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Completed

NCT Number: NCT03648385

Effects of DHEA in Pulmonary Hypertension

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.

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Key information

Conditions

Pulmonary Arterial Hypertension Hypertension, Pulmonary Lung Diseases Respiratory Tract Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Rhode Island Hospital Pulmonary Hypertension Center

Providence, Rhode Island, 02903, United States

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

DHEA tablet

Drug

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

Placebo

Other

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

Primary outcomes

  1. Change in Right Ventricular (RV) Longitudinal Strain, % Cardiac Magnetic Resonance Imaging (MRI)

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  2. Change in Right Ventricular (RV) †RV Radial Strain, %,

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    †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.

  3. †RV Circumferential Strain, %

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  4. RV End Diastolic Volume (RVEDV), mL

    Time frame: 18 Weeks, 40 Weeks

    % 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.

  5. Change in RV Ejection Fraction Measured by Cardiac MRI

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  6. RVESV, mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  7. RV Stroke Volume, mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  8. RV Mass, g

    Time frame: 18 weeks, 40 weeks

    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).

Secondary outcomes

  1. Change in Six Minute Walk Distance (6MWD) Between DHEA and Placebo

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    Change in 6MWD from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.

  2. Change in World Health Organization (WHO) Functional Class

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    Change in WHO Functional Class (I - IV with IV indicating worse symptoms) between DHEA and placebo.

  3. Change in Short Form-36 Summary Scores for Physical and Mental Components

    Time frame: 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 (range 0 - 100, higher scores indicating better quality of life).

  4. Change in emPHasis-10

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    Change in emPHasis-10 score (range 0 - 50, higher scores indicating worse quality of life) between DHEA and placebo.

  5. Change in NT-proBNP Between DHEA and Placebo

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    Change in serum level of NT-proBNP between DHEA and placebo.

  6. Change in DHEA-S (ug/dL)

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    Change in DHEA-S from baseline to 18 weeks (treatment period 1) and 18 week to 40 weeks (treatment period 2) in both groups.

  7. Change in Estradiol, pg/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  8. Change in Testosterone, ng/dL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  9. Change in Progesterone, ng/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  10. Change in Follicle Stimulating Hormone (FSH), mIU/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  11. Change in Sex Hormone Binding Globulin (SHBG), Nmol/L

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  12. Change in Luteinizing Hormone, mIU/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  13. Change in Prolactin, μIU/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  14. Change in C-peptide, ng/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  15. Change in Insulin, μU/mL

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  16. Cortisol, μg/dL^2

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 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.

  17. Left Ventricular Ejection Fraction, %

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  18. Left Ventricular End-diastolic Volume (LVEDV) (mL)

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  19. Left Ventricular End-systolic Volume (LVESV) (mL)

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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

  20. Left Ventricular Stroke Volume (mL)

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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.

  21. Left Ventricular End Diastolic Mass, g

    Time frame: Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2)

    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).

  22. Treatment-related Side Effects and Adverse Events

    Time frame: 18 weeks, 40 weeks

    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.

Sponsors and collaborators

Lead sponsor

Rhode Island Hospital

Other

Registry information

Acronym: EDIPHY

Important dates

Study start
2019
Primary completion
2024
Study completion
2024
First posted
Aug 27, 2018
Registry last updated
Nov 5, 2025

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

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This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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