Advanced therapies including biologics and small molecules target specific inflammatory pathways. IBD's multifactorial etiology means that blocking a single pathway may not be sufficient for all patients. Even when combination of advanced therapies are used, the incremental benefits often diminish, reflecting the therapeutic ceiling. Furthermore, safety concerns also limit the potential to push beyond this ceiling. Increasing the dose or adding more immunosuppressive agents can lead to a higher risk of infections, malignancies, and other adverse effects, making it impractical to continually intensify treatment. Understanding the therapeutic ceiling in IBD highlights the need for innovative approaches that go beyond current strategies. Given the diverse microbial and immunological landscapes in IBD combining fecal microbiota transplantation (FMT) and Crohn's Disease Exclusion Diet (CDED) with advanced therapies represents a promising approach to break the therapeutic ceiling in CD. This strategy leverages the complementary mechanisms of action of FMT/CDED and advance therapies, potentially offering a more comprehensive treatment modality that addresses the complex and multifactorial nature of IBD. FMT involves the transfer of gut microbiota from a healthy donor to a patient, aiming to restore a balanced microbial community in the intestines. This can help modulate the immune system and reduce inflammation, which are central to Crohn's disease pathology. This study seeks to provide evidence on whether addition of microbiota manipulation by FMT and CDED offers additional benefits when used alongside advance therapies in active CD. The findings from this RCT are expected to significantly enhance treatment strategies, ensuring that patients receive the most effective and appropriate care based on robust scientific evidence. This multi-center double blind placebo-controlled RCT will randomize patients in 1:1:1:1 ratio to FMT, CDED and advance therapy vs sham FMT with advance therapy and CDED vs FMT, Advance therapy and sham diet vs Advance therapy with sham FMT and sham diet for induction and maintenance of remission in patients of active Crohn's disease. Randomization will be held centrally to ensure concealment of allocation. Random numbers will be generated by computerized random number schedule (The RAND), and the randomization list and numbered packing of the intervention will be prepared by a person not involved in the study. Randomization will be performed using permuted blocks of 8. Both the patient and the investigator will be blinded to the intervention
Patients with active Crohn disease in whom FMT is feasible
Active Crohn's disease who are candidates for advanced therapy (steroid refractory, Immunomodulator intolerant or refractory and moderately severe disease at the time of inclusion) or patients who have an intolerance to or have lost response to advanced therapies must have had their last treatment at least five half-lives prior randomization.
Aged between 18-75 years
CDAI greater than 150 and/or SES-CD equal or greater than 6 (or equal or greater than 4 if isolated ileal disease)
Patients in remission (CDAI less than 150)
Stricturing disease (non-passable stricture) in whom FMT is not feasible
Fistulising phenotype or Perianal fistula or abscess
Isolated L4 disease
Factorial
Fecal Microbial Transplantation
Other interventionThis will involve colonoscopic instillation of fecal transplant
Crohns Disease Exclusion Diet
Other interventionThe modified diet plan will be given to each study participant
Sham transplantation
Other interventionSham transplantation will involve saline infusion via colonoscopy
Sham Diet
Other interventionDietary counselling alone
Advanced therapy
Other interventionAdvanced therapy as standard dose and schedule
Proportion of patients with clinical remission and endoscopic response at week 10
Proportion of patients with clinical remission (defined as CDAI less than 150) and endoscopic response( defined decline in SES-CD by greater than 50%)
Proportion of patients with clinical remission and endoscopic remission at week 10
Proportion of patients with clinical remission (defined as Crohn's disease activity index less than 150) and endoscopic remission (defined as Simple Endoscopic Score for Crohn's disease patients less than 3)
Proportion of patients with clinical response at Week 10
Proportion of patients with clinical response is defined as either CDAI decrease from baseline of at least 70 points or CDAI less than 150
Proportion of patients with PRO2 Remission at Week 10
Proportion of patients with PRO2 Remission which is defined as Abdominal pain subscore of not more than 1 (on a scale of 0-3) and liquid or very soft stool (Bristol stool scale type 6 or 7) frequency subscore of not more than 3 calculated as a mean of 7 day count
Proportion of patients with endoscopic response at Week 10
Proportion of patients with endoscopic response which is defined as 50% reduction from baseline on SES-CD
Fecal microbiome and metabolite signature between responders and non-responders at week 10
It involves combined analysis of the microorganisms (bacteria, viruses, fungi, etc.) and the small molecules (metabolites) present in a person's stool sample
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