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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
26
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
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
Rhode Island Hospital Pulmonary Hypertension Center
Providence, Rhode Island, United States
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.
Time frame: 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.
Time frame: 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.
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Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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).
Time frame: 18 weeks, 40 weeks
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.
Time frame: 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.
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
Change in Short Form-36 summary scores for physical and mental components (range 0 - 100, higher scores indicating better quality of life).
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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.
Time frame: 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
Time frame: 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.
Time frame: 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).
Time frame: 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.
Time frame: 18 weeks, 40 weeks