Effects of DHEA in Pulmonary Hypertension (EDIPHY)

Lifespan

Status and phase

Active, not recruiting

Phase 2

Conditions

Pulmonary Arterial Hypertension

Treatments

Other: Placebo

Drug: DHEA tablet

Study type

Interventional

Funder types

Other

Identifiers

NCT03648385

R01HL141268

Details and patient eligibility

About

The goal of this crossover trial is to determine whether the study drug dehydroepiandrosterone (DHEA) improves right ventricular longitudinal strain measured by cardiac magnetic resonance imaging at 18 weeks compared to placebo and to assess side effects and safety in pulmonary arterial hypertension.

Full description

Pulmonary hypertension (PH) is a heterogenous clinical disease characterized foremost by an abnormal increase in pulmonary artery pressure. Pulmonary vasculopathy, characterized by pathologic remodeling and vasoconstriction of the pulmonary arterioles, results in progressive dyspnea, exercise intolerance, right ventricular (RV) failure, and death. Female sex is the strongest clinical risk factor for PAH, with a 4:1 female-to-male ratio reported from the largest registry. Despite the increased risk of PAH in women, women with PAH have better survival than men. RV function is an important cause of morbidity and mortality in PAH as well as highly prevalent heart and lung diseases, but determinants of the RV response are entirely unknown. We and others have shown that female sex is associated with better RV systolic function in both health and disease, including PAH and left heart failure. Targeted PAH therapy leads to greater improvements in RVEF (demonstrated after just several months of treatment) in women as compared to men and partially explains better outcomes in women. Demonstration that DHEA has direct RV and sex-based effects will support the hypothesis that sex hormones play an important role in disease pathogenesis and provide insight into sex hormone manipulation as a treatment strategy in PAH.

The goal of this crossover trial is to correlate sex and sex hormones (particularly DHEA) to pulmonary vascular and RV phenotype differences in men and women with PAH. The study seeks to leverage a safe and available hormone treatment to gain further insight into 1) RV effects (a novel and critical end point in PH and PAH), 2) effects on two key PAH pathways in vivo and in vitro as a means for understanding sex-based differences in PAH, and 3) efficiency planning for a future Phase II parallel trial of DHEA as a novel treatment strategy in PAH.

Enrollment

24 estimated patients

Sex

All

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Diagnosis of PAH that is 1) idiopathic, 2) heritable or 3) associated with connective tissue disease, congenital systemic-to-pulmonary shunt, porto-pulmonary hypertension, drug or toxin use.

Documentation of the following at any time prior to study entry:

mPAP ≥ 25 mmHg at rest, pulmonary capillary wedge pressure or left ventricular end-diastolic pressure ≤ 15 mmHg, and PVR > 3 Wood units
Pulmonary function testing documenting forced expiratory volume in one second/forced vital capacity ratio ≥ 70% predicted and total lung capacity ≥ 70% predicted
If TLC is mildly reduced (60%<TLC%<70%), computerized tomography (HRCT or non-HRCT) documenting no significant interstitial lung disease may be used to fulfill this requirement.
Chest tomography documenting no more than moderate parenchymal lung disease with clinician designated WHO I PAH and meeting both TLC and FEV1/FVC criteria.
Normal or low probability V/Q scan
If no V/Q scan is available, a CT angiogram documenting the absence of thromboembolic disease may be used, provided the subject meets diagnostic PAH criteria

Exclusion criteria

Age < 18 years old
PAH associated with human immunodeficiency virus infection
New background PAH therapy within 12 weeks
Significant dose change in background PAH therapy within 12 weeks.
Untreated severe obstructive sleep apnea diagnosed by polysomnography
Evidence of left-sided valvular disease or systolic dysfunction on echocardiogram (≥ moderate mitral or aortic disease or LV ejection fraction ≤ 50%)
Glomerular filtration rate <40 mls/min/1.73m2
Child-Pugh Class C cirrhosis
Untreated hypo- or hyper-thyroidism
Pregnant or breastfeeding
Active or planned use of hormone supplements, oral contraceptive pills, hormonal therapies
History of breast, ovarian, uterine, testicular or prostate cancer
Current use of another investigational PAH therapy
Contraindication to MRI (e.g., metal device or fragment)
History of significant non-adherence or circumstance which would threaten ability to comply with cross-over design and study visit schedule