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Pulmonary Arterial Hypertension | Spironolactone for Pulmonary Arterial Hypertension

Pulmonary Arterial Hypertension research study

What is the primary objective of this study?

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 withPAH 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.

Who is eligible to participate?

- INCLUSION CRITERIA: 1. WHO Group 1 PH patients on either no medical therapy or stable medical therapy for at least the past 4 weeks (defined as no new PAH-specific therapy, no change in the dose of current PAH-specific therapy and no change in NYHA/WHO functional classification within the past 4 weeks) are eligible. The following parameters on RHC are required to meet the hemodynamic definition of PAH: 1. mean pulmonary artery pressure of > 25 mmHg at rest, 2. pulmonary capillary wedge pressure of less than or equal to 15 mmHg (or a left ventricular end-diastolic pressure of less than or equal to 12 mmHg) and 3. pulmonary vascular resistance of > 3 Wood units (240 dyn.s.cm(-5). 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. 2) Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to and for the duration of study participation. EXCLUSION CRITERIA: 1. Patients with WHO Group 1 PH and evidence of right heart failure as defined by: 1. NYHA/WHO class IV symptoms and 2. Echocardiographic evidence of severe RV dysfunction and 3. Clinical evidence of right heart failure which may include, but is not limited to elevated jugular venous pressure, ascites, and lower extremity edema 2. Patients with WHO Group 1 pulmonary hypertension and a prior diagnosis of cirrhosis with portal hypertension as evidenced by a history of ascites, hepatic encephalopathy and/or varices prior to enrollment 3. Patients with WHO Group 1 pulmonary hypertension and evidence of active infection, (HIV patients with two consecutive viral loads of < 500 on their most recent determinations within the past 12 months will be considered to have inactive infection) 4. Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or eplerenone within the last 30 days 5. Known or suspected allergy to spironolactone 6. Pregnant or breastfeeding women (all women of childbearing potential will be required to have a screening urine or blood pregnancy test) 7. Age <18 years 8. Inability to provide informed written consent for participation in the study 9. Chronic kidney disease (an estimated glomerular filtration rate of < 35 mL/min/1.73m(2) of body surface area) 10. Serum potassium at the time of enrollment of > 5 mEq/L 11. Concurrent use of an ACE inhibitor and angiotensin II receptor blocker OR Patients currently taking the maximum recommended dose of an ACE inhibitor or an angiotensin II receptor blocker [For patients taking one of these medicines (ACE-Inhibitors or ARBs), the investigators agree to do due diligence by consulting a clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to certify whether or not the patient is on a maximum dose of the drug.] 12. Women currently taking drospirenone-containing oral contraceptives Exclusion Criteria for MRI These contraindications include but are not limited to the following devices or conditions: 1. Implanted cardiac pacemaker or defibrillator 2. Cochlear Implants 3. Ocular foreign body (e.g. metal shavings) 4. Embedded shrapnel fragments 5. Central nervous system aneurysm clips 6. Implanted neural stimulator 7. Any implanted device that is incompatible with MRI 8. Unsatisfactory performance status as judged by the referring physician such that the subject could not tolerate an MRI scan. Examples of medical conditions that would not be accepted would include unstable angina and severe dyspnea at rest 9. Subjects requiring monitored sedation for MRI studies 10. Subjects with a condition precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.) 11. Subjects with severe back-pain or motion disorders who will be unable to tolerate supine positioning within the MRI scanner and hold still for the duration of the examination. EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY: 1. History of severe allergic reaction to gadolinium contrast agents despite pre- medication with diphenhydramine and prednisone 2. Chronic kidney disease (an estimated glomerular filtration rate of < 60 mL/min/1.73m(2) of body surface area)

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Pulmonary Arterial Hypertension

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:SpironolactoneInitial dose, 25 mg (pink capsule) orally, daily. If well tolerated at 7-9 wks then increased to 50 mg (brown capsule) daily.

Drug:PlaceboInitial dose, pink sugar capsule, daily. If well tolerated at 7-9 wks then changed to brown sugar capsule, daily.

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

Group A

Group B

Study Status

Recruiting

Start Date: September 25, 2012

Completed Date: December 21, 2021

Phase: Phase 1/Phase 2

Type: Interventional

Design:

Primary Outcome: Change in placebo corrected 6-minute walk distance

Secondary Outcome: Change in placebo corrected VO2 max

Study sponsors, principal investigator, and references

Principal Investigator: Michael A Solomon, M.D.

Lead Sponsor: National Institutes of Health Clinical Center (CC)

Collaborator: National Heart, Lung, and Blood Institute (NHLBI)

More information:https://clinicaltrials.gov/show/NCT01712620

Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ, Long WA, Levy PS. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med. 1994 Sep 15;121(6):409-15.

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