Effects of DHEA in Pulmonary Hypertension

Phase 2

Active, not recruiting

• Conditions: Pulmonary Arterial Hypertension
• Interventions: Drug: DHEA tablet; Other: Placebo

• Registration Number: NCT03648385
• Lead Sponsor: Rhode Island Hospital

Brief Summary

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.

Detailed 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.

Study Timeline

• Study First Submitted: 2018-08-10
• Study First Submitted QC: 2018-08-23
• Study First Posted: 2018-08-27
• Study Start: 2019-01-09
• Status Verified: 2024-11
• Last Update Submitted: 2024-11-19
• Last Update Posted: 2024-11-22
• Primary Completion: 2024-12
• Study Completion: 2025-12

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 24

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
DHEA	DHEA tablet	DHEA tablet (50 mg) taken by mouth once a day for 18 weeks
Placebo	Placebo	1 placebo tablet taken by mouth once a day for 18 weeks

Primary Outcome Measures

Name	Time	Method
Change in right ventricular (RV) longitudinal strain cardiac magnetic resonance imaging (MRI)	18 weeks, 40 weeks	Change in global RV longitudinal strain measured by cardiac magnetic resonance imaging (MRI) between DHEA and placebo

Secondary Outcome Measures

Name	Time	Method
Change in RV ejection fraction measured by cardiac MRI	18 weeks, 40 weeks	Change in RV ejection fraction measured by cardiac MRI between DHEA and placebo
Change in NT-proBNP between DHEA and placebo	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in serum level of NT-proBNP between DHEA and placebo
Change in sex hormone levels between DHEA and placebo	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in sex hormone levels between DHEA and placebo
Change in six minute walk distance (6MWD) between DHEA and placebo	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in 6MWD between DHEA and placebo
Change in World Health Organization (WHO) Functional Class	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in WHO Functional Class (I - IV with IV indicating worse symptoms) between DHEA and placebo
Change in Short Form-36 summary scores for physical and mental components	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in Short Form-36 summary scores for physical and mental components (range 0 - 100, higher scores indicating better quality of life) between DHEA and placebo
Change in emPHasis-10	2 weeks, 18 weeks, 24 weeks, 40 weeks	Change in emPHasis-10 score (range 0 - 50, higher scores indicating worse quality of life) between DHEA and placebo
Change in treatment-related side effects and adverse events	2 weeks, 18 weeks, 24 weeks, 40 weeks, 42 weeks	Difference in treatment-related side effects and adverse events (as assessed by CTCAE v4.0) between DHEA and placebo

Trial Locations

Locations (1)

Rhode Island Hospital Pulmonary Hypertension Center; 🇺🇸 Providence, Rhode Island, United States