Pulmonary Hypertension: Sotatercept versus Placebo (CADENCE)

What is the Purpose of this Study?

This study focuses on individuals who have been diagnosed with a form of pulmonary hypertension (PH) associated with left heart disease, known as heart failure with preserved ejection fraction (HFpEF). PH is a disease affecting the blood vessels of the lungs, leading to increased pressure in the blood vessels of the lungs and straining of the right side of the heart. The purpose of the study is to determine whether an experimental treatment called sotatercept (given with participants’ current medications) is safe and can help slow the progression of PH caused by left heart disease, compared with current medications alone. Participants will be randomly assigned to receive sotatercept in one of 2 doses (0.3 mg/kg or 0.7 mg/kg) or placebo (inactive substance).

Eligibility

Participants must meet the following criteria to be enrolled in this proof-of-concept study:
Age 18 to 85 years

Inclusion Criteria:

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 1. 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 1. 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

Exclusion Criteria:

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
Documented significant 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
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.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.
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 1. Participants must have completely recovered from any previous surgery prior to Visit 1
Prior heart-lung transplants or life expectancy of <12 months
Pregnancy or breastfeeding in females
History of 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
Untreated or more than mild obstructive sleep apnea
Any non-cardiopulmonary condition or acute/chronic impairment(s) (other than dyspnea) that limits the ability to perform 6-minute walk test (6MWT)

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Where can I participate?

Beverly

More about this Clinical Trial

What is the full name of this clinical trial?

A Phase 2, Double-blind, Randomized, Placebocontrolled Study to Evaluate the Effects of Sotatercept versus Placebo for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension due to Heart Failure with Preserved Ejection Fraction

Study Details

Disease Type/Condition

Pulmonary hypertension

Principal Investigator

Hage, Antoine

Age Group

Adult

Phase

IRB Number

STUDY00001839

ClinicalTrials.gov ID

NCT04945460

Key Eligibility

ClinicalTrials.gov

How do I learn more about this study?

clinicaltrials@cshs.org