The GRAFT Study: Gut RecolonizAtion by Fecal Transplantation

Clostridium difficile is the most frequent bacterial cause of antibiotic-associated diarrhea.
Those with a previous C. difficile infection (CDI) are at high risk of recurrent infection.
Recurrent CDI often occurs when the normal gut microbiota are disrupted. Dysbiosis of the gut
microbiota predisposes to CDI which, despite treatment can recur in 30% of patients. A novel
way to prevent CDI recurrence is by instilling feces from a healthy individual into the
intestine of the CDI patient, thereby restoring balance in the gut microbiota. However, it is
unknown whether or not fecal microbiota transplantation (FMT) is an efficacious choice for
CDI recurrence prevention when used concurrently with antibiotics. We propose a pilot
randomized, double-blind placebo controlled trial comparing oral FMT with placebo in patients
with a history of CDI, currently undergoing antibiotic treatment. We will collect fecal
samples from subjects prior to, during, and after FMT and collect metagenomics and
microbiologic data on microbiota composition and function, and CDI recurrence. The trial's
primary outcome is gut microbial composition and function. Secondary outcomes are feasibility
and safety, and recurrent CDI during the trial period. In this 3 group study, FMT will be
administered daily via oral capsules containing frozen fecal microbiota from universal donors
in group 1, administered at the end of antibiotic treatment for group 2, and group 3 will
receive daily placebo. The results of this study will provide the necessary pilot data to
examine whether or not concurrent FMT in antibiotic treated patients who are at high risk for
recurrent CDI can maintain a diverse healthy GI microbiota.

Inclusion Criteria:

1. Cognitively intact and willing to provide informed consent

2. Willing and able to comply with all study procedures for the duration of the study

3. Able to take oral medications

4. Age 18 or over

5. Recent CDI episode occurring in the last 90 days with completion of therapy as
confirmed by the electronic medical record (EMR)

6. Receiving antibiotics at enrollment for reasons other than CDI and having received no
more than three doses of the prescribed antibiotic before enrollment into the study.

7. Women of childbearing potential in a sexual relationship with men must use an
acceptable method of contraception (including, but not limited to, barriers with
additional spermicidal foam or jelly, intrauterine devices, hormonal contraception
started at least 30 days before enrollment into the study, or intercourse with men who
underwent a vasectomy) for 4 weeks following completion of the study treatment,

8. Males must agree to avoid impregnation of women during and for 4 weeks following
completion of the study treatment.

9. Able to take the test capsule successfully with no signs or symptoms of dysphagia.

Exclusion Criteria:

1. Admitted to the intensive care unit (ICU)

2. Females who are pregnant, lactating, or planning to become pregnant during the study.
Female patients of childbearing potential will take a pregnancy test at the
intervention visit and will be excluded if pregnant.

3. Inability (e.g. dysphagia) to or unwilling to swallow capsules

4. Known or suspected toxic megacolon and or known small bowel ileus

5. Bowel obstruction or other gut motility issues occurring in the last two weeks taht
are unresolved as noted by the patient or in the EMR

6. Major gastrointestinal surgery (e.g. significant bowel resection) within 3 months
before enrollment not including appendectomy or cholecystectomy.

7. History of bariatric or colectomy surgery

8. Concurrent intensive induction chemotherapy, radiation therapy, or biologic treatment
for an active malignancy. Patients on maintenance chemotherapy may be enrolled after
consultation with the medical monitor.

9. Expected life expectancy less than 6 months.

10. Patients with severe anaphylactic or anaphylactoid food allergy.

11. Solid organ transplant recipients ≤90 days post-transplant or on active treatment for
rejection

12. Neutropenia (≤500 neutrophils/mL) or other severe immunosuppression. Anti-tumor
necrosis factor (TNF) will be permitted. Patients on monoclonal antibodies to B and T
cells, glucocorticoids, antimetabolites (azathioprine, 6-mercaptopurine,
methotrexate), calcineurin inhibitors (tacrolimus, cyclosporine), and mycophenolate
mofetil may only be enrolled after consultation with the medical monitor.

13. At risk of CMV/EBV associated disease, negative immunoglobulin gamma (IgG) testing for
cytomegalovirus (CMV) or Epstein Barr Virus (EBV)

14. Any other gastrointestinal illness including diarrhea

15. On oral vancomycin or metronidazole

16. Taken greater than three doses of their current antibiotic treatment

17. Any condition that would jeopardize the safety or rights of the patient, would make it
unlikely for the patient to complete the study, or would confound the results of the
study.