Bioenergetic Effect of Pioglitazone in CLD-PH

March 28, 2024 updated by: Aaron W Trammell, Emory University

Effect of Pioglitazone on Mitochondrial Metabolism in Pulmonary Hypertension Due to Chronic Lung Disease

The goal of this clinical trial is to learn about the safety and efficacy of Pioglitazone in people with Pulmonary Hypertension (PH) due to Chronic Lung Disease (CLD). The main question it aims to answer is:

• Whether pioglitazone affects mitochondrial oxygen utilization in patients with PH due to CLD.

Participants will be asked to take pioglitazone or placebo once daily for 28 days followed by a washout period of 2 weeks followed by 28 days of the other study drug (participants randomized to placebo followed by pioglitazone or pioglitazone followed by placebo).

Study Overview

Detailed Description

Pulmonary hypertension (PH) is a state of chronic elevated pressure in the pulmonary circulation. PH has multiple possible causes, clinically classified into 5 separate groups according to the World Symposium on PH classification scheme. PH is common in adults, with increasing prevalence with age, and is associated with significant symptom burden and mortality. In the U.S., approximately 1.5 million U.S. adults have PH, including 5-10% of people >65.

Metabolic abnormalities have been highlighted recently as contributing to PH pathogenesis, disease severity, and outcome. In pre-clinical studies, reduced mitochondrial metabolism (oxidative phosphorylation) and reliance on alternative metabolic pathways (glycolysis) have been shown to promote pulmonary vascular remodeling and PH. Mechanistic investigation has shown that reduced PPARγ activity in lung vascular cells is necessary and sufficient to cause cellular proliferation and dysfunction followed by PH, all of which can be reversed by available pharmacotherapies designed to activate PPARγ.

Metabolic changes have been demonstrated in 1) lung vessels from multiple PH animal models and 2) humans with PAH 3) right ventricle from humans with PAH, 4) skeletal muscle from humans with PAH, 5) circulating platelets from humans with PAH and PH due to left heart disease. Clinical trials of therapies that activate PPARγ have not been previously conducted in patients with PH but are believed by experts in the field to be a highly promising therapeutic approach.

In this trial, the investigators will study the mitochondrial metabolic effects ("bioenergetics") of pioglitazone, an available medication from the class of thiazolidinedione (TZD) drugs that activate PPARγ. This medication is FDA-approved for the treatment of Type II diabetes mellitus (DM). Pioglitazone has been studied in non-diabetics with diverse other conditions demonstrating safety.

The study team will assess cellular energy metabolism through a sophisticated assay of bioenergetics. The investigators and others have shown that bioenergetics can be measured in isolated platelets obtained from a peripheral blood draw in patients with PH and other diseases. Furthermore, others have shown that in PAH, platelet bioenergetics correlate with known disease-relevant metabolic changes in lung blood vessels. In this study, the team will assess the effect of pioglitazone on bioenergetic parameters in platelets isolated from whole blood samples.

Study Type

Interventional

Enrollment (Estimated)

20

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures for the duration of the study
  • Confirmed to have pulmonary hypertension (PH) due to chronic lung disease at screening; Diagnosis must be confirmed by right heart catheterization. Right heart catheterization must be within 1 year of screening.
  • Ability to take oral medication and be willing to adhere to the study intervention regimen
  • For females of reproductive potential: agreement to use highly effective contraception during study participation and for an additional 4 weeks after the end of study participation.
  • For males of reproductive potential: use of condoms or other methods to ensure effective contraception with a partner
  • Agreement to adhere to Lifestyle Considerations (below) throughout the study duration o During this study, participants are asked to arrive in the clinic for study visits in the fasting state. Specifically, participants should abstain from any caloric intake for 6 hours prior to arrival for the study visit.

Exclusion Criteria:

  • Diabetes mellitus (type 1 or type 2), present within the preceding 1 year
  • Personal history of symptomatic hypoglycemia within 90 days preceding enrollment
  • Personal outpatient use of pioglitazone, rosiglitazone, metformin, insulin, or other medications for the indication of diabetes within 90 days preceding enrollment
  • New York Heart Association Class III or IV symptoms due to heart failure at enrollment
  • History of prior or active bladder cancer
  • Thrombocytopenia (diagnosis or known platelet count ≤120) within 90 days preceding enrollment
  • Platelet count ≤120 during screening or on the day of enrollment hypertension due to chronic lung disease
  • Cystic fibrosis
  • Pregnancy or lactation
  • Current tobacco use
  • Known allergic reaction to components of the study medication (pioglitazone)
  • Treatment with another investigational drug within 30 days

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Pioglitazone, Then Placebo
Participants will first receive a 30 mg tablet of Pioglitazone once daily for 28 days. After a washout period of 14 days, they will then receive a Placebo tablet (matching Pioglitazone 30 mg tablet) once daily for 28 days.
Study participants will take Pioglitazone 30 mg PO daily
Other Names:
  • Actos
Study participants will take a placebo PO daily
Labs will be performed for Urine HCG, Complete Blood count (CBC), Chemistry Panel, Fasting lipids, insulin, glucose, and Bioenergetic analysis (platelets).
Other Names:
  • Diagnostic labs
Experimental: Placebo, Then Pioglitazone
Participants will first receive a Placebo for 28 days. After a washout period of 14 days, they will then receive a 30 mg Pioglitazone tablet once daily for 28 days.
Study participants will take Pioglitazone 30 mg PO daily
Other Names:
  • Actos
Study participants will take a placebo PO daily
Labs will be performed for Urine HCG, Complete Blood count (CBC), Chemistry Panel, Fasting lipids, insulin, glucose, and Bioenergetic analysis (platelets).
Other Names:
  • Diagnostic labs

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in Mitochondrial metabolism parameters: Spare respiratory capacity
Time Frame: Day 1, Day 28, Day 70

Mitochondrial metabolism is measured using a research protocol employing the Agilent Seahorse extracellular flux bioanalyzer. Standard Seahorse assay protocols have been adapted for use with human platelets .

Spare respiratory capacity (SRC) is calculated by (maximal respiration) - (basal respiration) during the mitochondrial stress test. The value is reported in pmol/min.

Day 1, Day 28, Day 70
Change in Mitochondrial metabolism parameters: Maximal respiration
Time Frame: Day 1, Day 28, Day 70
Maximal Respiration is calculated by: (post-carbonyl cyanide 4-(trifluoromethoxy) phenylhydrazone(FCCP) - (nonmitochondrial respiration) during the mitochondrial stress test. The value is reported in pmol/min.
Day 1, Day 28, Day 70
Change in Mitochondrial metabolism parameters: Basal respiration
Time Frame: Day 1, Day 28, Day 70
Basal respiration is calculated by (Baseline) - (nonmitochondrial respiration) ) during the mitochondrial stress test. The value is reported in pmol/min.
Day 1, Day 28, Day 70

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Number of participants with leg edema
Time Frame: Day 1, Day 28, Day 70
Participants reporting edema (>2) will be captured.
Day 1, Day 28, Day 70
Change in BNP levels
Time Frame: Day 1, Day 28, Day 70
Change in Brain Natriuretic Peptide from the baseline will be calculated. Unit is pg/ml
Day 1, Day 28, Day 70
Number of hypoglycemia incidences
Time Frame: Day 1, Day 28, Day 70
Participants experiencing symptoms of hypoglycemia will be identified and reported.
Day 1, Day 28, Day 70
Change in Six minute walk distance (6MWT)
Time Frame: Day 1, Day 28, Day 70
The six-minute walk test (6MWT) is a standardized test of exercise capacity commonly used in patients with heart failure, lung disease, PH, and in pre-lung transplant evaluation. Results will be recorded as the distance walked in meters.
Day 1, Day 28, Day 70
Change in Borg dyspnea score
Time Frame: Day 1, Day 28, Day 70
Borg dyspnea score assessed before and after 6MWT. The Borg dyspnea score is a rating of dyspnea that is scored between 0 and 10. Higher scores indicate worse dyspnea.
Day 1, Day 28, Day 70
Change in NYHA/WHO Functional Classification
Time Frame: Day 1, Day 28, Day 70
The New York Heart Association / World Health Organization Functional Classification (NYHA/WHO FC) is a symptom-based score graded on a scale from I-IV. It is used to objectively assess severity of symptoms for patients with heart failure, PH, and other cardiopulmonary conditions. In this study, NYHA/WHO FC will be recorded at each study visit. Higher scores indicate a higher degree of functional limitation.
Day 1, Day 28, Day 70
Change in University of California San Diego Shortness of Breath Questionnaire score
Time Frame: Day 1, Day 28, Day 70
The University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) is a 24-item measure that assesses self-reported shortness of breath while performing a variety of activities of daily living. It is self-completed by participants and is validated in multiple languages (including US English) and in diseases including COPD, ILD, and general states of dyspnea. Each of the 24 items is scored on a six-point scale (0-5). Total scores range from 0 to 120 with higher scores indicating worse dyspnea.
Day 1, Day 28, Day 70
Change in emPHasis-10 Questionnaire score
Time Frame: Day 1, Day 28, Day 70
The emPHasis-10 questionnaire consists of 10 items that address breathlessness, fatigue, control, and confidence and is designed to assess the impacts that PH has on a person's quality of life. Each of the items is scored on a six-point scale (0-5). emPHasis-10 scores range from 0 to 50 with higher scores indicating worse quality of life.
Day 1, Day 28, Day 70

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Aaron Trammell, Emory University

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

May 1, 2024

Primary Completion (Estimated)

August 1, 2028

Study Completion (Estimated)

August 1, 2028

Study Registration Dates

First Submitted

March 22, 2024

First Submitted That Met QC Criteria

March 22, 2024

First Posted (Actual)

March 29, 2024

Study Record Updates

Last Update Posted (Actual)

April 1, 2024

Last Update Submitted That Met QC Criteria

March 28, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

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.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Pulmonary Hypertension

Clinical Trials on Pioglitazone 30mg

3
Subscribe