Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis

Western University, Canada

Status and phase: Enrolling; Phase 1

Conditions: Intestinal Microbiome; Atherosclerosis

Treatments: Biological: Fecal microbial transplant

Study type: Interventional

Funder types: Other

Identifiers

NCT04410003

115450

Details and patient eligibility

About

Patients with unexplained atherosclerosis (severe atherosclerosis not explained by traditional risk factors) will receive fecal microbial transplants (FMT) from patients with a Protected phenotype (patients who have high levels of risk factors but little or no carotid atherosclerosis). The objective is to determine what changes in the intestinal microbiome are associated with a decline in plasma levels of toxic metabolites of the itnestinal microbiome such as trimethylamine N-oxide (TMAO) and p-cresylsulfate. The intention is to develop an ecosystem therapeutic of cultured bacteria to treat atherosclerosis.

Full description

100 patients with Unexplained Atherosclerosis, and 5 donors with the protected phenotype will be recruited; there will be extensive microbial, viral and parasitic screening of the donors. Recipients will be randomized to receive capsules of stool from the donors, or cellulose placebo. Recipients will take cloxacillin 500 mg 4 times daily for 5 days before the FMT, and will undergo purging with an electrolyte solution, (PegLyte) the day before the FMT. Metagenomic analysis of the recipient stool will be performed before FMT, 6 weeks later and after 12 months.Plasma levels of toxic intestinal metabolites will be measured before FMT, at 6 weeks and 12 months after FMT; the levels to be measured will be TMAO, P-cresylsulfate, Hippuric acid. Indoxyl sulfate, P-cresyl glucuronide. Phenyl acetyl glutamine, and Phenyl sulfate.

The investigators will analyze the metagenomic changes in the intestinal microbiome of recipients that are associated with decline in the plasma levels of the metabolic products of the intestinal microbiome to identify candidate bacteria for an "ecosystem therapeutic for atherosclerosis. Based on previous experience of designing such a therapeutic for clostridium difficile, it is anticipated that ~ 40 bacterial species would be needed.

Enrollment: 100 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Severe atherosclerosis, with total plaque area in the top quartile (>119 mm2), not explained by traditional risk factors in linear regression (residual score >= 2)

Exclusion criteria

• Excluded will be patients unwilling/unable to provide informed consent, unwilling to ingest the stool capsules at baseline, patients with moderate to severe renal failure (eGFR<50), immunosuppressed patients, and patients with cancer, unstable angina, planned carotid revascularization or other conditions that might be expected to reduce their survival to < 1 year (including age >80).

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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100 participants in 2 patient groups, including a placebo group

Placebo

Placebo Comparator group

Description:

Cellulose capsules, cloxacillin, electrolyte purgative (Peglyte)

Treatment:

Biological: Fecal microbial transplant

Active

Active Comparator group

Description:

Capsules of stool from Protected donors, cloxacillin, electrolyte purgative (Peglyte)

Treatment:

Biological: Fecal microbial transplant