Pulmonary Arterial Hypertension
Conditions
Keywords
Pulmonary Arterial Hypertension (PAH), Ambrisentan, Spironolactone, Selective Endothelin A (ETA) inhibition, Aldosterone antagonism, Cardiac output (CO), Right ventricular (RV) function, Heart failure, Quality of life, Pro-inflammatory cytokine, Interleukin-6 (IL-6), Troponin-I, N-terminal pro-brain natriuretic peptide (NT-BNP), Collagen metabolism, N-terminal procollagen type I, Collagen III, Echocardiography, WHO Functional Class, Cardiopulmonary Exercise Test with Innocor, Peak oxygen consumption (pVO2), Liver function markers (AST/ALT), Renal function markers (creatinine and potassium)
Brief summary
The purpose of this study is to find out if spironolactone added to ambrisentan for Pulmonary Arterial Hypertension (PAH) will increase exercise capacity. We also want to find out if spironolactone and ambrisentan effect the cardiac output (amount of blood the heart pumps every minute), right ventricle function and quality of life.
Detailed description
A prospective, double blind, placebo-controlled clinical study involving 30 patients with World Health Organization (WHO) Group 1 pulmonary arterial hypertension being treated with ambrisentan randomized to receive placebo or spironolactone (50 mg/d) for 90 days using a cross-over trial design. Eligible participants will be randomized to receive placebo or spironolactone (50 mg/d) for 90 days (Phase I). At the completion of Phase I, participants will undergo repeat end-point assessment followed by a 21-day drug washout period. Then, the 90 day crossover phase of the trial will occur (Phase II), in which participants randomized to placebo in Phase I will be treated with spironolactone (50 mg/d) in Phase II and vice versa. At the conclusion of Phase II, end-point measures are reassessed. Spironolactone is a diuretic used in treatment of PAH patients. Spironolactone is usually added to medical treatment when doses of Lasix/Torsemide are increased and patients are at risk for hypokalemia. Study procedures being done for this research study are the standard procedures performed on all PAH patients when they are in clinic for follow-up except for the Cardiopulmonary Exercise Test (CPET) with Innocor.
Interventions
DRUGAmbrisentan plus Spironolactone
Cardiopulmonary fitness
DRUGAmbrisentan plus Placebo
Placebo is a sugar pill manufactured to resemble spironolactone 50 mg Cardiopulmonary fitness
Sponsors
Gilead Sciences
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Caregiver)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntarily gives informed consent to participate in the study. 2. Right heart catheterization demonstrating conventional mean pulmonary artery pressure (mPAP) \>25, pulmonary vascular resistance (PVR) \>3.0 Wood Units, pulmonary capillary wedge pressure (PCWP) \<16 mmHg within two years of enrollment 3. Subject is 18 years of age or older at Screening. 4. Diagnosis of symptomatic idiopathic or heritable PAH, PAH associated with Connective Tissue Disease (CTD), PAH associated with repaired/unrepaired congenital systemic-to-pulmonary shunt, Portopulmonary hypertension or PAH associated with HIV infection. 5. New York Heart Association Functional Class II or III 6. Stable therapy with ambrisentan 5 or 10 mg every day for \> 90 days. 7. Baseline 6-Minute Walk Distance 50-450m
Exclusion criteria
1. Substantial Primary Lung disease * forced expiratory volume at one second (FEV-1)/forced vital capacity (FVC) \<0.6 and FEV-1 \<70% predicted * diffusing capacity of lung for carbon monoxide (DLCO) \<30% predicted * Pulmonary fibrosis 2. Left ventricular ejection fraction \< 50% 3. Pulmonary capillary wedge pressure \> 16 mm Hg 4. Aortic valve disease 5. Ischemic heart disease 6. Systemic hypotension (SBP \<90 mm Hg) 7. Co-existing treatment with other endothelin receptor antagonists or prostacyclin analogues 8. New York Heart Association Functional Class IV 9. Chronic thromboembolic pulmonary hypertension 10. Known or suspected pulmonary veno-occlusive disease 11. Serum creatinine \>2.0 mg/dL in women, Serum creatinine \>2.5 mg/dL in men 12. Baseline serum potassium \>5.0 milliequivalent (mEq)/L 13. Participation in ongoing drug/intervention-based clinical trial 14. Pregnancy 15. Unable to provide consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Combination Ambrisentan + Spironolactone on Peak Volume of Oxygen Consumption (pVO2) and Cardiac Output | Up to average of 20 min | Study the effect of combination ambrisentan (5-10 mg/d) + spironolactone (50 mg/d) on pVO2 and cardiac output. The pVO2 refers to a measure of general physical fitness measured during exercise. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AMB + Spiro, Cardiopulmonary Fitness Ambrisentan 5 or 10 mg every day (QD) Spironolactone 50 mg QD
Ambrisentan plus Spironolactone: Cardiopulmonary fitness
Cross over design | 2 |
| Total | 2 |
Baseline characteristics
| Characteristic | AMB + Spiro, Cardiopulmonary Fitness | — |
|---|---|---|
| Age, Categorical <=18 years | 0 Participants | — |
| Age, Categorical >=65 years | 0 Participants | — |
| Age, Categorical Between 18 and 65 years | 2 Participants | — |
| Age, Continuous | 61 years | — |
| Race and Ethnicity Not Collected | — | — Participants |
| Region of Enrollment United States | 2 Participants | — |
| Sex: Female, Male Female | 2 Participants | — |
| Sex: Female, Male Male | 0 Participants | — |
| Study-Specific Measure | 2 Participants | — |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Effect of Combination Ambrisentan + Spironolactone on Peak Volume of Oxygen Consumption (pVO2) and Cardiac Output
Study the effect of combination ambrisentan (5-10 mg/d) + spironolactone (50 mg/d) on pVO2 and cardiac output. The pVO2 refers to a measure of general physical fitness measured during exercise.
Time frame: Up to average of 20 min
Population: Data were not reported due to patient privacy considerations owing to low enrollment.