This is a multicenter, double-blind, factorial randomized controlled trial (RCT) evaluating the efficacy of microbiome manipulation strategies in patients with active Crohn's Disease (CD) undergoing advanced therapy (biologics or small molecules). The study will be conducted across six clinical centers in India, with an additional center designated for microbiome analysis.
Randomization and Blinding:
Randomization: Centralized, computer-generated randomization using permuted blocks of 8, 12, and 16 to ensure equal distribution across intervention arms.
Stratification: Not more than 1/3rd patients should be biological therapy exposed
Blinding:
The blinded team includes patients and principal investigators. Endoscopists administering FMT/sham FMT and dietitians providing dietary counseling will be unblinded
Sham-Control Methods:
FMT Sham: Sterile clean water infusions via colonoscopy. Diet Sham: Dietary counseling without any modification
Intervention Arms:
Patients are randomized into one of four treatment groups:
FMT + CDED + Advanced Therapy (Group A) FMT + Sham Diet + Advanced Therapy (Group B) Sham FMT + CDED + Advanced Therapy (Group C) Sham FMT + Sham Diet + Advanced Therapy (Group D)
Fecal Microbiota Transplantation (FMT):
FMT Route: Administered via colonoscopy.
FMT Schedule:
Induction Phase: Weeks 0, 2, and 6. Maintenance Phase: Every 8 weeks (weeks 10, 18, 26, 34, 42) for responders.
Preparation:
Donor Selection: Multi-donor approach with prescreening FMT Processing: 50 g stool freshly prepared and instilled within 4 hours.
Delivery Locations:
Week 0 (Bowel Preparation): Right colon/terminal ileum. Weeks 2 and 6 (No Bowel Preparation): Left colon. Crohn's Disease Exclusion Diet (CDED)
Diet Structure:
Induction Phase (Weeks 0-6): Elimination of specific pro-inflammatory dietary components.
Maintenance Phase (Weeks 6-48): Gradual reintroduction of certain food groups. Monitoring: Adherence tracked using the IBD NutriCare app, diet recall logs, and DietCal software.
Sham Diet: Patients follow a standard healthy diet with general dietary counseling.
Assessments and Data Collection Baseline Assessments (Week 0) Clinical Data: Crohn's Disease Activity Index (CDAI), stool frequency, rectal bleeding, and symptom tracking.
Laboratory Tests:
Hemogram, renal/liver function tests, blood glucose. Inflammatory Markers: C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin (FCP).
Microbiome Analysis: Stool samples stored at -80°C for sequencing.
Endoscopic Evaluation:
Scoring: Simple Endoscopic Score for CD (SES-CD). Blinded Central Review: Videos assessed by two independent readers; discrepancies adjudicated by a third reader.
Histology: Biopsies analyzed using DCA score (Distribution Chronicity and Activity).
Follow-up Assessments
Visit Schedule:
Induction Phase: Weeks 2, 4, 6, and 10. Maintenance Phase: Every 8 weeks (weeks 18, 26, 34, 42, and 48). Clinical Assessments: CDAI, PRO2 symptom tracking, medication adherence checks. Endoscopy: Week 10 and Week 48; central scoring of videos. Diet Adherence: Assessed at weeks 2, 4, 6, and 10, then every 8 weeks. Microbiome Sampling: Stool samples collected at weeks 10 and 48. Safety Monitoring and Adverse Events
Adverse Event (AE) Classification:
CTCAE Grading (Grade 1-5) for treatment-related AEs. Serious Adverse Events (SAEs): Hospitalization, life-threatening events, or disability.
Safety Monitoring Plan:
Pre-procedural safety checks for each FMT session. Immediate post-FMT monitoring (48 hours). Late safety assessments (14 days post-FMT, then every visit). Unblinding Procedure: Allowed only for SAE management with DSMB approval. Data Management and Statistical Analysis
Electronic Data Capture (EDC):
Platform: REDCap database with tiered access permissions. Audit Trails: Secure logs of data entry and modification.
Dietary Data Processing:
IBD NutriCare app logs converted into macronutrient composition reports. Adherence scoring based on 80% compliance threshold.
Microbiome Data Processing:
Samples sequenced at IIIT-Delhi, analyzed for diversity indices and metabolic pathways.
Statistical Plan:
Primary Analysis: Intention-to-treat (ITT) and per-protocol (PP) analyses. Longitudinal Modeling: Mixed-effects models for repeated measures.
Effect Size Estimation:
Sample size: 168 patients (42 per arm).
