Fecal Microbiota Therapy Vs 5-aminosalicylates for Induction of Remission in Newly Diagnosed Mild-moderately Active UC

Phase 3

• Conditions: Ulcerative Colitis Chronic Mild; Ulcerative Colitis Chronic Moderate
• Interventions: Biological: Fecal Microbiota Transplantation; Drug: Mesalamine Granules; Other: Placebo granules; Other: Placebo infusion

• Registration Number: NCT03716388
• Lead Sponsor: Dayanand Medical College and Hospital

Brief Summary

Ulcerative colitis is a chronic idiopathic inflammatory disease of the colon that is characterized by abdominal pain and bloody diarrhea. The pathogenesis of UC involves a complex interplay of genetic factors, immune dysregulation and environmental triggers. Conventional therapies for UC (including 5-aminosalicylates, corticosteroids, azathioprine or 6-mercaptopurine and biologics) focus on altering the immune response by suppression of immune cells. However, the primary pathogenic mechanism underlying UC maybe gut microbiota dysbiosis and a dysfunctional intestinal barrier resulting in an aberrant host immune response. Several studies have shown reduced microbial diversity in UC patients with under representation of anti-inflammatory phyla (Bacteroides and Firmicutes), and a relative increase of pro-inflammatory phyla (Proteobacteria and Actinobacteria). Motivated by this, therapies targeting intestinal dysbiosis (prebiotics, probiotics, synbiotics and fecal microbiota transplant (FMT)) have thus been tried in patients with UC. Though several case series and subsequently four high quality randomized controlled trails have established the efficacy of FMT in induction of remission in active UC, all these studies have used it as an add-on therapy, along with the previously ongoing conventional therapies. The investigators aim to assess the safety and efficacy of FMT as the sole modality for induction of remission in patients with newly diagnosed active UC.

Detailed Description

This will be a prospective randomised placebo-controlled trial. Newly diagnosed treatment naive patients with mild to moderately severe UC will be recruited (n=15). The patients will be randomized into 3 groups; i.e group I (n=5): FMT with placebo, group II (n=5): FMT with mesalamine, group III (n=5): Placebo infusion with mesalamine. The patients will undergo colonoscopic administration of fecal slurry (groups I and II) or placebo (group III) at weeks 0,2,6,10 and 14. Mesalamine will be administered in a dose of 4g/day. In case of clinical worsening during the study, a short course of steroids will be added. The primary end point will be clinical remission (Mayo score ≤2, all subscores ≤ 1) at week 14. Secondary end points will be achievement of endoscopic remission (endoscopic Mayo score 0) and histological remission (Nancy grade 0, 1) at the end of 14 weeks.

Study Timeline

• Study First Submitted: 2018-10-21
• Study First Submitted QC: 2018-10-22
• Study First Posted: 2018-10-23
• Study Start: 2018-12-01
• Status Verified: 2019-02
• Last Update Submitted: 2019-02-10
• Last Update Posted: 2019-02-12
• Primary Completion: 2019-12-01
• Study Completion: 2019-12-01

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: All
• Target Recruitment: 20

Inclusion Criteria

• Active UC:

  1. UC diagnosed based on history of chronic (>4 weeks), inflammatory (with blood and mucous) diarrhoea
  2. Total Mayo Score 4-10, Mayo endoscopic sub-score of >1
  3. Histopathology suggestive of UC

Exclusion Criteria

• Severe UC (Total Mayo 11-12, Endoscopic Mayo Score 3)
• Uncertainty about diagnosis of UC : Infective colitis/ Indeterminate Colitis/ Crohn's Colitis
• Associated irritable bowel syndrome (IBS)
• Past history of surgery or colorectal surgery
• Exposure to antibiotics or probiotics in the last 4 weeks
• Patients with evidence of infections like C. difficile, cytomegalovirus, HIV, parasitic infections or extra-intestinal infections requiring antibiotics.
• Significant cardiopulmonary co-morbidities (high risk for repeated colonoscopy)
• Pregnancy
• Refusal to consent for repeated colonoscopies.

Donor

• Single donor (voluntary healthy individual) after informed consent

• Inclusion criteria for donor

  • No personal or family history of UC or any other autoimmune disease or malignancy
  • Screened by stool microscopy and culture for common detectable enteric pathogens (Salmonella, Shigella, Campylobacter, Vibrio cholera, E. coli, Clostridium difficile, Giardia lamblia and Cryptosporidium) at the start of the study and every 4 weeks thereafter.
  • Negative for antibodies against hepatitis A, C and E, hepatitis B surface antigen (HBsAg), syphilis and human immunodeficiency virus (HIV).

• Exclusion criteria for donor

  • High-risk sexual behaviors
  • Communicable illnesses
  • Antibiotic treatment within the past 3 months
  • Intrinsic gastrointestinal illnesses such as irritable bowel syndrome, inflammatory bowel disease, gastrointestinal malignancies or major gastrointestinal surgical procedures
  • Ongoing immune-modulator therapy for any concurrent illness
  • Chronic pain syndromes
  • Neurologic/neurodevelopmental disorders
  • Metabolic syndrome
  • Obesity (BMI >30 kg/m2)
  • Malignant illnesses

• Donor's diet will be monitored with a diet diary.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
FMT Vs Placebo	Fecal Microbiota Transplantation	Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus placebo granules (4g/day)
FMT Vs Placebo	Placebo granules	Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus placebo granules (4g/day)
FMT Vs Mesalamine	Fecal Microbiota Transplantation	Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)
Placebo Infusion Vs Mesalamine	Mesalamine Granules	Placebo infusion (colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)
Placebo Infusion Vs Mesalamine	Placebo infusion	Placebo infusion (colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)
FMT Vs Mesalamine	Mesalamine Granules	Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)

Primary Outcome Measures

Name	Time	Method
Clinical remission	Week 14	Mayo score ≤2, each subscore ≤1

Secondary Outcome Measures

Name	Time	Method
Endoscopic remission	Week 14	Endoscopic Mayo subscore 0
Clinical response	Weeks 0,2,6,10,14	Reduction of Mayo score ≥30% and ≥3 points compared to baseline
Histological remission	Week 14	Nancy grade 0 or 1

Trial Locations

Locations (1)

Dayanand Medical College and Hospital; 🇮🇳 Ludhiana, Punjab, India