typical pre-clinical steps in development

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

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

“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

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.

Rational for Early Intervention - Dysbiosis is Established Early

Gevers D et al Cell Host Microbe. 2014 Mar 12;15(3):382-92

Rationale for Genotype Enrichment

Frank DN, Inflamm Bowel Dis. 2011 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. 2013 Apr;11(4):227-38

Interventions

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

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

Scenarios for Intervention – Cross-Over

Randomize

100g Freeze-Thaw FMT

Sham FMT 100g 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

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

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

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

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