Interventional Bioremediation of Microbiota in Metabolic Syndrome

• Vancomycin (Drug): Vancomycin 3 times a day for 7 days
• Placebo (Other): Placebo pills identical in appearance to each antibiotics to be taken on the same schedule as each antibiotic
• Neomycin (Drug): Neomycin 3 times a day for 1 day
• Clindamycin (Drug): Clindamycin 3 times a day for 5 days
• Fecal Microbiota Transplantation (Procedure): FMT conducted via colonoscopy

Primary outcomes

• Insulin Sensitivity [10 weeks]: Insulin sensitivity measured by standard euglycemic insulin clamp.

Secondary outcomes

• Microbiome Composition [7 days]: Outcome is reported as the Shannon alpha diversity index (unitless measure) at baseline and 7 days post FMT.
• Changes in Fecal Bacterial Composition Associated With FMT Overall Antibiotic and Placebo Conditioning Groups) by Laboratory Analysis. [Baseline and 10 weeks]: Microbiome composition was assessed post FMT using fecal DNA extraction and sequences. Outcome is reported as the change in relative abundance of the family Ruminococcaceae.
• Adverse Event Rates [10 weeks]: Outcome is reported as a patient self report of adverse events over 10 weeks.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

1. Provide informed consent
2. Ambulatory and community dwelling
3. Age 18 - 70 years of age
4. Able and willing to comply with the study schedule and procedures
5. Pre-diabetic with fasting blood glucose > 100 mg/dL and/or blood glucose 140-200 mg/dL 2-hours after ingestion of 75 gm glucose and/or Hemoglobin A1c > 5.7-6.5 percent

Exclusion Criteria:

1. Serious, concomitant illness that, in the opinion of the Investigator, would interfere with evaluation of safety or efficacy, or put the subject at risk of harm from study participation.
2. Known inflammatory bowel disease (Crohn's disease, ulcerative colitis, lymphocytic colitis).
3. Current abnormal liver tests that may be attributed to a cause other than non-alcoholic liver disease. Note: These exclusionary conditions may include viral hepatitis, alcoholic liver disease, hemochromatosis, Wilson's disease, medication-induced liver test abnormalities, celiac disease.
4. Renal insufficiency, defined as creatinine ≤ 1.25 mg/dL
5. Significant alcohol use, defined as > 20 g/day in females and > 30 g/day in males for a period of 3 months within one year prior to screening.
6. Underlying chronic gastrointestinal disease that can cause diarrhea, including short bowel syndrome, diarrhea-predominant irritable bowel syndrome, malabsorption, celiac disease.
7. History of partial or complete colectomy.
8. History of malabsorptive bariatric surgery.
9. Use of insulin or hypoglycemic medications.
10. History of anaphylactic food allergies, e.g., peanuts, seafood.
11. Food intolerances and allergies, including gluten sensitivity, lactose intolerance, and intolerance of high fiber dietary content.
12. Symptomatic problems associated with intestinal gas and bloating.
13. Irritable bowel syndrome, including diarrhea-dominant, constipation-dominant, and mixed.
14. Functional GI disorder.
15. Unable to tolerate a colonoscopy.
16. Presence of an indwelling intravenous line.
17. Infection requiring antibiotics other than the conditioning antibiotics during the study period.
18. Inability to take vancomycin, neomycin, and clindamycin antibiotics prior to FMT due to known hypersensitivity or intolerance.
19. Major genetic immune dysfunction (e.g., common variable immune deficiency).
20. Acquired immune deficiencies due to infections such as HIV.
21. Immunosuppressive medications including one of the following: systemic corticosteroids, calcineurin inhibitors, thiopurines, methotrexate, biologics (e.g., anti-tumor necrosis factor drugs), cancer chemotherapy.
22. Planned use of oral probiotics while on study.
23. Planned or ongoing chemotherapy for malignancy.
24. Planned antibiotic therapy within the period of the study, e.g., perioperative antibiotics.
25. Pregnant or lactating. Female participants of child-bearing age and their partners will be counseled on contraceptive measures to prevent pregnancy during the study period.
26. History of drug or alcohol abuse in the past 2 years.
27. Currently participating in another clinical study.
28. Legally incompetent and unable to understand the study's purpose, significance and consequences, and to make decisions accordingly.
29. Presence of metal implants, such as surgical clips or pacemakers, which will preclude performance of MRI tests.
30. Inability to undergo MRI testing for any reason, e.g., claustrophobia.

Participant flow

Outcome results

• Insulin Sensitivity (Primary)
• Microbiome Composition (Secondary), Mean, unitless measure: Antibiotics Prior to FMT 3.3 +/- 0.5; Placebo Prior to FMT 3.3 +/- 0.5
• Changes in Fecal Bacterial Composition Associated With FMT Overall Antibiotic and Placebo Conditioning Groups) by Laboratory Analysis. (Secondary), Mean, percent relative abundance: Antibiotics Prior to FMT 5 +/- 2; Placebo Prior to FMT 17 +/- 1
• Adverse Event Rates (Secondary), Number, Number of adverse events: Antibiotics Prior to FMT 6; Placebo Prior to FMT 4

Adverse events

Time frame: Adverse events were collected at each study visit during study participation, which was approximately 3-4 months, and collected again at a 6 month follow up visit after study completion.

Serious adverse events by term

Other adverse events by term

• Study Protocol and Statistical Analysis Plan (PDF, 2016-05-19)

• Alexander Khoruts, MD, Principal investigator, University of Minnesota