Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis

Atherosclerosis Clinical Trial

Official title:

Metabolic and Metagenomic Effects of Repopulation of the Intestinal Microbiome in Patients With Severe Unexplained Atherosclerosis

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04410003
• Other study ID #: 115450
• Status: Recruiting
• Phase: Phase 1
• Start date: June 2, 2020
• Est. completion date: April 30, 2025

Study information

• Verified date: April 2024
• Source: Western University, Canada
• Contact: J. David Spence, M.D.
• Phone: 1-519-931-5731
• Email: dspence[@]robarts.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: April 30, 2025
• Est. primary completion date: April 30, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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).

Related Conditions & MeSH terms

• Atherosclerosis
• Intestinal Microbiome

Intervention

Biological:
• Fecal microbial transplant
Fecal microbial transplant

Locations

Country	Name	City	State
Canada	Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute	London	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Western University, Canada	European Bioinformatics Institute

Country where clinical trial is conducted

Canada, 

References & Publications (1)

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Changes in plasma levels of metabolites of the intestinal microbiome	The primary outcome is changes in plasma levels of trimethylamine N-oxide and p-cresylsulfate	6 weeks and 12 months
Primary	Metagenomic changes of the intestinal microbiome	Metagenomic changes in the stool of transplant recipients will be analyzed to determine what changes in the intestinal bacteria are associated with changes in the plasma levels of the intestinal metabolites.	6 weeks and 12 months