-colonic involvement
* Active disease at screening defined by a Harvey Bradshaw Index \>4
* Clinical remission (Harvey Bradshaw Index \<5) in the 3 weeks following corticosteroid onset
* Patient with health insurance
* Written consent obtained

Exclusion Criteria:

* Fistulizing disease
* Anoperineal or abdominal abscess
* Complication requiring surgical treatment
* Treatment with anti-TNFa (ongoing or stopped in the 1 month preceding randomization)
* Immunosuppressant treatment started or stopped in the 3 months preceding randomization
* Non-steroidal anti inflammatory drugs (NSAIDs) intake in the 4 weeks preceding randomization
* Antibiotics or antifungic treatment in the 4 weeks preceding colonoscopy
* Probiotics intake in the 4 weeks preceding colonoscopy
* Clostridium difficile infection in the 10 days preceding randomization
* contraindication to colonoscopy or anesthesia
* Pregnancy

Donor

Inclusion Criteria:

* Age \> 20 years and \< 50 years
* 27kg/m² \> BMI \> 17 kg/m²
* Regular bowel movement with usually one bowel movement in the morning
* Subject with health insurance
* Written consent obtained

Exclusion Criteria:

* Infection risk:

  * Known infection by human immunodeficiency virus (HIV), Human T Leukemia Virus (HTLV), Hepatitis B or C virus.
  * At risk behavior: Travel (in the preceding 3 months, excepting in Euro area, United Kingdom, Bulgaria, Poland, Romania, Croatia, Hungary, Republic Tcheque, Denmark, Norway, Sweden, Swiss, USA or Canada), at risk sexual activity (intercourse without protection with a new partner) in the preceding 6 months, blood transfusion, piercing or tattoo in the preceding 6 months residence of several years in intertropical area, abroad hospitalization more than 24 hours in the last 12 months (including patient and his immediate family).
  * Positive result at one of the screening tests for infectious disease. : HIV, HCV, HBV, HTLV, syphilis, Enteric viruses (Rotavirus, HEV, Adenovirus, Norovirus, Enterovirus, HAV, Poliovirus, Astrovirus, Aichi virus, Sapovirus), parasites in stool (Cyclospora, Isospora, Cryptosporidium, Microsporidium, Strongyloides stercoralis, Entamoeba histolitica, Giardia intestinalis, Dientamoeba fragilis), and in blood (Strongyloides stercoralis, Trichinella spiralis, Amoebiasis), pathogenic bacteria in stool (Clostridium difficile, Shigella, Campylobacter, Yersinia, Salmonella, Listeria monocytogenes, Vibrio cholerae/parahemolyticus, verotoxin-producing E. coli)
  * Anal lesions suggesting viral infection or positive test for HSV anal and/or multi-drug resistant bacteria (Enterobacteria producing extended spectrum betalactamase, Actinobacter baumanii, Vancomycin resistant enterococci and carbapenemase producing bacteria).
  * Positive test for multidrug resistant bacteria
  * If receiver is EBV negative, EBV positive donor will be excluded
  * If receiver is CMV negative, CMV positive donor will be excluded.
  * If receiver is negative for Toxoplasma gondii, positive donor for Toxoplasma gondii will be excluded
  * Known transmissible infectious disease
  * Infection (or possible infection) in the 7 days preceding screening
  * Risk factors for Creutzfeldt-Jakob disease
  * Personal history of Typhoid fever
* Gastrointestinal comorbidity

  * Personal history or first degree relative :

    * Inflammatory bowel disease
    * Coeliac disease
  * Personal history of irritable bowel syndrome, chronic constipation, chronic diarrhea
  * Personal history of gastrointestinal neoplasia or polyposis
  * First degree relative with gastrointestinal neoplasia or polyposis before 60 years old
  * Gastrointestinal infection in the 3 preceding months (defined by the occurrence of an acute diarrhea that last less than a week)
* Factors possibly affecting the composition of the microbiota:

  * Antibiotics or antifungic intake in the 3 preceding months before FT
  * Non-steroidal anti inflammatory drugs (NSAIDs) intake in the 4 weeks preceding FT
  * Specific diet (exclusion diet, vegetarian diet)
  * Pregnancy
  * Immunosuppressant intake (corticosteroids, calcineurin inhibitors, biologics, etc)
  * Anti neoplastic chemotherapy
  * Hemorrhoid disease
  * Personal history or first degree relative with inflammatory or autoimmune disease
* Other Factors :

  * Known chronic disease
  * Abnormality at initial biological check up: blood cells count, fasting, glycaemia, kidney function, liver tests, haemostasis, calprotectin
  * Long term curative therapy
  * Recent intake of food allergens related of receiver's known allergy
* between screening and FT :

  * At risk behavior (Travel, at risk sexual activity, blood transfusion, piercing tattoo, accidental blood exposure)
  * Anal lesions suggestive of viral infection or positivity for HSV in anal area
  * Infection or possible infection
  * Occurrence of gastro-intestinal symptoms
  * Medicine intake in the 48 hours preceding FT (except contraceptive)
  * In case of woman: menstruation in the 48 hours preceding FT

Primary outcomes:
measure: FT success defined by : Sorensen's index [receiver 6 weeks after FT vs donor] > Sorensen's index [receiver 6 weeks after FT vs receiver before FT]) with Sorensen's index [receiver 6 weeks after FT vs donor] ≥ 0.6.
timeFrame: 6 weeks after FT
Secondary outcomes:
measure: FT feasibility
timeFrame: 6 weeks after FT
measure: Clinical relapse rate in the 24 weeks following FT procedure
timeFrame: 24 weeks following FT
measure: Effect of FT compared to sham transplantation on CRP
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on Leukocytes level
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on fecal calprotectin
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on Crohn's Disease Endoscopic Index of Severity
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on fecal microbiota composition
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on lymphocytes population in blood
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on lymphocytes population in colon
timeFrame: 6 weeks after FT
measure: Effect of FT compared to sham transplantation on colon transcriptomics
timeFrame: 6 weeks after FT
Other outcomes:
Locations:
city: Paris
country: France
facility: Gastroenterology department, Saint Antoine Hospital
Study officials:
affiliation: Assistance Publique
name: Harry Sokol, MD, PhD
role: STUDY_DIRECTOR
References:
citation: Sokol H, Landman C, Seksik P, Berard L, Montil M, Nion-Larmurier I, Bourrier A, Le Gall G, Lalande V, De Rougemont A, Kirchgesner J, Daguenel A, Cachanado M, Rousseau A, Drouet E, Rosenzwajg M, Hagege H, Dray X, Klatzman D, Marteau P; Saint-Antoine IBD Network; Beaugerie L, Simon T. Fecal microbiota transplantation to maintain remission in Crohn's disease: a pilot randomized controlled study. Microbiome. 2020 Feb 3;8(1):12. doi: 10.1186/s40168-020-0792-5.