Bioenergetic Effect of Pioglitazone in CLD-PH

NCT ID: NCT06336798

Last Updated: 2025-07-03

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 20 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-12-17
• Study Completion Date: 2028-02-29

Brief Summary

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).

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.

Conditions

Pulmonary Hypertension; Pulmonary Hypertension Due to Lung Diseases

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

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.

Group Type: EXPERIMENTAL

Pioglitazone 30mg

Intervention Type: DRUG

Study participants will take Pioglitazone 30 mg PO daily

Placebo

Intervention Type: DRUG

Study participants will take a placebo PO daily

Labs

Intervention Type: DIAGNOSTIC_TEST

Labs will be performed for Urine HCG, Complete Blood count (CBC), Chemistry Panel, Fasting lipids, insulin, glucose, and Bioenergetic analysis (platelets).

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.

Group Type: EXPERIMENTAL

Pioglitazone 30mg

Intervention Type: DRUG

Study participants will take Pioglitazone 30 mg PO daily

Placebo

Intervention Type: DRUG

Study participants will take a placebo PO daily

Labs

Intervention Type: DIAGNOSTIC_TEST

Labs will be performed for Urine HCG, Complete Blood count (CBC), Chemistry Panel, Fasting lipids, insulin, glucose, and Bioenergetic analysis (platelets).

Interventions

Pioglitazone 30mg

Study participants will take Pioglitazone 30 mg PO daily

Intervention Type: DRUG

Placebo

Study participants will take a placebo PO daily

Intervention Type: DRUG

Labs

Labs will be performed for Urine HCG, Complete Blood count (CBC), Chemistry Panel, Fasting lipids, insulin, glucose, and Bioenergetic analysis (platelets).

Intervention Type: DIAGNOSTIC_TEST

Other Intervention Names

Actos; Diagnostic labs

Eligibility Criteria

Inclusion Criteria

• Provision of a 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

• Pulmonary hypertension is defined based on meeting all three of the following measured at rest during the RHC:

• Mean pulmonary artery pressure >20 mmHg
• Pulmonary artery wedge pressure ≤15 mmHg
• Pulmonary vascular resistance > 2 Wood units
• Pulmonary hypertension is classified in Group 3: PH associated with lung diseases and/or hypoxia
• Medications approved for the treatment of pulmonary hypertension must be at a stable dose for at least 30 days
• 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 before 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
• History of left ventricular failure (systolic or diastolic)
• Pulmonary hypertension due to Group 2 PH (PH due to left heart disease)
• 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

Emory University

OTHER

Sponsor Role: lead

Responsible Party

Aaron W Trammell

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Aaron Trammell

Role: PRINCIPAL_INVESTIGATOR

Emory University

Locations

Emory Healthcare System

Atlanta, Georgia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Aaron Trammell, MD, MSc

Role: CONTACT

awtramm@emory.edu

404-712-8204

Jane Gillespie, RN

Role: CONTACT

jegille@emory.edu

404-712-8204

Facility Contacts

Jane Gillespie, RN

Role: primary

jegille@emory.edu

404-712-8204

Other Identifiers

K23HL166775

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STUDY00005871

Identifier Type: -

Identifier Source: org_study_id