Effects of DHEA in Pulmonary Hypertension
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 26
- 试验地点
- 1
- 主要终点
- Change in Right Ventricular (RV) Longitudinal Strain, % Cardiac Magnetic Resonance Imaging (MRI)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Crossover
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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
干预措施: DHEA tablet (Drug)
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
干预措施: Placebo (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
干预措施: DHEA tablet (Drug)
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
干预措施: Placebo (Other)
结局指标
主要结局
Change in Right Ventricular (RV) Longitudinal Strain, % Cardiac Magnetic Resonance Imaging (MRI)
时间窗: 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.
Change in Right Ventricular (RV) †RV Radial Strain, %,
时间窗: 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.
†RV Circumferential Strain, %
时间窗: 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.
RV End Diastolic Volume (RVEDV), mL
时间窗: 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.
Change in RV Ejection Fraction Measured by Cardiac MRI
时间窗: 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.
RVESV, mL
时间窗: 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.
RV Stroke Volume, mL
时间窗: 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.
RV Mass, g
时间窗: 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).
次要结局
- Change in NT-proBNP 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(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in DHEA-S (ug/dL)(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Testosterone, ng/dL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in World Health Organization (WHO) Functional Class(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Six Minute Walk Distance (6MWD) Between DHEA and Placebo(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in emPHasis-10(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Progesterone, ng/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Follicle Stimulating Hormone (FSH), mIU/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Sex Hormone Binding Globulin (SHBG), Nmol/L(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Luteinizing Hormone, mIU/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Prolactin, μIU/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in C-peptide, ng/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Insulin, μU/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Cortisol, μg/dL^2(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Left Ventricular Ejection Fraction, %(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Change in Estradiol, pg/mL(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Left Ventricular Stroke Volume (mL)(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Left Ventricular End Diastolic Mass, g(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Treatment-related Side Effects and Adverse Events(18 weeks, 40 weeks)
- Left Ventricular End-diastolic Volume (LVEDV) (mL)(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))
- Left Ventricular End-systolic Volume (LVESV) (mL)(Baseline to 18 weeks (treatment period 1), 18 weeks to 40 weeks (treatment period 2))