A Pilot Study of the Effect of Spironolactone Therapy on Exercise Capacity and Endothelial Dysfunction in Pulmonary Arterial Hypertension

  • STATUS
    Recruiting
  • End date
    Dec 31, 2024
  • participants needed
    70
  • sponsor
    National Institutes of Health Clinical Center (CC)
Updated on 29 October 2022
hypertension
medical therapy
pulmonary function test
spironolactone
walk tests

Summary

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.

Description

INTRODUCTION

Pulmonary arterial hypertension (PAH) is a rare disorder associated with poor survival. Endothelial dysfunction resulting from 1) genetic susceptibility, and 2) a triggering stimulus that initiates pulmonary vascular injury, the two-hit hypothesis, appears to play a central role both in the pathogenesis and progression of PAH. Inflammation appears to drive this dysfunctional endothelial phenotype, propagating cycles of injury and repair in genetically susceptible patients with idiopathic PAH (IPAH) and patients with disease-associated PAH. Therapy targeting pulmonary vascular inflammation to interrupt cycles of injury and repair and thereby delay or prevent RV failure and death has not been tested. Spironolactone, a mineralocorticoid receptor (MR) and androgen receptor (AR) antagonist, has been shown to improve endothelial function and reduce inflammation. Current management of patients with severe PAH and NYHA/WHO class IV symptoms includes use of MR antagonists for their diuretic and natriuretic effects once clinical right heart failure has developed. We hypothesize that initiating therapy with spironolactone at an earlier stage of disease in subjects with PAH could provide additional benefits through anti-inflammatory effects and improvements in pulmonary artery endothelial function.

OBJECTIVES

Patients with IPAH and disease-associated PAH will be recruited to the NIH and enrolled in a randomized, double blinded, placebo-controlled study of early treatment with spironolactone to investigate its effects on exercise capacity, clinical worsening, and vascular inflammation in vivo.

METHODS

The total number of PAH subjects enrolled will be up to 70. Subjects will undergo 1) standard clinical examinations including 6-minute walk distance and echocardiography; 2) cardiopulmonary exercise testing; 3) plasma profiling of inflammatory and neurohormonal markers; 4) gene expression profiling of peripheral blood mononuclear cells (PBMCs); and 5) high-resolution MRI-based determination of pulmonary vascular and RV structure and function. Safety and tolerability of spironolactone in PAH will be assessed with periodic monitoring for hyperkalemia and renal insufficiency as well as the incidence of drug discontinuation for untoward effects.

Details
Condition Pulmonary Arterial Hypertension
Treatment Placebo, Spironolactone
Clinical Study IdentifierNCT01712620
SponsorNational Institutes of Health Clinical Center (CC)
Last Modified on29 October 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

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
mean pulmonary artery pressure of > 25 mmHg at rest
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
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
) 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

Patients with WHO Group 1 PH and evidence of right heart failure as defined by
NYHA/WHO class IV symptoms and
Clinical evidence of right heart failure which may include, but is not limited to
Echocardiographic evidence of severe RV dysfunction and
elevated jugular venous pressure, ascites, and lower extremity edema
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
Known or suspected allergy to spironolactone
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
Age <18 years
determinations within the past 12 months will be considered to have inactive
infection)
Inability to provide informed written consent for participation in the study
Patients with WHO Group 1 pulmonary hypertension who have taken spironolactone or
Serum potassium at the time of enrollment of > 5 mEq/L
eplerenone within the last 30 days
Concurrent use of an ACE inhibitor and angiotensin II receptor blocker
Pregnant or breastfeeding women (all women of childbearing potential will be required
OR
to have a screening urine or blood pregnancy test)
Chronic kidney disease (an estimated glomerular filtration rate of < 35
mL/min/1.73m(2) of body surface area)
Exclusion Criteria for MRI
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
Implanted cardiac pacemaker or defibrillator
clinical center pharmacist and/or a standard pharmacy reference (i.e. Micromedex) to
Cochlear Implants
certify whether or not the patient is on a maximum dose of the drug.]
Ocular foreign body (e.g. metal shavings)
Women currently taking drospirenone-containing oral contraceptives
Embedded shrapnel fragments
Central nervous system aneurysm clips
These contraindications include but are not limited to the following devices or conditions
Implanted neural stimulator
Any implanted device that is incompatible with MRI
Subjects requiring monitored sedation for MRI studies
EXCLUSION CRITERIA FOR GADOLINIUM BASED MRI STUDIES ONLY
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
Subjects with a condition precluding entry into the scanner (e.g. morbid obesity
claustrophobia, etc.)
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
History of severe allergic reaction to gadolinium contrast agents despite pre-
medication with diphenhydramine and prednisone
Chronic kidney disease (an estimated glomerular filtration rate of < 60
mL/min/1.73m(2) of body surface area)
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