Microbiota Transplant Therapy for Pulmonary Arterial Hypertension: Early Safety and Feasibility Study

This pilot clinical trial will evaluate the initial safety and feasibility of intestinal microbiota transplantation (IMT) in patients with pulmonary arterial hypertension (PAH). This trial will inform development of future trials in treatment of PAH. Active drug in capsule form composed of freeze-dried, encapsulated intestinal microbiota from healthy donors will be administered to patients with PAH. This study will also allow for limited evaluation of pharmacokinetics in terms of donor microbiota engraftment and pharmacodynamics in terms of potential mechanisms. It will also allow for limited evaluation of cardiac endurance and function prior to and after IMT.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: Intestinal microbiota transplant (IMT)

Detailed Description

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by pulmonary vascular remodeling of precapillary pulmonary arteries resulting in obstruction, increased pulmonary vascular resistance, right-sided cardiac failure, and ultimately death. Although pharmacologic therapies have been developed, these modestly improve cardiac function and primarily act to improve symptoms and quality of life; therefore, PAH remains a very lethal disease. Perivascular lung inflammation drives these vascular changes in PAH. This inflammatory profile could be driven by an imbalance of pro- and anti-inflammatory intestinal microbial metabolites, cytokines, other mediators, and/or direct effects of circulating bacteria all stemming from dysbiosis, gut-barrier dysfunction, and possibly, decreased hepatic filtration. Because PAH is characterized by a microbiome distinct from healthy controls, the investigators hypothesize that intestinal microbiota transplant (IMT) will help to reduce severity of PAH and improve quality of life, and that the healthy microbiome may exert these effects by decreasing inflammation. In this pilot clinical trial, the investigators aim to test the safety and feasibility of IMT from healthy donors into patients with PAH. Additionally, in the exploratory objectives, the investigators will obtain limited data to study pharmacokinetics of IMT, including engraftment and stability of donor intestinal microbiota, and pharmacodynamics to include circulating microbial products and markers of inflammation. Proposed circulating markers that may be assessed include interleukin-6, C-reactive protein, soluble CD14, lipopolysaccharide (LPS), phenylacetylglutamine, trimethylamine N-oxide, intestinal fatty acid binding protein, zonulin, claudin, short-chain fatty acids (SCFAs), tumor necrosis factor-α, interleukin-1β, and transforming growth factor-β.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Diagnosis of pulmonary arterial hypertension (PAH)
• On stable treatment for PAH for one month prior to enrollment
• Able to swallow capsultes
• Able to provide blood sample and fecal sample

Exclusion Criteria:

• Dysphagia to pills
• Clinically active inflammatory bowel disease
• Pregnancy or breastfeeding
• Life expectancy of <6 months
• Presence of ileostomy or colostomy
• Taking immunosuppressants (calcineurin inhibitors, prednisone greater than or equal to 20mg/day, methotrexate, azathioprine, immunosuppressive biologics, JAK inhibitors)
• Neurotropenia (an absolute neurotrophil count < 0.5 x 10^9 cells/L)
• History of solid organ or bone marrow transplant
• Anticipated recurrent antibiotic use (participants with frequent urinary tract infections or sinusitis)
• History of severe anaphylactic food allergy
• History of celiac disease
• History of receiving cancer chemotherapy, immunotherapy, or radiation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Microbiota Treatment Arm; Participants will receive the encapsulated microbiota intervention daily for seven days and will be subsequently monitored for six months.	Drug: Intestinal microbiota transplant (IMT); Two size 00 capsules from a single lot will be taken daily. Approximately 2.0 x 10^11 bacteria from a healthy donor are contained in each capsule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Frequency of Serious Adverse Events	In order to assess the safety of the trial, the frequency of adverse events will be reported. Outcome will be reported as the mean number of serious adverse events per participant.	6 months
Proportion of IMT Compliance	In order to assess the feasibility of the trial, the proportion of subjects taking 100% of the intestinal microbiota transplantation (IMT) doses per protocol will be reported. Outcome is reported as the percent of participants who consume 100% of IMT doses.	6 months

Collaborators and Investigators

• Sponsor: University of Minnesota
• Investigators: Principal Investigator: Thenappan Thenappan, MD, University of Minnesota Division of Cardiology; Principal Investigator: Kurt Prins, MD, PhD, University of Minnesota Division of Cardiology; Principal Investigator: Edward Weir, MD, University of Minnesota Division of Cardiology; Principal Investigator: Alexander Khoruts, MD, University of Minnesota Division of Gastroenterology

Study record dates

Study Major Dates

• Study Start (Actual): November 3, 2021
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: May 7, 2021
• First Submitted That Met QC Criteria: May 7, 2021
• First Posted (Actual): May 13, 2021

Study Record Updates

• Last Update Posted (Actual): February 12, 2024
• Last Update Submitted That Met QC Criteria: February 9, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Hypertension; Pulmonary Arterial Hypertension; Familial Primary Pulmonary Hypertension
• Other Study ID Numbers: CV-2021-29604

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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