Typical Pre-Clinical Steps in Development
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FMT Trial Design: How Do We Design Meaningful Studies in Inflammatory Bowel Disease?
Alan C. Moss MD, FEBG, FACG, AGAF
Associate Professor of Medicine
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Typical Pre-Clinical Steps in Development
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Elements of Clinical Trial Design in IBD
1. Patient Selection
2. Intervention
3. Outcomes
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Patient Selection
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Populations in Prior FMT Trials in IBD
StudyDuration of
DiseaseDisease Activity
Current Meds
Vaughn 2014 14 yrs 10 (HBI) Steroids, AZA/6MP
Moayyedi 2014 ? >4 (Mayo) Steroids, AZA/6MP, Anti-TNF
Kunde S 2013 1-7 yrs 30-55 (PUCAI)
5-ASA, 6MP, Steroids
Kump P 2013 2-12 yrs 8-11 (Mayo) Steroids, Anti-TNF, 5-ASA
Angelberger S 2013 2-10 yrs 8-11 (Mayo) 5-ASA, Probiotics
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“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
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Rationale for Earlier Intervention - Window of Inflammation
0
2400 12 24 36 48 60 72 84 96 108 120 132 144 156 168 180 192 204 216 228
100
90
80
70
60
50
40
30
20
10
Penetrating
Stricturing
Cu
mu
lati
ve P
rob
abili
ty (
%)
Inflammatory
Months
Cosnes J, et al. Inflamm Bowel Dis. 2002;8:244-250.
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Rational for Early Intervention - Dysbiosis is Established Early
Gevers D et al Cell Host Microbe. 2014 Mar 12;15(3):382-92
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Rationale for Genotype Enrichment
Frank DN, Inflamm Bowel Dis. 2011 Jan;17(1):179-84
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Who to Exclude
• Food allergies• Pregnant• Cancer• Immunocompromised• Cirrhosis• History of valvular heart disease
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Variables to Control for in Enrolled Population
Sommer F, Nat Rev Microbiol. 2013 Apr;11(4):227-38
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Interventions
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Variables to Consider for Intervention
1. Dose 2. Delivery 3. Duration
• Stool weight• Solution
concentration• Microbial
consituents• Aerobe / Anerobic
prep
• Naso-jejnual• Enema• Colonoscopy• Capsule• Fresh / Frozen
• Loading & Maintenance
• Frequency of administration
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Scenarios for Intervention – Parallel Design
Study Population Randomize
100g Freeze-Thaw FMT
Sham FMT
50g Freeze-Thaw FMT
Study Population Randomize
100g Fresh FMT
Probiotics
100g Freeze-Thaw FMT
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Scenarios for Intervention – Cross-Over
Randomize
100g Freeze-Thaw FMT
Sham FMT 100g Freeze-Thaw FMT
Sham FMT
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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
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Carroll I, PLoS One. 2012; 7(10): e46953
Frozen Donor Stool Retains its Diversity
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Baseli
ne
FM
T
Week
1
Week 2
Week 4
Week
8
Week 1
2
Week 2
40
5
10
15
20
R1001
R1002
R1003
R1004
R1005
R1006
R1007
R1008
R1009
R101 1
R1012
HB
I
Single FMT Not Sufficient – Data in Crohn’s
Vaughn B, DDW 2014
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Outcomes
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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)
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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)
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Physiological Outcomes
• Paired diversity assessments (pre- & post-)• Metabolomics• Inflammatory markers – CRP, Fecal Calprotectin• T-cell phenotypes
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04
12 24Weeks
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:NCT01847170
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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