Spironolactone for Pulmonary Arterial Hypertension

Recruiting at 1 trial location

Overseen By Michael A Solomon, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institutes of Health Clinical Center (CC)

Must not be taking: Spironolactone, Eplerenone, ACE inhibitors, ARBs

Disqualifiers: Right heart failure, Cirrhosis, Active infection, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 7 weeks

70 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 you must not have taken spironolactone or eplerenone in the last 30 days. Also, you cannot be on the maximum dose of ACE inhibitors or angiotensin II receptor blockers.

What data supports the effectiveness of the drug spironolactone for pulmonary arterial hypertension?

Spironolactone, a drug commonly used for heart failure, has shown potential benefits in pulmonary arterial hypertension by improving heart and lung function and reducing inflammation. However, studies specifically on its effectiveness for pulmonary arterial hypertension have not shown significant changes in exercise capacity or collagen metabolism, though it is considered safe and well-tolerated. ^{1 2 3 4 5}

Is spironolactone safe for humans?

In a study involving patients with pulmonary arterial hypertension, spironolactone was used alongside another medication, ambrisentan, and no patients treated with both medications experienced progressive illness, hospitalizations, or death, suggesting it may be safe in this context. However, more research is needed to confirm these findings. ^{6 7 8 9 10}

How does the drug Spironolactone differ from other drugs for pulmonary arterial hypertension?

Spironolactone is unique because it is primarily a diuretic (a drug that helps remove excess fluid from the body) and an aldosterone antagonist (a drug that blocks the effects of the hormone aldosterone), which is different from other treatments for pulmonary arterial hypertension that often target specific pathways like prostacyclin analogues or phosphodiesterase inhibitors. This makes Spironolactone potentially beneficial in managing fluid retention and heart function in patients with pulmonary arterial hypertension. ^{11 12 13 14 15}

What is the purpose of this trial?

Background: - High blood pressure in the lungs, known as pulmonary arterial hypertension (PAH), is a rare disorder. In spite of recent advances in treatment, the death rate remains unacceptably high. Lung blood vessel function can be harmed by progressive injuries, such as inflammation, leading to worsening of the disease. A drug called spironolactone has been known to improve blood vessel function and reduce inflammation. Some people with PAH take spironolactone to help treat fluid retention. However, its effect on inflammation and blood vessel function in patients with PAH is not known. Researchers want to see if spironolactone can help these conditions in people with PAH. Objectives: - To test the effectiveness of spironolactone in treating pulmonary arterial hypertension. Eligibility: - Individuals at least 18 years of age with pulmonary arterial hypertension. Design: * This study will last for 24 weeks. Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. * Participants will take either spironolactone or a placebo. They will take their study drug or placebo for 7 weeks. Treatment will be monitored with regular blood tests. * In Week 8, participants who have had no reaction to the treatment will receive a higher dose of the drug or placebo. * In Week 12, participants will have a study visit with heart and lung function tests. They will also have a 6-minute walk test, and provide blood and urine samples. * After additional study visits for blood samples, participants will have a final visit in Week 24. The tests from Week 12 will be repeated at this visit.

Research Team

Michael A Solomon, M.D.

Principal Investigator

National Institutes of Health Clinical Center (CC)

Eligibility Criteria

Adults with pulmonary arterial hypertension (PAH) who are either not on treatment or have been stable on current therapy for at least 4 weeks. Participants must meet specific criteria related to heart and lung pressure measurements, and women of childbearing age must use contraception. Excluded are those with severe right heart failure, infections, high potassium levels, certain medication uses, kidney disease, under 18 years old, recent spironolactone users, allergies to it, or pregnant/breastfeeding women.

Inclusion Criteria

I have WHO Group 1 pulmonary hypertension and have been on stable or no treatment for the last 4 weeks.

If clinically indicated at the time of enrollment, then a RHC will be performed at the NIH Clinical Center upon study entry under a procedural consent

Females who are able to become pregnant must agree to use adequate contraception prior to and for the duration of study participation

Exclusion Criteria

Pregnant or breastfeeding women

You are allergic to spironolactone.

I am taking both an ACE inhibitor and an angiotensin II blocker.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants take either spironolactone or a placebo for 7 weeks, with regular blood tests to monitor treatment

7 weeks

Regular visits for blood tests

Dose Adjustment

Participants who have had no reaction to the treatment receive a higher dose of the drug or placebo

1 week

1 visit (in-person)

Mid-study Assessment

Participants undergo heart and lung function tests, a 6-minute walk test, and provide blood and urine samples

1 week

1 visit (in-person)

Continued Treatment

Participants continue treatment with regular monitoring until the final visit

12 weeks

Regular visits for monitoring

Final Assessment

Final visit with repeated tests from the mid-study assessment

1 week

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Placebo
• Spironolactone

Trial Overview The trial is testing if spironolactone can improve the condition of patients with PAH by reducing inflammation and improving blood vessel function. Over a period of 24 weeks, participants will receive either spironolactone or a placebo while undergoing regular monitoring through physical exams as well as heart and lung function tests.

Participant Groups

Group I: Group A Experimental Treatment 1 Intervention

Spironolactone

Group II: Group B Placebo Group 1 Intervention

Placebo

Spironolactone is already approved in United States, European Union for the following indications:

Approved in United States as Aldactone for:

• High blood pressure
• Heart failure
• Liver scarring
• Kidney disease
• Low blood potassium
• Early puberty in boys
• Acne
• Excessive hair growth in women

Approved in European Union as Aldactone for:

• Fluid retention due to heart failure
• Liver scarring
• Kidney disease
• High blood pressure
• Low blood potassium

Who Is Running the Clinical Trial?

National Institutes of Health Clinical Center (CC)

Lead Sponsor

Trials

391

Recruited

30,880,000+

University of Maryland, Baltimore

Collaborator

Trials

729

Recruited

540,000+

Medstar Health Research Institute

Collaborator

Trials

202

Recruited

187,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

New England Medical Center, Tufts University School of Medicine

Collaborator

Trials

1

Recruited

70+

University of Maryland Medical Center

Collaborator

Trials

4

Recruited

850+

National Heart, Lung, and Blood Institute (NHLBI)

Collaborator

Trials

3,987

Recruited

47,860,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

A randomized, double-blinded, placebo-controlled trial will assess the effects of early spironolactone treatment in 70 patients with pulmonary arterial hypertension, focusing on exercise capacity and vascular inflammation over 24 weeks.

The study aims to determine if spironolactone can improve endothelial function and reduce inflammation, potentially delaying right ventricular failure, while also monitoring safety for side effects like hyperkalemia and renal insufficiency.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial. Elinoff, JM., Rame, JE., Forfia, PR., et al.[2021]

In ovariectomized female Wistar rats, administration of estradiol at doses of 15 mcg and 60 mcg per day for 21 days led to the development of pulmonary arterial hypertension (PAH), suggesting a direct link between estrogen and PAH.

The study indicates that the development of PAH due to estrogen is mediated through estrogen receptors alpha and beta, as shown by the effects of the estrogen receptor antagonist fulvestrant when administered alongside estrogen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chronic administration of estrogen receptors antagonist reduces degree of hypoxia-induced pulmonary hypertension caused by chronic injections of estrogen in ovariectomised female Wistar rats]. Kovaleva, IuO., Artem'eva, MM., Medvedev, OS., et al.[2018]

In a study of 1229 patients with pulmonary arterial hypertension (PAH), spironolactone did not show improved survival or reduced clinical worsening compared to those not receiving the treatment, despite its known benefits in other heart conditions.

The analysis indicated that the effects of spironolactone in PAH patients may differ significantly from its effects in patients with chronic heart failure, suggesting that its use in PAH requires further investigation to understand its true impact.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of spironolactone use in pulmonary arterial hypertension - analysis from pivotal trial databases. Safdar, Z., Cho, E.[2021]

In a 16-week study involving 42 patients with pulmonary arterial hypertension, spironolactone did not significantly change collagen metabolism markers or improve exercise capacity, as measured by the six-minute walk distance.

Spironolactone was found to be safe and well tolerated, with no cases of hyperkalemia or liver function abnormalities reported during the trial.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone in pulmonary arterial hypertension: results of a cross-over study. Safdar, Z., Frost, A., Basant, A., et al.[2020]

Spironolactone (SPL) demonstrates anti-inflammatory effects in heart failure and pulmonary arterial hypertension by suppressing inflammatory signaling through a mechanism that does not involve mineralocorticoid receptors (MR), unlike its counterpart eplerenone (EPL).

The suppression of inflammation by SPL is linked to the degradation of the protein XPB via the proteasome pathway, suggesting that targeting this mechanism could be a promising therapeutic strategy for treating inflammatory cardiovascular diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spironolactone-induced degradation of the TFIIH core complex XPB subunit suppresses NF-κB and AP-1 signalling. Elinoff, JM., Chen, LY., Dougherty, EJ., et al.[2019]

In a study involving patients with pulmonary arterial hypertension (PAH), combining spironolactone with the endothelin type-A receptor antagonist ambrisentan showed promising improvements in exercise capacity and heart function, suggesting a potential new treatment strategy.

Patients receiving both ambrisentan and spironolactone had a significant increase in their 6-minute walk distance and a notable reduction in severe outcomes like hospitalizations or death, indicating that this combination therapy may enhance patient safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). Maron, BA., Waxman, AB., Opotowsky, AR., et al.[2021]

Veletri, a new formulation of epoprostenol for treating pulmonary arterial hypertension (PAH), offers improved stability and convenience for continuous intravenous infusion, allowing for room temperature storage and advance preparation of infusion pump cassettes.

Despite its benefits, Veletri carries risks such as potential life-threatening rebound PAH if discontinued abruptly and common side effects like flushing (58%), headache (49%), and nausea (32%), necessitating careful evaluation of medication-use practices to ensure patient safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A new epoprostenol formulation for the treatment of pulmonary arterial hypertension. Fuentes, A., Coralic, A., Dawson, KL.[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 involving 64 patients with pulmonary arterial hypertension (PAH), ambrisentan significantly improved exercise capacity, as measured by a 36.1 meter increase in the 6-minute walk distance after 12 weeks, with consistent benefits across all tested doses (1, 2.5, 5, and 10 mg).

The treatment also led to improvements in symptoms and hemodynamics, including reduced pulmonary arterial pressure and increased cardiac index, while showing a low incidence of mild adverse events, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ambrisentan therapy for pulmonary arterial hypertension. Galié, N., Badesch, D., Oudiz, R., et al.[2023]

Inhaled iloprost did not significantly affect pulmonary artery pressure or vascular resistance before surgery in patients with chronic thromboembolic pulmonary hypertension (CTEPH), indicating limited efficacy in the preoperative setting.

Post-surgery, iloprost significantly reduced mean pulmonary artery pressure and pulmonary vascular resistance while increasing cardiac index, suggesting it is beneficial for improving hemodynamics shortly after pulmonary thromboendarterectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy. Kramm, T., Eberle, B., Krummenauer, F., et al.[2019]

In a study involving adult male rats with induced pulmonary hypertension, both simvastatin and dehydroepiandrosterone sulfate (DHEA S) effectively reduced mean pulmonary artery pressure (mPAP), but their combination did not provide additional benefits over either drug alone.

The lack of enhanced effectiveness when using both drugs together may be due to their similar mechanism of action, specifically their inhibitory effect on an enzyme called 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, which suggests that combining these treatments may not be necessary.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simvastatin and dehydroepiandrosterone sulfate effects against hypoxic pulmonary hypertension are not additive. Krása, K., Vajnerova, O., D Uris Ova, J., et al.[2023]

Sildenafil citrate, a phosphodiesterase-5 inhibitor, is an effective oral treatment for pulmonary arterial hypertension, showing both short- and long-term clinical efficacy when used alone or with other therapies.

While sildenafil has demonstrated significant benefits in managing pulmonary arterial hypertension, its safety profile requires further investigation to ensure patient well-being.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sildenafil for pulmonary arterial hypertension: when blue turns into white. Antoniu, SA.[2019]

Epoprostenol, the first approved treatment for pulmonary arterial hypertension (PAH), has significantly improved patient survival rates, which are now double compared to the pre-treatment era.

The therapy has been shown to enhance exercise capacity, improve key heart function measurements, alleviate PAH symptoms, and reduce mortality, while its role continues to evolve with new formulations and combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. Sitbon, O., Vonk Noordegraaf, A.[2022]

Pharmacotherapeutic options for managing pulmonary arterial hypertension (PAH) have significantly expanded over the last decade, with treatments including prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase inhibitors, among others.

Combination therapy is becoming a standard approach in PAH management, supported by increasing evidence of its effectiveness, while pharmacists play a crucial role in ensuring access to these therapies and providing patient counseling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Key articles and guidelines in the management of pulmonary arterial hypertension: 2011 update. Johnson, SG., Kayser, SR., Attridge, RL., et al.[2012]

Initial combination therapy using PAH-specific drugs, such as ambrisentan with riociguat, shows promising pharmacological synergy in treating pulmonary arterial hypertension (PAH) in low or intermediate risk patients, suggesting a potential for improved outcomes.

High-risk PAH patients may benefit from combinations like inhaled iloprost with sildenafil, but further clinical trials are necessary to confirm these findings and establish the efficacy of other combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Advantages and limitations of initial combination therapy in pulmonary arterial hypertension patients in Russia]. Shmalts, AA., Gorbachevsky, SV.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

A pilot study of the effect of spironolactone therapy on exercise capacity and endothelial dysfunction in pulmonary arterial hypertension: study protocol for a randomized controlled trial. [2021]

2. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Chronic administration of estrogen receptors antagonist reduces degree of hypoxia-induced pulmonary hypertension caused by chronic injections of estrogen in ovariectomised female Wistar rats]. [2018]

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

Effect of spironolactone use in pulmonary arterial hypertension - analysis from pivotal trial databases. [2021]

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

Spironolactone in pulmonary arterial hypertension: results of a cross-over study. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Spironolactone-induced degradation of the TFIIH core complex XPB subunit suppresses NF-κB and AP-1 signalling. [2019]

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

Effectiveness of spironolactone plus ambrisentan for treatment of pulmonary arterial hypertension (from the [ARIES] study 1 and 2 trials). [2021]

7. England pubmed.ncbi.nlm.nih.gov

A new epoprostenol formulation for the treatment of pulmonary arterial hypertension. [2019]

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

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

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

Ambrisentan therapy for pulmonary arterial hypertension. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Inhaled iloprost in patients with chronic thromboembolic pulmonary hypertension: effects before and after pulmonary thromboendarterectomy. [2019]

11. Czech Republic pubmed.ncbi.nlm.nih.gov

Simvastatin and dehydroepiandrosterone sulfate effects against hypoxic pulmonary hypertension are not additive. [2023]

12. England pubmed.ncbi.nlm.nih.gov

Sildenafil for pulmonary arterial hypertension: when blue turns into white. [2019]

13. England pubmed.ncbi.nlm.nih.gov

Epoprostenol and pulmonary arterial hypertension: 20 years of clinical experience. [2022]

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

Key articles and guidelines in the management of pulmonary arterial hypertension: 2011 update. [2012]

15. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Advantages and limitations of initial combination therapy in pulmonary arterial hypertension patients in Russia]. [2021]