A Study to Evaluate the Effect of Fecal Transplant and Dietary Changes on Disease Activity in Patients With Newly Diagnosed Active Crohn Disease

This study is a multi-center, double-blind, factorial randomized controlled trial designed to evaluate the efficacy of microbiome manipulation strategies using fecal microbiota transplantation (FMT), Crohn's Disease Exclusion Diet (CDED), or their combination in treatment-naïve patients with mild to moderate active Crohn's Disease (CD).

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 Sion Hospital, Mumbai, India IIIT-Delhi, India(for microbiome analysis)

Intervention Details:

Fecal Microbiota Transplantation (FMT)- Patients receive a 3-day course of oral vancomycin (500 mg BD) before the first FMT.

Freshly prepared 50 g stool is used for each FMT, and the transplant is administered within 4 hours of preparation.

FMT is delivered via colonoscopy at weeks 0, 2, and 6, followed by 8-weekly maintenance sessions for responders at weeks 10, 18, 26, 34, 42.

Multiple donors (n≥2) are used to ensure microbiome diversity. The first FMT session is instilled in the right colon/terminal ileum post bowel preparation, whereas maintenance sessions involve left-colon infusion without bowel preparation.

Crohn's Disease Exclusion Diet (CDED)- Patients assigned to CDED follow a phased dietary protocol designed to limit exposure to pro-inflammatory dietary components and enhance gut microbiome stability.

CDED consists of an induction and maintenance phase, with structured dietary charts and counseling provided by a dietitian.

Compliance is monitored via telephonic interviews and a dedicated diet tracking app (IBD NutriCare).

Sham Interventions- Sham FMT: Patients receive sterile water or saline infusions via colonoscopy at the same time points as FMT.

Sham Diet: Patients receive general dietary advice but do not follow the CDED protocol.

Randomization and Blinding- Central randomization is conducted using a secure web-based system (REDCap), utilizing stratified randomization based on disease extent.

The study follows a double-blind approach:

Blinded: Patients, clinical assessors, and endoscopic scorers. Unblinded: Endoscopists administering FMT/sham FMT and dietitians providing dietary counseling.

Oral vancomycin and placebo capsules are identically packed to maintain blinding.

Data Collection and Assessments- Baseline Assessments (Week 0) Clinical Assessment: Crohn's Disease Activity Index (CDAI), symptom scoring, and dietary adherence evaluation.

Laboratory Tests: Hemogram, renal/liver function, CRP, ESR, fecal calprotectin, and microbiome profiling.

Endoscopy: SES-CD scoring with high-definition endoscopic video recording. Histology: Biopsy samples are analyzed using Distribution Chronicity and Activity (DCA) scoring.

Follow-up Assessments- Clinical assessments at weeks 0, 2, 4, 6, 10, and every 8 weeks thereafter. Endoscopic assessments at baseline, week 10, and week 48, with central reading of all videos.

Fecal microbiome analysis at baseline, week 10, and week 48. Safety and Monitoring- Adverse Events (AEs) graded per CTCAE criteria (Grades 1-5). Serious Adverse Events (SAEs) include hospitalization, life-threatening conditions, or death.

DSMB reviews interim safety data at week 10 and 24. Emergency unblinding is permitted for critical medical decisions. Data Management- Data is collected using REDCap, with role-based access controls. Endoscopic images and videos are securely stored for centralized analysis. Microbiome sequencing data is processed at IIIT-Delhi. Statistical Considerations- Sample size calculation: 168 patients (42 per arm, 90% power).

Analysis Plan:

Intention-to-treat (ITT) and per-protocol (PP) analyses. Longitudinal mixed-effects modeling for microbiome shift

Inclusion criteria

• Patients with treatment-naive Crohns disease accessible with ileocolonoscopy
• Symptom onset of less than 12 months
• Mild to moderate disease activity with endoscopically active disease

• CDAI of greater than 150 and less than 450
• SES-CD of or equal to or greater than 6 (or equal to or greater than 4 if isolated ileal disease)
• Aged between 18-75 years

Exclusion criteria

• Patients with severe disease (CDAI greater than 450, SES-CD greater than 16) or requiring hospitalization
• Patients who have been received on corticosteroids, immunosuppressants (azathioprine/ 6- mercaptoprine/methotrexate) for greater than 2 weeks
• Biologicals or small molecule exposure
• Stricturing (non-passable stricture), fistulising phenotype or perianal fistula/abscess
• L4 disease
• Pregnant or lactating women
• Previous surgery for CD
• Declining consent
• Not willing for FMT/Dietary advise
• Patients with current or recent history of clinically severe, progressive, or uncontrolled renal, hepatic, hematological, 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.