The GRAFT Study: Gut RecolonizAtion by Fecal Transplantation

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT03621657
• Collaborator: Agency for Healthcare Research and Quality (AHRQ) (U.S. Fed)
• Enrollment: 1
• Location: 1
• Arms: 3
• Actual Duration (Months): 11.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The primary objective of this study is to compare the gut microbiota and clinical outcomes of oral FMT during antibiotic treatment, immediately following antibiotic treatment, and placebo. The second objective is to assess the safety and feasibility of daily oral Fecal Microbiome Transplant (FMT) as a treatment option.

Condition or Disease	Intervention/Treatment	Phase
Clostridium Difficile Infection; C.Difficile Diarrhea; CDI	Drug: Low Dose FMT Capsule DE; Drug: Single Dose FMT Capsule DE; Drug: Placebo oral capsule	Phase 2

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: This is a phase 2, double-blind, randomized, placebo-controlled trial assessing the effects of either daily (group 1) or one-time (group 2) oral FMT on the composition and function of gut microbiome compared to placebo (group 3) in a population of patients with a history of Clostridium difficile infection (CDI).This is a phase 2, double-blind, randomized, placebo-controlled trial assessing the effects of either daily (group 1) or one-time (group 2) oral FMT on the composition and function of gut microbiome compared to placebo (group 3) in a population of patients with a history of Clostridium difficile infection (CDI).
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II Randomized, Double-blind Placebo-controlled Trial to Determine if Fecal Microbiota Transplantation is Efficacious for Hospitalized Patients With C. Difficile Infection History During Antibiotic Treatment
• Actual Study Start Date: Mar 21, 2019
• Actual Primary Completion Date: Feb 27, 2020
• Actual Study Completion Date: Feb 27, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low dose FMT Capsule DE FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic	Drug: Low Dose FMT Capsule DE; 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.; Other Names: FMT Capsule DE
Active Comparator: Single dose FMT Capsule DE FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course.	Drug: Single Dose FMT Capsule DE; 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.; Other Names: FMT Capsule DE
Placebo Comparator: Placebo Oral Capsule Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic	Drug: Placebo oral capsule; Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.; Other Names: Placebo

Outcome Measures

Primary Outcome Measures

1. Assess Efficacy of Oral FMT on Composition and Function of the Gut Microbiota Compared to Placebo. [60 days]

   Assess microbial composition of stool using 16s targeted sequencing and shotgun metagenomics

Secondary Outcome Measures

1. Comparison of Treatment-related Adverse Events in the Oral FMT Regimens Versus Placebo. [60 days]

   Proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0, including serious adverse events, will be assessed. We will also assess proportion of newly diagnosed infectious diseases, which are considered adverse events of special interest (AESI) after randomization.

2. Determine the Rate of Clostridium Difficile Infection (CDI) During Oral FMT Regimens Versus Placebo [60 days]

   Collection of CDI infection rates from baseline to end of study and comparison between both oral FMT groups versus placebo.

3. Evaluate Time to Clostridium Difficile Infection (CDI) and/or Colonization With C. Difficile. [60 days]

   C. difficile colonization will be detected in stool samples submitted at baseline through end of study. If patients' become colonized, time from randomization to colonization is collected. Comparisons are made between the oral FMT groups and placebo.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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 180 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 taken the antibiotics for no longer than 10 days.

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. 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.

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

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

4. 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

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

6. History of bariatric or colectomy surgery

7. 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.

8. Expected life expectancy less than 6 months.

9. Patients with severe anaphylactic or anaphylactoid food allergy.

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

11. 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.

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

13. Any other gastrointestinal illness including diarrhea

14. On oral vancomycin or metronidazole

15. Having been taking the currently prescribed antibiotic for over 10 days

16. 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Wisconsin Hospital & Clinics	Madison	Wisconsin	United States	53794

Sponsors and Collaborators

• University of Wisconsin, Madison
• Agency for Healthcare Research and Quality (AHRQ)

Investigators

• Principal Investigator: Nasia Safdar, MD, PhD, University of Wisconsin, Madison

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Dec 5, 2018

More Information

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT03621657
• Other Study ID Numbers: 2017-0789; A534265; SMPH/MEDICINE/INFECT DIS; 1R03HS025257-01
• First Posted: Aug 8, 2018
• Last Update Posted: Mar 15, 2021
• Last Verified: Feb 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of Wisconsin, Madison: FMT; Fecal Microbiota Transplant
• Additional relevant MeSH terms: Infections; Clostridium Infections; Diarrhea

Study Results

Participant Flow

Arm/Group Title	Low Dose FMT Capsule DE	Placebo Oral Capsule	Single Dose FMT Capsule DE
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.
Period Title: Overall Study
STARTED	0	0	1
COMPLETED	0	0	1
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	Low Dose FMT Capsule DE	Placebo Oral Capsule	Single Dose FMT Capsule DE	Total
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.	Total of all reporting groups
Overall Participants	0	0	1	1
Age (Count of Participants)
<=18 years	0 NaN	0 NaN	0 0%	0 0%
Between 18 and 65 years	0 NaN	0 NaN	0 0%	0 0%
>=65 years	0 NaN	0 NaN	1 100%	1 100%
Sex: Female, Male (Count of Participants)
Female	0 NaN	0 NaN	0 0%	0 0%
Male	0 NaN	0 NaN	1 100%	1 100%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 NaN	0 NaN	0 0%	0 0%
Not Hispanic or Latino	0 NaN	0 NaN	1 100%	1 100%
Unknown or Not Reported	0 NaN	0 NaN	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 NaN	0 NaN	0 0%	0 0%
Asian	0 NaN	0 NaN	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 NaN	0 NaN	0 0%	0 0%
Black or African American	0 NaN	0 NaN	0 0%	0 0%
White	0 NaN	0 NaN	1 100%	1 100%
More than one race	0 NaN	0 NaN	0 0%	0 0%
Unknown or Not Reported	0 NaN	0 NaN	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Assess Efficacy of Oral FMT on Composition and Function of the Gut Microbiota Compared to Placebo.
Description	Assess microbial composition of stool using 16s targeted sequencing and shotgun metagenomics
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

There are no results due to low enrollment (N=1).

Arm/Group Title	Low Dose FMT Capsule DE	Placebo Oral Capsule	Single Dose FMT Capsule DE
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.
Measure Participants	0	0	0

2. Secondary Outcome

Title	Comparison of Treatment-related Adverse Events in the Oral FMT Regimens Versus Placebo.
Description	Proportion of participants with treatment-related adverse events as assessed by CTCAE v4.0, including serious adverse events, will be assessed. We will also assess proportion of newly diagnosed infectious diseases, which are considered adverse events of special interest (AESI) after randomization.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

There are no results due to low enrollment (N=1)

Arm/Group Title	Low Dose FMT Capsule DE	Single Dose FMT Capsule DE	Placebo Oral Capsule
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.
Measure Participants	0	0	0

3. Secondary Outcome

Title	Determine the Rate of Clostridium Difficile Infection (CDI) During Oral FMT Regimens Versus Placebo
Description	Collection of CDI infection rates from baseline to end of study and comparison between both oral FMT groups versus placebo.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

There are no results due to low enrollment (N=1)

Arm/Group Title	Low Dose FMT Capsule DE	Single Dose FMT Capsule DE	Placebo Oral Capsule
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.
Measure Participants	0	0	0

4. Secondary Outcome

Title	Evaluate Time to Clostridium Difficile Infection (CDI) and/or Colonization With C. Difficile.
Description	C. difficile colonization will be detected in stool samples submitted at baseline through end of study. If patients' become colonized, time from randomization to colonization is collected. Comparisons are made between the oral FMT groups and placebo.
Time Frame	60 days

Outcome Measure Data

Analysis Population Description

There are no results due to low enrollment (N=1)

Arm/Group Title	Low Dose FMT Capsule DE	Single Dose FMT Capsule DE	Placebo Oral Capsule
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.	FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.	Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.
Measure Participants	0	0	0

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	Insufficient participant population, low enrollment
Arm/Group Title	Low Dose FMT Capsule DE		Placebo Oral Capsule		Single Dose FMT Capsule DE
Arm/Group Description	FMT Capsule double-encapsulated (DE) by mouth, 5 capsules once daily with antibiotic, followed by 5 capsules daily for 7 days post-antibiotic Low Dose FMT Capsule DE: 5 FMT Capsule DE along with antibiotic; followed by five capsules FMT Capsule DE x 7 days post-antibiotic course.		Oral placebo capsules manufactured to mimic study capsule, 5 capsules daily with antibiotic course, followed by 5 capsules for 7 days post-antibiotic Placebo oral capsule: Five capsules per day along with antibiotic; followed by five capsules per day for seven days post-antibiotic treatment.		FMT Capsule DE by mouth, 30 capsules in a single one-time dose 48-72 post-antibiotic course. Single Dose FMT Capsule DE: 30 pill FMT Capsule DE treatment x 1, 48-72 hours following completion of antibiotic treatment.
All Cause Mortality
	Low Dose FMT Capsule DE		Placebo Oral Capsule		Single Dose FMT Capsule DE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/1 (0%)
Serious Adverse Events
	Low Dose FMT Capsule DE		Placebo Oral Capsule		Single Dose FMT Capsule DE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		0/1 (0%)
Other (Not Including Serious) Adverse Events
	Low Dose FMT Capsule DE		Placebo Oral Capsule		Single Dose FMT Capsule DE
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/0 (NaN)		0/0 (NaN)		1/1 (100%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/0 (NaN)	0	0/0 (NaN)	0	1/1 (100%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.