Clinical trial NCT04884971: Microbiota Transplant Therapy for Pulmonary Arterial Hypertension: Early Safety and Feasibility Study
Official title: Microbiota Transplant Therapy for Pulmonary Arterial Hypertension: Early Safety and Feasibility Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Arterial Hypertension
Lead sponsor: University of Minnesota
Sponsor class: OTHER
First posted: 2021-05-13
Enrollment: 11
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Frequency of Serious Adverse Events
timeFrame: 6 months
measure: Proportion of IMT Compliance
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Minneapolis
country: United States
facility: University of Minnesota
state: Minnesota
Study officials:
affiliation: University of Minnesota Division of Cardiology
name: Thenappan Thenappan, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota Division of Cardiology
name: Kurt Prins, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota Division of Cardiology
name: Edward Weir, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Minnesota Division of Gastroenterology
name: Alexander Khoruts, MD
role: PRINCIPAL_INVESTIGATOR
References: