NCT04945460已完成2 期
A Phase 2, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effects of Sotatercept Versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) Due to Heart Failure With Preserved Ejection Fraction (HFpEF)
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA238 个研究点 分布在 1 个国家目标入组 164 人开始时间: 2021年12月29日最近更新:
适应症
干预措施
相关药物
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 发起方
- 入组人数
- 164
- 试验地点
- 238
- 主要终点
- Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24
研究概览
简要总结
This is a Phase 2, double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of sotatercept versus placebo in adults with Cpc-PH due to HFpEF.
The objective of this study is to evaluate the efficacy, safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to HFpEF. Efficacy is measured by change from baseline in pulmonary vascular resistance (PVR, primary endpoint) and 6-minute walk distance (6MWD, key secondary endpoint).
详细描述
Participants enrolled in the study will have a diagnosis of Cpc-PH due to HFpEF with New York Heart Association (NYHA) functional class (FC) II or III. Participants will be randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups (placebo, 0.3mg/kg sotatercept and 0.7mg/kg sotatercept) during the placebo-controlled Treatment Period. In the extension phase, sotatercept-treated participants will continue on their current dose. Placebo participants will be re-randomized in a 1:1 ratio to one of the two sotatercept treatment groups utilized in the placebo-controlled Treatment Period. Each participant will be enrolled in the study for up to 114 weeks, including a 28-day Screening Period, a 24-week, double-blind, placebo-controlled Treatment Period, an 18-month Extension Period, and an 8-week Follow-up Period.
As of protocol amendment 6, the 18-month Extension Period is being removed. Participants who have completed at least the 24-week placebo controlled treatment period and the end of study visit, and who have not discontinued study treatment early, may be eligible to participate in an extension study.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 85 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants must meet the following criteria to be enrolled in this proof-of-concept study:
- •Age 18 to 85 years
- •Clinical diagnosis of HFpEF:
- •Left ventricular ejection fraction ≥50%, with no history of LVEF below 45% in more than two consecutive measurements under stable conditions
- •Demonstrated Cpc-PH by all of the following:
- •Baseline RHC performed within 28 days of randomization documenting a minimum PVR of ≥320 dyn•sec/cm5 (4 wood units)
- •Mean pulmonary arterial pressure (mPAP) of >20 mmHg
- •Pulmonary capillary wedge pressure (PCWP) >15 mmHg but < 30 mmHg
- •New York Heart Association FC of II or III
- •Six-minute Walk Distance ≥100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
- •Chronic medication for HF or for any underlying condition, administered at a stable (per investigator) dose for ≥30 days prior to Visit
- •Diuretics and/or anticoagulants are excepted from this rule but should not be newly started or stopped within 30 days of Visit 1, and a prescribed dose change should not occur within 7 days of Visit
- •Anticoagulation may be suspended for RHC if necessary
- •Women of childbearing potential must:
- •Have 2 negative urine or serum pregnancy tests as verified by the investigator during the Screening Period; must agree to ongoing pregnancy testing during the course of the study and until 8 weeks after the last dose of the study drug
- •If sexually active with a male partner: use highly effective contraception without interruption for at least 28 days prior to starting the investigational product AND agree to use the same highly effective contraception in combination with a barrier method during the study (including dose interruptions), and for 16 weeks (112 days) after discontinuation of study treatment
- •Refrain from breastfeeding a child or donating blood, eggs, or ovum for the duration of the study and for at least 16 weeks (112 days) after the last dose of study drug
- •Male participants must:
- •Agree to use a condom, defined as a male latex condom or non latex condom NOT made out of natural (animal) membrane (e.g., polyurethane), during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions, and for at least 16 weeks (112 days) following investigational product discontinuation, even if he has undergone a successful vasectomy
- •Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study drug
- •Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
- •Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
- •Ability to understand and provide documented consent for participation
排除标准
- •Participants will be excluded from the study if any of the following criteria are met:
- •A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
- •Clinically significant and active lung disease:
- •Chronic obstructive pulmonary disease with post-bronchodilator forced expiratory volume in the first second (FEV1) <60% predicted
- •Restrictive lung disease with total lung capacity <70% predicted
- •More than mild interstitial lung disease (ILD), with FVC<70% or FEV1<60% predicted (still appropriate if absence of more than mild ILD, fibrosis, or COPD on computed tomography [CT] imaging)
- •Cardiovascular co-morbidities, which include any of the following:
- •History of more than mild mitral or aortic stenosis
- •Ongoing more than mild mitral or aortic regurgitation
- •More than one valve replacement or repair (mechanical or biomechanical) or anticipation of any valve replacement or repair
- •Severe tricuspid regurgitation due to primary valvular disease
- •Occurrence of myocardial infarction, acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention within 180 days of Visit 1
- •History of serious life-threatening or hemodynamically significant arrhythmia
- •History of or anticipated heart transplant or ventricular assist device implantation
- •History of implantable cardioverter defibrillator placement or anticipated implantation of pacemaker, pacemaker implantation within 30 days of Screening
- •Anticipated implantation of pacemaker, pacemaker implantation within 30 days of Screening or history of implantable cardioverter defibrillator placement
- •Occurrence of myocardial infarction within 180 days of Visit 1
- •History of known pericardial constriction, hypertrophic cardiomyopathy, sarcoidosis, or amyloid cardiomyopathy
- •Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure >160 mmHg or sitting diastolic blood pressure >110 mmHg during Screening after a period of rest
- •Systemic hypotension as evidenced by sitting systolic blood pressure <90 mmHg or sitting diastolic blood pressure <50 mmHg during Screening
- •Resting heart rate of <45 bpm or >115 bpm
- •Stroke within 90 days of Visit 1
- •Acutely decompensated HF that required hospitalization within 30 days of Visit 1
- •Electrocardiogram during Screening Period with Fridericia's corrected QT interval (QTcF) >470 msec for males or >480 msec for females, or >500 msec if a ventricular conduction defect (right bundle branch block; left bundle branch block; or interventricular conduction delay) is present
- •Personal or family history of Brugada syndrome, sudden cardiac arrest or unexplained sudden cardiac death or arrest
- •Personal or family history of long QT syndrome unless the participant's ECG shows a normal QTc
- •Arrhythmogenic right ventricular dysplasia (ARVD) unless the participant has a recent cardiac MRI that shows no evidence of this diagnosis
- •Hospitalization for any worsening of medical conditions or any significant surgery per investigator within 30 days of Visit 1
- •Received any approved PAH-specific therapies (i.e., endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators) within 30 days of Visit 1.The use of an oral phosphodiesterase type 5 inhibitor, if only indicated for erectile dysfunction, is permitted, if not administered within 48 hours of a study visit or procedure
- •Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin, or levosimendan) within 30 days of Visit 1
- •Received erythropoietin within 6 months of Visit 1
- •Known history of chronic liver disease, including untreated hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), with severe hepatic impairment and/or cirrhosis (e.g., hepatic encephalopathy)
- •Prior exposure to sotatercept or luspatercept
- •Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for investigational biologics prior to the date of documented consent
- •Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days of Visit 1 or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
- •Any of the following clinical laboratory values prior to Visit 1 as specified:
- •Hemoglobin (Hgb) above the gender-specific upper limit of normal (ULN) per local laboratory test within 28 days of Visit 1or <10 g/dL per local laboratory within 28 days of Visit 1
- •Serum alanine aminotransferase or aspartate aminotransferase levels >3× ULN or total bilirubin >3× ULN within 28 days of Visit 1
- •Estimated glomerular filtration rate <30 ml/min/1.73 m2 (4-variable Modification of Diet in Renal Disease equation) within 28 days of Visit 1 or required renal replacement therapy within 90 days of Visit 1
- •Glycated hemoglobin (HbA1c) >10% within 28 days of Visit 1
- •Platelet count < 75,000/mm3 within 28 days of Visit 1
- •History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product
- •Major surgery within 60 days of Visit
- •Participants must have completely recovered from any previous surgery prior to Visit 1
- •Prior organ transplantation (e.g., heart, lung, liver, kidney), bone marrow transplantation, or life expectancy of < 12 months
- •Pregnancy or breastfeeding in females
- •Active malignancy, with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in situ, or ≤ 2 squamous cell carcinomas of the skin
- •History of clinically significant (as determined by the investigator) endocrine, hematologic, hepatic, (auto)immune, infectious (requiring chronic antibiotics), metabolic, urologic, pulmonary, neurologic, neuromuscular, dermatologic, psychiatric, renal, and/or another disease that may limit participation in the study
- •Body mass index ≥50 kg/m2
- •More than mild obstructive sleep apnea (treated or untreated)
- 另有 1 项未显示
研究组 & 干预措施
Placebo
Placebo Comparator
Delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks in the placebo-controlled treatment period.
干预措施: Placebo (Drug)
Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg
Experimental
Sotatercept SC at a starting dose level of 0.3 mg/kg for 3 dosing visits (Q3W), then escalating to 0.7 mg/kg SC on the fourth dosing visit and Q3W for the remainder of the 24-week treatment Period.
干预措施: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg (Drug)
Sotatercept 0.3 mg/kg
Experimental
Participants will receive sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks in the placebo-controlled treatment period.
干预措施: Sotatercept 0.3 mg/kg (Drug)
结局指标
主要结局
Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24
时间窗: Baseline and Week 24
PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).
次要结局
- Percentage of Participants with One or More Adverse Events (AEs)(Week 24)
- Percentage of Participants who Discontinue Study Treatment Due to an AE(Week 24)
- Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 24(Baseline and Week 24)
- Time to First Clinical Worsening Event (TTCW) at Weeks 24(Week 24)
- Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 24(Baseline and Week 24)
- Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 24(Baseline and Week 24)
- Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 24(Baseline and Week 24)
- Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 24(Baseline and Week 24)
- Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24(Baseline and Week 24)
- Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 24(Baseline and Week 24)
- Change From Baseline in ratio of mitral inflow velocity I to mitral annular velocity'(e') (E/e' ratio) at Week 24(Baseline and Week 24)
- Change From Baseline in the Ratio of the Peak Velocity Flow of the E Wave in Early Diastole to Peak Velocity Flow of the A Wave in Late Diastole (E/A Ratio) at Week 24(Baseline and Week 24)
- Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 24(Baseline and Week 24)
- Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 24(Baseline and Week 24)
- Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 24(Baseline and Week 24)
研究者
研究点 (238)
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