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

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

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.

Study Overview

• Status: Unknown
• Conditions: Ulcerative Colitis Chronic Moderate; Ulcerative Colitis Chronic Mild
• Intervention / Treatment: Biological: Fecal Microbiota Transplantation; Other: Placebo granules; Drug: Mesalamine Granules; Other: Placebo infusion

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 Type: Interventional
• Enrollment (Anticipated): 20
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Ajit Sood, DM; Phone Number: +919779497094; Email: ajitsood10@gmail.com

Study Locations

• India
  • Punjab
    • Ludhiana, Punjab, India, 141001
      • Recruiting
      • Dayanand Medical College and Hospital
      • Contact: Ajit Sood, DM

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: FMT Vs Placebo; Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus placebo granules (4g/day)	Biological: Fecal Microbiota Transplantation; Freshly passed stools (80 g) will be diluted with normal saline (200 ml) and homogenized using a blender, filtered, filled into 4 syringes (50 ml each) and used within 1 hour of preparation or 6 hours of passage of stools. Polyethylene glycol lavage will be done for bowel preparation and the slurry administered into the ileum and/or caecum by colonoscopy. Post FMT, recipients will be encouraged to retain the slurry for 4-6 hours. FMT sessions will be scheduled at weeks 0,2,6,10,14.; Other: Placebo granules; Granules resembling mesalamine granules, 4 grams a day
ACTIVE_COMPARATOR: FMT Vs Mesalamine; Fecal microbiota transplantation (fresh sample, colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)	Biological: Fecal Microbiota Transplantation; Freshly passed stools (80 g) will be diluted with normal saline (200 ml) and homogenized using a blender, filtered, filled into 4 syringes (50 ml each) and used within 1 hour of preparation or 6 hours of passage of stools. Polyethylene glycol lavage will be done for bowel preparation and the slurry administered into the ileum and/or caecum by colonoscopy. Post FMT, recipients will be encouraged to retain the slurry for 4-6 hours. FMT sessions will be scheduled at weeks 0,2,6,10,14.; Drug: Mesalamine Granules; Mesalamine granules 4 grams a day; Other Names: Rowasa
ACTIVE_COMPARATOR: Placebo Infusion Vs Mesalamine; Placebo infusion (colonoscopic administration at weeks 0,2,6,10,14) plus mesalamine granules (4g/day)	Drug: Mesalamine Granules; Mesalamine granules 4 grams a day; Other Names: Rowasa; Other: Placebo infusion; Water with food grade colour to resemble fecal slurry

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical remission	Mayo score ≤2, each subscore ≤1	Week 14

Secondary Outcome Measures

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

Collaborators and Investigators

• Sponsor: Dayanand Medical College and Hospital
• Collaborators: Colitis & Crohn's Foundation (India)
• Investigators: Principal Investigator: Ajit Sood, DM, Professor and Head Gastroenterology

Study record dates

Study Major Dates

• Study Start (ACTUAL): December 1, 2018
• Primary Completion (ANTICIPATED): December 1, 2019
• Study Completion (ANTICIPATED): December 1, 2019

Study Registration Dates

• First Submitted: October 21, 2018
• First Submitted That Met QC Criteria: October 22, 2018
• First Posted (ACTUAL): October 23, 2018

Study Record Updates

• Last Update Posted (ACTUAL): February 12, 2019
• Last Update Submitted That Met QC Criteria: February 10, 2019
• Last Verified: February 1, 2019

More Information

Terms related to this study

• Keywords: Fecal Microbiota Transplantation; Ulcerative Colitis; Induction of Remission
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Gastrointestinal Diseases; Gastroenteritis; Colonic Diseases; Intestinal Diseases; Inflammatory Bowel Diseases; Ulcer; Colitis; Colitis, Ulcerative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Mesalamine
• Other Study ID Numbers: 2018-362

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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