FMT Trial Design: How Do We Design Meaningful Studies in Inflammatory Bowel Disease? Alan C. Moss MD, FEBG, FACG, AGAF Associate Professor of Medicine

Typical Pre-Clinical Steps in Development

Elements of Clinical Trial Design in IBD 1.Patient Selection 2.Intervention 3.Outcomes

Patient Selection

Populations in Prior FMT Trials in IBD Study Duration of Disease Disease Activity Current Meds Vaughn yrs10 (HBI)Steroids, AZA/6MP Moayyedi 2014?>4 (Mayo)Steroids, AZA/6MP, Anti-TNF Kunde S yrs30-55 (PUCAI) 5-ASA, 6MP, Steroids Kump P yrs8-11 (Mayo)Steroids, Anti-TNF, 5-ASA Angelberger S yrs8-11 (Mayo)5-ASA, Probiotics

“Ideal” Populations to Study 1.Early after diagnosis, prior to immunosuppresive therapy 2.Early after Crohn’s resection to prevent endoscopic recurrence 3.Genotype-specific 4.Patients in remission to reduce risk of relapse 5.Proctitis (UC) – mode of administration 6.Pouchitis (UC) 7.Active ileal Crohn’s - ?more dysbiosis driven

Rationale for Earlier Intervention - Window of Inflammation Penetrating Stricturing Cumulative Probability (%) Inflammatory Months Cosnes J, et al. Inflamm Bowel Dis. 2002;8:

Rational for Early Intervention - Dysbiosis is Established Early Gevers D et al Cell Host Microbe Mar 12;15(3):382-92

Rationale for Genotype Enrichment Frank DN, Inflamm Bowel Dis Jan;17(1):179-84

Who to Exclude Food allergies Pregnant Cancer Immunocompromised Cirrhosis History of valvular heart disease

Variables to Control for in Enrolled Population Sommer F, Nat Rev Microbiol Apr;11(4):227-38

Interventions

Variables to Consider for Intervention 1. Dose2. Delivery 3. Duration Stool weight Solution concentration Microbial consituents Aerobe / Anerobic prep Naso-jejnual Enema Colonoscopy Capsule Fresh / Frozen Loading & Maintenance Frequency of administration

Scenarios for Intervention – Parallel Design Study PopulationRandomize 100g Freeze-Thaw FMT Sham FMT 50g Freeze-Thaw FMT Study PopulationRandomize 100g Fresh FMT Probiotics 100g Freeze-Thaw FMT

Scenarios for Intervention – Cross-Over Randomize 100g Freeze-Thaw FMT Sham FMT100g Freeze-Thaw FMT Sham FMT

Solutions to Uncertainties in Intervention 1.Tailor administration to site of inflammation 2.Standard concentration (fecal slurry by donor weight and re-constitution solution) 3.Frozen pre-screened aliquots 4.Regular administration - colonization alone does not guarantee efficacy

Carroll I, PLoS One. 2012; 7(10): e46953 Frozen Donor Stool Retains its Diversity

Single FMT Not Sufficient – Data in Crohn’s Vaughn B, DDW 2014

Outcomes

Clinical Efficacy Outcomes 1.Measure of Response / Remission - endoscopic measure important - Patient Reported Outcomes (PROs) - CDAI, SCCAI no longer convincing alone - Quality of Life 2.Timing of Outcome Assessment - 4 & 8 weeks for response - week 8 and 26 for remission (endoscopic)

Safety Reporting of Adverse Events has been inadequate to date Use of industry-standards for attribution and severity important Long-term surveillance critical (storage of archival donor samples for testing)

Physiological Outcomes Paired diversity assessments (pre- & post-) Metabolomics Inflammatory markers – CRP, Fecal Calprotectin T-cell phenotypes

Weeks FMT 8 Microbiome Sequencing PB T-cell phenotypes LP T-cell phenotypes Clinical / Safety Assessment “Impact of Fecal Biotherapy (FBT) on Microbial Diversity in Patients Inflammatory Bowel Disease” ClinicalTrials.gov Identifier:NCT

Conclusions FMT should be studied in similar manner to drug therapy to test its efficacy & safety - risk:benefit, cost-effectiveness Challenges – regulatory, funding, standardization Initial promise tempered by variable open-label study outcomes Need for tailored intervention in targeted sub-groups of patients with IBD