Metabolic and Metagenomic Effects of Intestinal Microbiome Repopulation in Unexplained Atherosclerosis

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

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.

Study Overview

• Status: Recruiting
• Conditions: Atherosclerosis; Intestinal Microbiome
• Intervention / Treatment: Biological: Fecal microbial transplant

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.

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: J. David Spence, M.D.; Phone Number: 1-519-931-5731; Email: dspence@robarts.ca
• Study Contact Backup: Name: Leslie Paddock, R.N.; Phone Number: 1-519-931-5731; Email: leslie.paddock@lhsc.on.ca

Study Locations

• Canada
  • Ontario
    • London, Ontario, Canada, N6G 2V4
      • Recruiting
      • Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute
      • Contact: J. David Spence, M.D.; Phone Number: 1-519-931-5731; Email: dspence@robarts.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Cellulose capsules, cloxacillin, electrolyte purgative (Peglyte)	Biological: Fecal microbial transplant; Fecal microbial transplant
Active Comparator: Active; Capsules of stool from Protected donors, cloxacillin, electrolyte purgative (Peglyte)	Biological: Fecal microbial transplant; Fecal microbial transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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

Collaborators and Investigators

• Sponsor: Western University, Canada
• Collaborators: European Bioinformatics Institute
• Investigators: Principal Investigator: J. David Spence, M.D., Western University, Canada; Study Director: Chrysi Bogiatzi, M.D., Division of Neurology, Western University

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): June 2, 2020
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): July 30, 2025

Study Registration Dates

• First Submitted: February 24, 2020
• First Submitted That Met QC Criteria: May 27, 2020
• First Posted (Actual): June 1, 2020

Study Record Updates

• Last Update Posted (Actual): October 17, 2024
• Last Update Submitted That Met QC Criteria: October 15, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Atherosclerosis
• Other Study ID Numbers: 115450

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Data might be made available with approval of the ethics committee

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No