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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the safety and effectiveness of Pioglitazone for individuals with pulmonary hypertension due to chronic lung disease. Researchers aim to determine if Pioglitazone improves cellular oxygen utilization. Participants will take either Pioglitazone or a placebo for 28 days, then switch after a break. Individuals with pulmonary hypertension from lung issues, who have not recently had diabetes, may qualify for this study. As a Phase 2 trial, this research measures Pioglitazone's effectiveness in an initial, smaller group, providing an opportunity to contribute to significant findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that pioglitazone has been studied for various health conditions, and its safety is well-documented. The IRIS trial found no increase in heart failure among people taking pioglitazone. However, other studies reported a higher risk of hospitalization for heart failure with this medication. While some research shows no added risk, other studies have raised concerns.

Reports of liver problems in people taking pioglitazone vary. It's important to note that the FDA has approved pioglitazone for treating Type 2 diabetes, indicating it is generally considered safe for that use. Since this trial tests it for pulmonary hypertension, the study will determine its safety and effectiveness for this new purpose. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for pulmonary hypertension?

Researchers are excited about pioglitazone for pulmonary hypertension because it offers a fresh approach compared to standard treatments like endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclin analogs. Most existing therapies focus on dilating blood vessels or reducing blood pressure in the lungs. Pioglitazone, however, is a thiazolidinedione, primarily used for diabetes, which might offer additional anti-inflammatory and metabolic benefits that could address underlying causes of pulmonary hypertension. This unique mechanism of targeting metabolic pathways sets it apart and holds promise for improving patient outcomes in new ways.

What evidence suggests that pioglitazone might be an effective treatment for pulmonary hypertension?

Research has shown that pioglitazone, a drug originally used for diabetes, might help with pulmonary hypertension, which is high blood pressure in the lungs. Animal studies found that pioglitazone can improve symptoms of this condition and help prevent heart issues. This effect may occur because pioglitazone activates a part of the body that controls genes related to lung and heart health. Although studies in humans have not always shown strong results, the drug's ability to affect important body processes offers hope for its potential benefits. In this trial, participants will receive either pioglitazone or a placebo in different sequences to evaluate its effectiveness. Experts continue to discuss its potential, but its mechanism suggests it might be useful for treating this condition. ^{1 2 3 6 7}

Who Is on the Research Team?

Aaron Trammell

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

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Activation of the Metabolic Master Regulator PPARγ Intriguingly, 5-week oral treatment with pioglitazone reverses PAH and prevents RV failure in the SuHx rat model by directing distinct mRNA and miRNA networks, ...

2. withpower.com withpower.com/trial/phase-2-pulmonary-hypertension-ph-4-2024-b2e27

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 ...

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Association of Pioglitazone With Major Adverse ... Results argue against a single effect of TZDs on cardiovascular outcomes, with pioglitazone perhaps having a better risk profile when compared ...

4. mdpi.com mdpi.com/1422-0067/24/6/5850

New Drugs and Therapies in Pulmonary Arterial ... The primary outcomes were safety and change in pulmonary vascular resistance. The study, however, failed to show any consistent treatment effect, and adverse ...

5. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2008/021073s034lbl.pdf

CONGESTIVE HEART FAILURE - accessdata.fda.gov ACTOS (pioglitazone hydrochloride) is an oral antidiabetic agent that acts primarily by decreasing insulin resistance. ACTOS is used in the management of ...

6. nature.com nature.com/articles/s41598-019-41854-2

Efficacy and Safety of Pioglitazone Monotherapy in Type 2 ... Analyses of safety outcomes​​ From safety outcomes analyses, improvements in BP was non-significantly greater (1.05 mmHg) in pioglitazone-treated ...

7. content.takeda.com content.takeda.com/?contenttype=PI&product=ACOS&language=ENG&country=GBL&documentnumber=1

highlights of prescribing information - Takeda 5.3 Hepatic Effects There have been postmarketing reports of fatal and non-fatal hepatic failure in patients taking ACTOS, although the reports contain ...