Microbiota Transplant Therapy for Pulmonary Hypertension

Overseen by Edward Weirs, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: University of Minnesota

Must not be taking: Immunosuppressants, Chemotherapy

Disqualifiers: Pregnancy, Inflammatory bowel disease, others

Trial Summary

What is the purpose of this trial?

This pilot clinical trial will evaluate the initial safety, feasibility, and pharmacokinetics of microbiota transplant therapy (MTT) with antibiotic pre-conditioning and fiber supplementation vs. placebo in patients with pulmonary arterial hypertension (PAH). This trial will inform development of future trials of MTT as a treatment for PAH. 24 PAH patients will be randomized to receive either MTT with antibiotic preconditioning + fiber supplementation, MTT with antibiotic preconditioning + placebo supplementation, or placebo + placebo supplementation. MTT will in a capsule form composed of freeze-dried, encapsulated intestinal microbiota from healthy donors. Fiber supplementation will be 10-14 gm oral fiber supplement. Patients will be followed at week 1, week 2, week 4, week 12, and week 24. Patient will undergo stool sample collection at baseline, week 1, week 4, and week 12, blood sample collection at baseline, week 4, and week,12. In addition, patient will undergo an echocardiogram, six-minute walk test (6MWT) and quality of life questionnaire at baseline and at week 12.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications, but you must be on stable treatment for pulmonary arterial hypertension for at least one month before joining. If you are on immunosuppressants or receiving cancer treatments, you cannot participate.

What data supports the effectiveness of this treatment for pulmonary hypertension?

Fecal microbiota transplantation (FMT), a component of the treatment, is known to be effective for recurrent Clostridium difficile infections and is being studied for other conditions like inflammatory bowel disease, showing promising results. This suggests potential benefits in other conditions where gut microbiota plays a role. ^{1 2 3 4 5}

Is Microbiota Transplant Therapy generally safe for humans?

Fecal microbiota transplantation (FMT), a form of Microbiota Transplant Therapy, is considered a safe treatment option for patients with recurrent Clostridium difficile infection. ^{6 7 8 9 10}

How is Microbiota Transplant Therapy different from other treatments for pulmonary hypertension?

Microbiota Transplant Therapy (MTT) is unique because it involves transferring healthy gut bacteria from a donor to a patient, which is different from traditional drug treatments. This approach aims to modify the gut microbiome, potentially impacting conditions like pulmonary hypertension by addressing underlying microbiome imbalances. ^{1 3 4 11 12}

Research Team

Thenappan Thenappan, MD

Principal Investigator

University of Minnesota

Alexander Khoruts, MD

Principal Investigator

University of Minnesota

Levi Teigen, MD, PhD

Principal Investigator

University of Minnesota

Christopher Staley, PhD

Principal Investigator

University of Minnesota

Kurt Prins, MD,PhD

Principal Investigator

University of Minnesota

Edward Weirs, MD

Principal Investigator

University of Minnesota

Eligibility Criteria

This trial is for adults aged 18-75 with pulmonary arterial hypertension (PAH) who have been on stable PAH treatment for at least a month. Participants must be able to swallow capsules, provide blood and stool samples, and commit to the study's schedule including follow-ups.

Inclusion Criteria

I can provide blood and stool samples.

I have signed and agreed to the consent form.

I have been on a stable treatment for PAH for at least one month.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive microbiota transplant therapy (MTT) with antibiotic preconditioning and fiber supplementation or placebo

12 weeks

Visits at week 1, week 2, week 4, and week 12

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 weeks

Visit at week 24

Treatment Details

Interventions

• MTT with antibiotic preconditioning + fiber supplementation (Microbiota Therapy)
• MTT with antibiotic preconditioning + placebo supplementation (Microbiota Therapy)
• MTT with placebo + placebo supplementation (Other)

Trial Overview The trial tests microbiota transplant therapy (MTT) with antibiotic preconditioning and fiber supplementation versus placebo in PAH patients. It aims to assess safety, feasibility, and how the body processes MTT. Patients are randomly assigned to one of three groups: MTT plus fiber, MTT plus placebo fiber or double placebo.

Participant Groups

Group I: Drug group Experimental Treatment 1 Intervention

PAH patients randomized to MTT with antibiotic preconditioning + fiber supplementation

Group II: Control 1 Active Control 1 Intervention

MTT with antibiotic preconditioning + placebo supplementation

Group III: Control 2 Placebo Group 1 Intervention

placebo + placebo supplementation.

Who Is Running the Clinical Trial?

University of Minnesota

Lead Sponsor

Trials

1,459

Recruited

1,623,000+

Shashank Priya

University of Minnesota

Chief Executive Officer since 2023

PhD in Materials Engineering from Penn State

Charles Semba

University of Minnesota

Chief Medical Officer since 2021

MD from the University of Minnesota Medical School

Findings from Research

Fecal microbiota transplantation (FMT) using targeted colonic release capsules (FMTcr) showed a slightly higher clinical cure rate for recurrent Clostridium difficile infection (rCDI) at 80.6% compared to 75% for gastric release capsules (FMTgr), although the difference was not statistically significant.

Both FMT formulations were found to be safe with no serious adverse events, but FMTcr was more effective in increasing gut microbial diversity, suggesting better microbial engraftment patterns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose. Allegretti, JR., Fischer, M., Sagi, SV., et al.[2020]

Fecal microbiota transplantation (FMT) has a total adverse event (AE) incidence rate of 28.5%, with abdominal discomfort being the most common AE reported in 19 studies, highlighting the need for careful monitoring during the procedure.

Serious adverse events (SAEs) occurred in 9.2% of patients, with a notable incidence of death (3.5%) and infections (2.5%), indicating that while FMT can be beneficial, it carries significant risks that require further investigation through high-quality randomized controlled trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic Review: Adverse Events of Fecal Microbiota Transplantation. Wang, S., Xu, M., Wang, W., et al.[2023]

Fecal microbiota transplantation (FMT) is a cost-effective treatment for recurrent Clostridium difficile infection (rCDI), with all economic evaluations showing it to be more cost-effective than other standard treatments at a threshold of ≤$50,000 per quality-adjusted life year (QALY).

The systematic review included 9 high-quality economic evaluations, primarily focusing on rCDI and inflammatory bowel disease (IBD), indicating that while FMT is effective for rCDI, further studies are needed to explore its economic impact for other conditions like IBD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of economic evaluation in fecal microbiota transplantation. Stalder, T., Kapel, N., Diaz, S., et al.[2021]

Pulmonary arterial hypertension (PAH) in rats leads to gut dysbiosis, characterized by a three-fold increase in the Firmicutes-to-Bacteroidetes ratio, indicating an imbalance in gut bacteria.

The altered microbiota composition in PAH rats, along with reduced serum acetate levels, suggests that these changes could contribute to the disease's pathophysiology by affecting immune, hormonal, and metabolic functions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome. Callejo, M., Mondejar-Parreño, G., Barreira, B., et al.[2019]

Fecal microbiota transplantation (FMT) is a safe and effective treatment for recurrent Clostridium difficile infections and may also help in understanding the link between gut microbiota dysbiosis and cardiovascular and metabolic disorders.

This study provides a detailed protocol for conducting FMT in murine models, which can aid in exploring gut microbiome effects on cardiovascular disease and potentially lead to new microbiota-targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Murine Fecal Isolation and Microbiota Transplantation. Ishimwe, JA., Zhong, J., Kon, V., et al.[2023]

Mesenchymal stem cell (MSC) therapy effectively reduces pulmonary hypertension (PH) in hypoxia-induced mice, suggesting a potential new treatment avenue for this condition.

The study found that MSC treatment restores gut microbiota balance, reversing harmful bacterial increases and enhancing beneficial bacteria, indicating that gut microbiota may play a significant role in the therapeutic mechanism of MSCs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

MSCs Therapy Reverse the Gut Microbiota in Hypoxia-Induced Pulmonary Hypertension Mice. Luo, L., Chen, Q., Yang, L., et al.[2021]

The study found that gut microbiota is disrupted in rat models of pulmonary hypertension induced by hypoxia, hypoxia/Sugen5416, and monocrotaline, indicating a potential link between gut health and pulmonary hypertension.

Specific changes in gut microbiota diversity were observed, with distinct patterns in different models of pulmonary hypertension, and six plasma biomarkers associated with the condition were identified, suggesting a complex relationship between gut microbiota and disease progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gut Microbiota and Metabolome Changes in Three Pulmonary Hypertension Rat Models. Luo, L., Yin, H., Gou, D.[2023]

Gut microbiota dysbiosis contributes to the development of pulmonary arterial hypertension (PAH) by increasing gut permeability and allowing harmful bacterial products to enter the bloodstream, which exacerbates inflammation and vascular remodeling.

Emerging therapies like probiotic treatment and fecal microbiota transplantation show promise in complementing existing PAH treatments, highlighting the potential of targeting gut health in managing this serious condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Role and Mechanism of Gut Microbiota in Pulmonary Arterial Hypertension. Chen, YH., Yuan, W., Meng, LK., et al.[2022]

Fecal microbiota transplantation (FMT) is highly effective and considered safe for treating recurrent Clostridium difficile infections, even in patients with complex medical conditions like tetraplegia.

In this case, a self-advancing nasal jejunal feeding tube was successfully used for a minimally invasive FMT, but the patient experienced persistent arterial hypertension post-procedure, suggesting a potential new side effect and a possible link between the intestinal microbiome and blood pressure regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Non-invasive fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient presenting with hypertensive disorder post interventionem. Goeser, F., Schlabe, S., Ruiner, CE., et al.[2020]

Fecal microbiota transplantation (FMT) is effective in treating recurrent Clostridium difficile infections, as demonstrated in a case study of a woman who was successfully treated with this method.

The case raises concerns about potential side effects, such as new-onset obesity, when using stool from overweight donors, suggesting the need for further research on the impact of donor characteristics on FMT outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Weight gain after fecal microbiota transplantation. Alang, N., Kelly, CR.[2022]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

[Fecal microbiota transplantation : current status and prospects]. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation Capsules with Targeted Colonic Versus Gastric Delivery in Recurrent Clostridium difficile Infection: A Comparative Cohort Analysis of High and Lose Dose. [2020]

3. United States pubmed.ncbi.nlm.nih.gov

Fecal Microbiota Transplantation and Medical Therapy for Clostridium difficile Infection : Meta-analysis of Randomized Controlled Trials. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Systematic Review: Adverse Events of Fecal Microbiota Transplantation. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

A systematic review of economic evaluation in fecal microbiota transplantation. [2021]

6. England pubmed.ncbi.nlm.nih.gov

Pulmonary Arterial Hypertension Affects the Rat Gut Microbiome. [2019]

7. United States pubmed.ncbi.nlm.nih.gov

Murine Fecal Isolation and Microbiota Transplantation. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

MSCs Therapy Reverse the Gut Microbiota in Hypoxia-Induced Pulmonary Hypertension Mice. [2021]

9. Switzerland pubmed.ncbi.nlm.nih.gov

Gut Microbiota and Metabolome Changes in Three Pulmonary Hypertension Rat Models. [2023]

10. Switzerland pubmed.ncbi.nlm.nih.gov

The Role and Mechanism of Gut Microbiota in Pulmonary Arterial Hypertension. [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

Non-invasive fecal microbiota transplantation for recurrent Clostridium difficile infection in a patient presenting with hypertensive disorder post interventionem. [2020]

12. United States pubmed.ncbi.nlm.nih.gov

Weight gain after fecal microbiota transplantation. [2022]