Clinical trial NCT04410003: Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis
Official title: Metabolic and Metagenomic Effects of Repopulation of the Intestinal Microbiome in Patients with Severe Unexplained Atherosclerosis
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Atherosclerosis
Intestinal Microbiome
Lead sponsor: Western University, Canada
Sponsor class: OTHER
Collaborators: name: European Bioinformatics Institute
First posted: 2020-06-01
Enrollment: 100
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized controlled trial
Primary purpose: PREVENTION

Brief summary: 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.

Detailed 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.

Eligibility criteria: 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).

Primary outcomes:
measure: Changes in plasma levels of metabolites of the intestinal microbiome
timeFrame: 6 weeks and 12 months
measure: Metagenomic changes of the intestinal microbiome
timeFrame: 6 weeks and 12 months
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: Canada
facility: Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute
state: Ontario
Study officials:
affiliation: Western University, Canada
name: J. David Spence, M.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: Division of Neurology, Western University
name: Chrysi Bogiatzi, M.D.
role: STUDY_DIRECTOR
References:
citation: Bogiatzi C, Gloor G, Allen-Vercoe E, Reid G, Wong RG, Urquhart BL, Dinculescu V, Ruetz KN, Velenosi TJ, Pignanelli M, Spence JD. Metabolic products of the intestinal microbiome and extremes of atherosclerosis. Atherosclerosis. 2018 Jun;273:91-97. doi: 10.1016/j.atherosclerosis.2018.04.015. Epub 2018 Apr 17.