Effects of DHEA in Pulmonary Hypertension (EDIPHY)

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 AND 40 weeks compared to placebo and to assess side effects and safety in pulmonary arterial hypertension.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Drug: DHEA tablet; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • Rhode Island Hospital Pulmonary Hypertension Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: DHEA to placebo; DHEA tablet (50 mg) taken by mouth once a day for 18 weeks, followed by 4 week washout period and then 1 placebo tablet taken by mouth once a day for 18 weeks	Drug: DHEA tablet; DHEA tablet (50 mg) taken by mouth once a day for 18 weeks. All participants in this crossover trial will receive DHEA during Treatment Period 1 or Treatment Period 2. There is a 4 week washout between Treatment Period 1 and Treatment Period 2; Other Names: Dehydroepiandrosterone; Other: Placebo; 1 placebo tablet taken by mouth once a day for 18 weeks. All participants in this crossover trial will receive placebo during this crossover study during Treatment Period 1 or Treatment Period 2. There is a 4 week washout between Treatment Period 1 and Treatment Period 2
Other: Placebo to DHEA; 1 placebo tablet taken by mouth once a day for 18 weeks, followed by 4 week washout period and then 1 DHEA tablet taken by mouth once a day for 18 weeks	Drug: DHEA tablet; DHEA tablet (50 mg) taken by mouth once a day for 18 weeks. All participants in this crossover trial will receive DHEA during Treatment Period 1 or Treatment Period 2. There is a 4 week washout between Treatment Period 1 and Treatment Period 2; Other Names: Dehydroepiandrosterone; Other: Placebo; 1 placebo tablet taken by mouth once a day for 18 weeks. All participants in this crossover trial will receive placebo during this crossover study during Treatment Period 1 or Treatment Period 2. There is a 4 week washout between Treatment Period 1 and Treatment Period 2

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Right Ventricular (RV) Longitudinal Strain, % Cardiac Magnetic Resonance Imaging (MRI)	Longitudinal strain is determined using standard cine imaging and Tissue Tracking (Strain) software (Tissue Tracking plugin, Circle Cardiovascular Imaging). Study MRIs were performed at a core MRI facility on a single Siemens 1.5T Aera with full Advanced Cardiac Package and XQ Gradients (45 mT/m @ 200 T/m/s) used for research grade imaging. 2D RV longitudinal strain: Measured from RV free wall of 4-chamber view cine CMR image. RV wall is divided into 6 equal segments. Strain can be either positive, which indicates lengthening, or negative, which indicates shortening. Normal circumferential and longitudinal strain are negative numbers, those for radial strain are positive.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Right Ventricular (RV) †RV Radial Strain, %,	†Short axis, RV radial strain, % by Cardiac Magnetic Resonance Imaging (MRI). Study MRIs were performed at a core MRI facility on a single Siemens 1.5T Aera with full Advanced Cardiac Package and XQ Gradients (45 mT/m @ 200 T/m/s) used for research grade imaging. Measurements were made using CVI42, Circle Cardiovascular Imaging. 2D RV longitudinal strain: Measured from RV free wall of 4-chamber view cine CMR image. RV wall is divided into 6 equal segments. Strain can be either positive, which indicates lengthening, or negative, which indicates shortening. Normal circumferential and longitudinal strain are negative numbers, those for radial strain are positive.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
†RV Circumferential Strain, %	Circumferential strain is determined using standard cine imaging and Tissue Tracking (Strain) software (Tissue Tracking plugin, Circle Cardiovascular Imaging). Cardiac Study MRIs were performed at a core MRI facility on a single Siemens 1.5T Aera with full Advanced Cardiac Package and XQ Gradients (45 mT/m @ 200 T/m/s) used for research grade imaging. Measurements were made using CVI42, Circle Cardiovascular Imaging. 2D RV circumferential strain: Measured from RV free wall of 4-chamber view cine CMR image. RV wall is divided into 6 equal segments. Strain can be either positive, which indicates lengthening, or negative, which indicates shortening. Normal circumferential and longitudinal strain are negative numbers, those for radial strain are positive.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
RV End Diastolic Volume (RVEDV), mL	% Change in RV End Diastolic Volume (RVEDV), mL by Cardiac Magnetic Resonance Imaging (MRI), strain from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging was obtained from the base of the heart through the apex. The endocardial and epicardial borders of both ventricles are be traced manually on short axis cine images at end-diastole and end-systole with exclusion of the papillary muscles and trabeculae. EDV and ESV are calculated using Simpson's rule by summation of areas on each slice multiplied by the sum of slice thickness and image gap.	18 Weeks, 40 Weeks
Change in RV Ejection Fraction Measured by Cardiac MRI	Change in RV ejection fraction measured by Cardiac Magnetic Resonance Imaging (MRI), % Change in strain from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging from the base of the heart through the apex. Ventricular EFs are calculated by dividing respective stroke volumes (EDV-ESV) by EDVs.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
RVESV, mL	Change in right ventricular end-systolic volume from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging was obtained from the base of the heart through the apex. The endocardial and epicardial borders of both ventricles are be traced manually on short axis cine images at end-diastole and end-systole with exclusion of the papillary muscles and trabeculae. EDV and ESV are calculated using Simpson's rule by summation of areas on each slice multiplied by the sum of slice thickness and image gap.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
RV Stroke Volume, mL	Change in Right ventricular stroke volume by cardiac MRI from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Stroke volume is calculated through breath-hold through-plane phase contrast imaging with a velocity encoding gradient (VENC) of <120 cm/s (larger if aliasing present) in the main PA ~2-3 cm above the pulmonary valve plane, with imaging plane oriented orthogonal to the main PA. Free-breathing phase contrast imaging in the same plane and VENC with averaging over 4 respiratory cycles.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
RV Mass, g	Right ventricular mass, Change in RV mass from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging from the base of the heart through the apex. RV mass is determined at the end-diastole phase as the difference between end-diastolic epicardial and endocardial volumes X heart specific gravity (1.05 g/cm3).	18 weeks, 40 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Six Minute Walk Distance (6MWD) Between DHEA and Placebo	Change in 6MWD from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in World Health Organization (WHO) Functional Class	Change in WHO Functional Class (I - IV with IV indicating worse symptoms) between DHEA and placebo.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Short Form-36 Summary Scores for Physical and Mental Components	Change in Short Form-36 summary scores for physical and mental components (range 0 - 100, higher scores indicating better quality of life).	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in emPHasis-10	Change in emPHasis-10 score (range 0 - 50, higher scores indicating worse quality of life) between DHEA and placebo.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in NT-proBNP Between DHEA and Placebo	Change in serum level of NT-proBNP between DHEA and placebo.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in DHEA-S (ug/dL)	Change in DHEA-S from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Estradiol, pg/mL	Change in Estradiol, pg/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Testosterone, ng/dL	Change in Testosterone, ng/dL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Progesterone, ng/mL	Change in Progesterone, ng/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Follicle Stimulating Hormone (FSH), mIU/mL	Change in FSH, mIU/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Sex Hormone Binding Globulin (SHBG), Nmol/L	Change in SHBG, nmol/L from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Luteinizing Hormone, mIU/mL	Change in Luteinizing hormone, mIU/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Prolactin, μIU/mL	Change in Prolactin, μIU/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in C-peptide, ng/mL	Change in C-peptide, ng/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Change in Insulin, μU/mL	Change in Insulin, μU/mL from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Cortisol, μg/dL^2	Change in Cortisol, μg/dL^2 (micrograms per deciliter squared) from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Left Ventricular Ejection Fraction, %	Change in left ventricular ejection fraction (%) measured by Cardiac Magnetic Resonance Imaging (MRI). Change in LVEG from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging from the base of the heart through the apex was used.. Ventricular EFs are calculated by dividing respective stroke volumes (EDV-ESV) by EDVs. Normal Values: 56-78% for both males and females.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Left Ventricular End-diastolic Volume (LVEDV) (mL)	Change in left ventricular LVEDV measured by Cardiac Magnetic Resonance Imaging (MRI). Change in LVEDV from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging was obtained from the base of the heart through the apex. The endocardial and epicardial borders of both ventricles are be traced manually on short axis cine images at end-diastole and end-systole with exclusion of the papillary muscles and trabeculae. EDV and ESV are calculated using Simpson's rule by summation of areas on each slice multiplied by the sum of slice thickness and image gap. Normal values (Male):77-195 ml. Normal values (female):58-154 ml.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Left Ventricular End-systolic Volume (LVESV) (mL)	Change in LVESV measured by Cardiac Magnetic Resonance Imaging (MRI). Change in LVEDV from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging was obtained from the base of the heart through the apex. The endocardial and epicardial borders of both ventricles are be traced manually on short axis cine images at end-diastole and end-systole with exclusion of the papillary muscles and trabeculae. EDV and ESV are calculated using Simpson's rule by summation of areas on each slice multiplied by the sum of slice thickness and image gap. Normal Values (Female):13-51 ml. Normal values (Male):19-72 ml	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Left Ventricular Stroke Volume (mL)	Change in Left ventricular stroke volume measured by Cardiac Magnetic Resonance Imaging (MRI). Change in Left ventricular stroke volume from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Stroke volume is calculated through breath-hold through-plane phase contrast imaging with a velocity encoding gradient (VENC) of <120 cm/s (larger if aliasing present) in the main PA ~2-3 cm above the pulmonary valve plane, with imaging plane oriented orthogonal to the main PA. Free-breathing phase contrast imaging in the same plane and VENC with averaging over 4 respiratory cycles.	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Left Ventricular End Diastolic Mass, g	Change in Left ventricular end diastolic mass, g measured by Cardiac Magnetic Resonance Imaging (MRI). Change in Left ventricular end diastolic mass, g from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups: DHEA to Placebo (DHEA taken first, followed by washout and then Placebo) and Placebo to DHEA (placebo taken first, followed by washout and then DHEA). Short-axis steady state free precession (SSFP) imaging from the base of the heart through the apex. LV mass is determined at the end-diastole phase as the difference between end-diastolic epicardial and endocardial volumes X heart specific gravity (1.05 g/cm3).	Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)
Treatment-related Side Effects and Adverse Events	Treatment-related side effects and adverse events (as assessed by CTCAE v4.0). All participants in this trial received both DHEA and Placebo during the trial, therefore, side-effects and adverse events are listed according to the treatment or washout period in which they occurred.	18 weeks, 40 weeks

Collaborators and Investigators

• Sponsor: Rhode Island Hospital
• Investigators: Principal Investigator: Corey E Ventetuolo, MD, MS, Brown University

Publications and helpful links

General Publications

• Sanders R, Walsh T, Baird GL, Atalay MK, Agarwal S, Arcuri D, Klinger JR, Mullin CJ, Simmons J, Singh N, Whittenhall M, Ventetuolo CE. Effects of Dehydroepiandrosterone in Pulmonary Hypertension (EDIPHY): A Randomized, Double-Blind, Placebo-Controlled Crossover Trial. medRxiv [Preprint]. 2025 Aug 2:2025.08.01.25332627. doi: 10.1101/2025.08.01.25332627.

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2019
• Primary Completion (Actual): June 24, 2024
• Study Completion (Actual): December 30, 2024

Study Registration Dates

• First Submitted: August 10, 2018
• First Submitted That Met QC Criteria: August 23, 2018
• First Posted (Actual): August 27, 2018

Study Record Updates

• Last Update Posted (Estimated): November 5, 2025
• Last Update Submitted That Met QC Criteria: October 15, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Polycyclic Compounds; Steroids; Fused-Ring Compounds; Gonadal Steroid Hormones; Gonadal Hormones; Androstenes; Androstanes; Adrenal Cortex Hormones; Androstenols; Testosterone Congeners; 17-Ketosteroids; Ketosteroids; Dehydroepiandrosterone
• Other Study ID Numbers: R01HL141268 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No