Pioglitazone for Pulmonary Hypertension

Overseen By Jane Gillespie, RN

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Pioglitazone, Rosiglitazone, Metformin, Insulin

Disqualifiers: Diabetes, Heart failure, Bladder cancer, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 3

Duration: 12 weeks

20 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but it requires that any medications for pulmonary hypertension be at a stable dose for at least 30 days before joining. If you are taking diabetes medications like pioglitazone, rosiglitazone, metformin, or insulin, you must stop them at least 90 days before enrolling.

What data supports the effectiveness of the drug pioglitazone for pulmonary hypertension?

Recent studies suggest that pioglitazone, a drug originally used for diabetes, may help treat pulmonary arterial hypertension (a type of high blood pressure affecting the lungs) by reducing inflammation and improving heart function. This is based on its ability to activate PPARγ, a protein that helps regulate metabolism and inflammation, and has shown promise in animal studies and some clinical trials. ^{1 2 3 4 5}

Is pioglitazone safe for humans?

Pioglitazone is generally well tolerated in humans, with weight gain and swelling being the most common side effects. It has been used safely in people with type 2 diabetes, either alone or with other medications, without known drug interactions. ^{4 5 6 7 8}

How does the drug Pioglitazone work for pulmonary hypertension?

Pioglitazone is unique for pulmonary hypertension because it activates PPARγ (a type of protein that helps control gene expression), which can relax blood vessels in the lungs and reduce high blood pressure. This mechanism is different from other treatments that mainly focus on dilating blood vessels through different pathways. ^{3 4 9 10 11}

What is the purpose of this trial?

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).

Research Team

Aaron Trammell

Principal Investigator

Emory University

Eligibility Criteria

This trial is for individuals with Pulmonary Hypertension due to Chronic Lung Disease, confirmed by a test within the last year. Participants must be able to take oral medication and follow study procedures, including fasting before visits. Women who can have children and men must use effective contraception during the study.

Inclusion Criteria

I have signed and dated the consent form.

I am willing to follow all study rules for its duration.

I agree to not eat for 6 hours before my study visits.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either Pioglitazone or placebo once daily for 28 days, followed by a 2-week washout period, then switch to the other treatment for another 28 days

12 weeks

3 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Pioglitazone

Trial Overview The trial tests if Pioglitazone affects mitochondrial oxygen utilization in PH patients with CLD. It involves taking Pioglitazone or a placebo daily for 28 days, a two-week break, then switching treatments for another 28 days.

Participant Groups

Group I: Placebo, Then Pioglitazone Experimental Treatment 3 Interventions

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 II: Pioglitazone, Then Placebo Experimental Treatment 3 Interventions

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.

Pioglitazone is already approved in United States for the following indications:

Approved in United States as Actos for:

• Type 2 diabetes mellitus

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

Findings from Research

PPARγ agonists, particularly pioglitazone, have shown promise as effective treatments for pulmonary arterial hypertension (PAH) due to their antiproliferative and anti-inflammatory properties, supported by recent clinical trial data.

Despite past concerns about potential adverse effects, recent studies indicate that pioglitazone has a favorable safety profile in high-risk populations, warranting further clinical trials to explore its repurposing for PAH treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activation of the Metabolic Master Regulator PPARγ: A Potential PIOneering Therapy for Pulmonary Arterial Hypertension. Hansmann, G., Calvier, L., Risbano, MG., et al.[2021]

Pioglitazone, approved in 1999 for type 2 diabetes, not only improves glycemic control by reducing insulin resistance but also positively affects lipid metabolism, blood pressure, and inflammation markers, making it beneficial beyond just glucose management.

Despite concerns about potential cancer risks associated with pioglitazone, it is generally considered a safer option among thiazolidinedione-class drugs, and its continued use is recommended for patients who can benefit from its multiple effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pioglitazone: Indian perspective. Shukla, R., Kalra, S.[2021]

In a study involving 32 rats, rosiglitazone significantly reduced mean pulmonary arterial pressure (mPAP) and the thickness of small pulmonary arteries in a dose-dependent manner, indicating its protective effects against monocrotaline-induced pulmonary arterial hypertension (PAH).

The reduction in mPAP and inflammation markers (IL-6, TNF-α, MCP-1) suggests that the mechanism of rosiglitazone's protective effects may involve the inhibition of inflammatory processes associated with PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Protective effects of rosiglitazone intervention on monocrotaline-induced pulmonary arterial hypertension in rats and related inflammatory mechanisms]. Wang, XF., Lu, WX., Guo, J., et al.[2018]

Selexipag is a newly approved oral medication that acts as an IP receptor agonist, targeting the prostacyclin pathway to treat pulmonary arterial hypertension (PAH) by promoting pulmonary vasodilation and improving right ventricular function.

While selexipag shows promise as a treatment option for PAH, its effectiveness as a first-line therapy is uncertain, and it is likely to be used in combination with other PAH-specific medications rather than as a standalone treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. Richter, MJ., Gall, H., Grimminger, J., et al.[2018]

Pioglitazone effectively increases insulin sensitivity and improves glycemic control in patients with type 2 diabetes, whether used alone or in combination with other medications, based on clinical trials.

The medication is generally well tolerated, with weight gain and edema being the most common side effects, and it also shows potential benefits in reducing cardiovascular risk and arteriosclerosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. Waugh, J., Keating, GM., Plosker, GL., et al.[2019]

Sitaxsentan, a selective oral endothelin receptor antagonist, has been proven to significantly improve exercise capacity, functional class, and pulmonary hemodynamics in patients with pulmonary arterial hypertension (PAH).

The treatment is well tolerated, shows a durable response, and has a low incidence of liver toxicity, making it a safe and effective option for managing PAH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sitaxsentan for the treatment of pulmonary arterial hypertension. Girgis, RE., Dixon, RA.[2012]

In a study of 15 children with pulmonary arterial hypertension (PAH), add-on selexipag was found to be safe and well-tolerated, with no deaths during treatment and improvements in key health metrics for about 50% of the patients.

Selexipag therapy led to significant improvements in right ventricular function and pulmonary pressures, indicating its potential efficacy in managing PAH in pediatric patients, especially in those who are less severely affected.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy. Hansmann, G., Meinel, K., Bukova, M., et al.[2021]

Ambrisentan is an effective treatment for pulmonary arterial hypertension (PAH), improving exercise capacity and hemodynamics while maintaining a good safety profile.

In the AMBITION trial, combining ambrisentan with tadalafil significantly reduced the risk of clinical failure compared to using either drug alone, highlighting the benefits of upfront combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ambrisentan: a review of its use in pulmonary arterial hypertension. Rivera-Lebron, BN., Risbano, MG.[2023]

PPARγ agonists, specifically rosiglitazone and pioglitazone, effectively relax isolated human pulmonary arteries, suggesting their potential as a treatment for pulmonary arterial hypertension.

The relaxation induced by rosiglitazone involves multiple mechanisms, including PPARγ receptor activation, nitric oxide production, and KATP channel involvement, indicating a complex pathway that could be targeted for therapeutic benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Relaxation of human pulmonary arteries by PPARγ agonists. Kozłowska, H., Baranowska-Kuczko, M., Schlicker, E., et al.[2021]

In a study involving rats with monocrotaline-induced pulmonary hypertension, treatment with PPARgamma ligands (pioglitazone and troglitazone) significantly reduced pulmonary artery pressure and vessel wall thickening over three weeks.

The reduction in pulmonary hypertension was linked to the inhibition of cell proliferation in the pulmonary arterial walls, suggesting that PPARgamma ligands may be effective in managing this condition by targeting vascular smooth muscle cell growth.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats]. Matsuda, Y., Hoshikawa, Y., Ameshima, S., et al.[2013]

LASSBio-1386 significantly reduced right ventricular (RV) systolic pressure in a rat model of pulmonary arterial hypertension (PAH), demonstrating its potential efficacy in alleviating RV dysfunction associated with the disease.

The treatment with LASSBio-1386 improved endothelial function and normalized levels of key proteins involved in cardiac and vascular function, suggesting it may be a promising therapeutic option for PAH and warrants further clinical evaluation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity. Alencar, AK., Pereira, SL., da Silva, FE., et al.[2016]

References

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

Activation of the Metabolic Master Regulator PPARγ: A Potential PIOneering Therapy for Pulmonary Arterial Hypertension. [2021]

2. India pubmed.ncbi.nlm.nih.gov

Pioglitazone: Indian perspective. [2021]

3. China pubmed.ncbi.nlm.nih.gov

[Protective effects of rosiglitazone intervention on monocrotaline-induced pulmonary arterial hypertension in rats and related inflammatory mechanisms]. [2018]

4. England pubmed.ncbi.nlm.nih.gov

Selexipag for the treatment of pulmonary arterial hypertension. [2018]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Spotlight on pioglitazone in type 2 diabetes mellitus. [2019]

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

Sitaxsentan for the treatment of pulmonary arterial hypertension. [2012]

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

Selexipag for the treatment of children with pulmonary arterial hypertension: First multicenter experience in drug safety and efficacy. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Ambrisentan: a review of its use in pulmonary arterial hypertension. [2023]

9. Germany pubmed.ncbi.nlm.nih.gov

Relaxation of human pulmonary arteries by PPARγ agonists. [2021]

10. Japan pubmed.ncbi.nlm.nih.gov

[Effects of peroxisome proliferator-activated receptor gamma ligands on monocrotaline-induced pulmonary hypertension in rats]. [2013]

11. Netherlands pubmed.ncbi.nlm.nih.gov

N-acylhydrazone derivative ameliorates monocrotaline-induced pulmonary hypertension through the modulation of adenosine AA2R activity. [2016]