Overview
Ulcerative colitis (UC) is a chronic inflammatory condition affecting the colon and rectum, characterized by mucosal inflammation and symptomslike diarrhea, abdominal pain, and rectal bleeding. It is a subtype of inflammatory bowel disease (IBD) and results from a combination of genetic predisposition, environmental factors, and immune dysregulation. UC is associated with significant gut microbiota dysbiosis, marked by reduced beneficial bacteria and increased harmful taxa. With rising prevalence in developing countries like India, effective and accessible treatments remain a critical need. This multi-center randomized factorial double blind placebo controlled treat through trial will utilize a 2x 2 factorial design to randomize patients of mild to moderate (modified Mayo score 3-6) endoscopically active (Mayo endoscopic score: >1) treatment naÃive UC in 1:1:1:1 ratio to fecal microbiota transplantation (FMT) + anti-inflammatory diet (AID) +5-aminisalicylic acid (5-ASA) (Intervention, Group A) vs fecal microbiota transplantation + sham diet +5-aminisalicylic acid(Intervention, Group B) vs sham transplantation + anti-inflammatory diet +5-aminisalicylic acid(Intervention, Group C) vs sham transplantation
+ sham diet +5-aminisalicylic acid(Control, Group D). In the induction phase patients will receive FMT/sham transplantation at 0, 2 and 6 weeks along with AID/Sham diet and 5-ASA for 10 weeks. Outcome will be assessed at 10 weeks, Treatment failure will be out of trial. Patients with clinical response at 10 weeks will continue in the maintenance phase and will receive FMT/sham transplantation at 10, 18, 26, 34, and 42 weeks along with AID/Sham diet and 5-ASA till48 weeks. Outcome will be assessed at 48 weeks. Treatment failure will be out of trial. The primary efficacy outcome will evaluate fecal microbial transplantation or anti- inflammatory diet or combination of both vs placebo. The primary outcomes are proportion of patients having clinical remission and endoscopic response at week 10 and proportion of patients having clinical remission and endoscopic remission at week 48. Modified intention to treat analysis will be done and patients who receive at least 1 dose of intervention will be included for outcome assessment.
Description
This study is a multi-center, double-blind, 2 × 2 factorial, randomized sham-controlled trial designed to evaluate the effects of fecal microbiota transplantation (FMT) and dietary modification in treatment-naïve patients with mild to moderate active ulcerative colitis (UC). The trial consists of four treatment arms:
FMT + Anti-inflammatory Diet (AID) + 5-ASA (Group A) FMT + Sham Diet + 5-ASA (Group B) Sham Transplantation + AID + 5-ASA (Group C) Sham Transplantation + Sham Diet + 5-ASA (Group D) All groups receive 5-aminosalicylic acid (5-ASA) as the standard medical therapy.
Study Setting
The trial is conducted at six FMT centers across India, with one additional center dedicated to microbiome analysis:
AIIMS, New Delhi, India Dayanand Medical College, Ludhiana, India PGIMER, Chandigarh, India Lisie Hospital, Kochi, India IMS, BHU, Varanasi, India Lokmanya Tilak Municipal Medical College, Mumbai, India IIIT-Delhi, India (for microbiome analysis)
Intervention Details Fecal Microbiota Transplantation (FMT) Patients receive three FMT sessions (weeks 0, 2, 6) during induction and additional 8-weekly maintenance sessions (weeks 10, 18, 26, 34, 42) for responders.
FMT is delivered via colonoscopy; at week 0, it is instilled into the right colon/terminal ileum (post bowel preparation), while for maintenance sessions, it is instilled in the left colon without bowel preparation.
Each FMT dose is 50 g stool, freshly prepared within 4 hours of collection. Multiple donors are used to ensure microbiome diversity
Anti-Inflammatory Diet (AID) Patients assigned to AID receive a nutritionally tailored diet that promotes T-regulatory cell expansion, microbiome stability, and gut barrier integrity.
The diet excludes gluten-based grains, dairy products, and pro-inflammatory foods while including fermented foods, cruciferous vegetables, and polyphenols.
Patients are provided diet charts, receive dietary counseling, and are monitored via diet app named IBDNutricare.
Sham Interventions Sham FMT: Instead of donor stool, patients receive sterile water infusions via colonoscopy at the same time points as FMT.
Sham Diet: Patients receive dietary counselling without specific modifications
Randomization and Blinding Central randomization is conducted via REDCap. Block randomization will be done in which blocks of 8 will be created for the randomization. Further, stratified randomization will also be done in which <25% Proctitis involving Ulcerative Colitis patients.
- Blinding
Patients, investigators collecting clinical data, and those assessing endoscopic images are blinded. The endoscopist administering FMT and the dietitian providing dietary counseling are unblinded
Data Collection and Assessments Baseline Assessments (Week 0) Clinical Evaluation: Patient-reported outcomes (PRO-2), stool frequency, rectal bleeding assessments.
Laboratory Tests: Hemogram, renal/liver function, CRP, ESR, fecal calprotectin, and microbiome profiling.
Endoscopy: Mayo Endoscopic Score (MES) assessment with high-definition recordings.
Histology: Biopsy samples assessed using Robarts Histologic Index (RHI) and Distribution Chronicity and Activity (DCA) score
Follow-up Assessments Week 10 (Induction phase endpoint): Endoscopy, histology, laboratory tests. Week 48 (Maintenance phase endpoint): Same assessments as baseline. Microbiome Analysis: Fecal samples collected at baseline, 10 weeks, and 48 weeks for metagenomics and metabolomics
Safety Monitoring Adverse events graded using CTCAE criteria (Grade 1-5). Serious adverse events (SAEs) include hospitalization, disability, or life-threatening conditions
Data Management Data is collected using paper Case Report Forms (CRF's) and then data will be entered in REDCap.
Endoscopic images and videos are securely stored and centrally reviewed.
Eligibility
Inclusion Criteria:
- Patients with treatment-naive ulcerative colitis of any disease extent. Patients with proctitis will be limited to 25% of the entire pool of patients.
- Mild to moderate endoscopically active disease (modified Mayo clinic score (mMS) 3-6, with Mayo endoscopic score greater than or equal to 2).
- Aged between 18-75 years.
- Patients giving consent for FMT.
- Patients who agree to adhere to the diet schedule.
- Patients on oral or topical ASA for less than 4 weeks.
- Patients on oral steroids/ topical steroids for less than 1 week.
- Infective colitis should be ruled out by histologic appearance of crypt architecture distortion/basal plasmacytosis, or two sigmoidoscopies, at least 7 days apart showing evidence of endoscopic activity.
Exclusion Criteria:
- Patients with severe disease (mMS equal to 7-9)
- Clinical signs of fulminant colitis or toxic megacolon
- Presence of IBD-unclassified, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohns Disease.
- Patients who have been initiated on other therapies (biologicals or immunosuppressants (azathioprine/ 6-mercaptoprine/methotrexate)) for greater than 2 weeks
- Patients requiring hospitalization
- Pregnant or lactating women
- Patients with current or recent history of clinically severe, progressive, or uncontrolled renal, hepatic, haematological, gastrointestinal, metabolic, endocrine, pulmonary, cardiac or neurological disease.
- Positive assay or stool culture for pathogens (ova and parasite examination, bacteria) or positive test for Clostridioides difficile toxin at screening#
- Patients infected with human immunodeficiency virus (HIV) # The patients with positive assay will be treated appropriately and tests will be repeated. Those with negative assay and persistent activity will be included in the study.