A Study of Sotatercept for the Treatment of Cpc-PH Due to HFpEF (MK-7962-007/A011-16)

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

Official Title
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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)

Conditions
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Hypertension, Pulmonary

Intervention / Treatment
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* Drug: Sotatercept 0.3 mg/kg
* Drug: Placebo
* Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg


Participation Criteria
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Eligibility Criteria
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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 Demonstrated Cpc-PH by all of the following: Baseline RHC performed within 28 days of or at Visit 1 (during the Screening Period) 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 prior to starting study drug administration; 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 drug 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: Any history of greater than mild mitral or aortic regurgitation valvular disease or greater than mild aortic or mitral stenosis. Severe tricuspid regurgitation may be included unless it is due to primary valvular disease, e.g., from endocarditis, carcinoid, or mechanical destruction Acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention within 180 days of Visit 1 Uncontrolled heart rate (> 100 bpm) from atrial fibrillation or atrial flutter History of serious life-threatening or hemodynamically significant arrhythmia History of or anticipated heart transplant or ventricular assist device implantation 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 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 Personal history of sudden cardiac arrest or family history of unexplained sudden cardiac death or arrest History of or anticipated cardiac valve replacement or repair (mechanical or biomechanical) Hospitalization for any indication 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) 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 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)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Each eligible participant will be randomly assigned in a 1:1:1 ratio to 1 of the 3 treatment groups during the Treatment Period: Arm 1: Treatment Group 1: Placebo delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks Arm 2: Treatment Group 2: Sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks Arm 3: Treatment Group 3: 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Delivered subcutaneously (SC) every 3 weeks (Q3W) for 24 weeks in the placebo-controlled treatment period. After completion of the placebo-controlled treatment period, placebo participants will enter into 1 of the 2 sotatercept dose groups in an extension period. | Drug: Placebo<br>* Administered by subcutaneous injection<br>|
| Experimental: Sotatercept 0.3 mg/kg<br>Participants will receive sotatercept SC at a dose level of 0.3 mg/kg Q3W for 24 weeks in the placebo-controlled treatment period. After completion of the placebo-controlled treatment period, participants will continue to receive sotatercept SC at a dose level of 0.3 mg/kg Q3W in an extension period for up to 18 months. | Drug: Sotatercept 0.3 mg/kg<br>* Administered by subcutaneous injection. Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;|
| Experimental: Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg<br>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. | Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg<br>* Administered by subcutaneous injection. Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;|
| Experimental: Extension Period: Placebo Crossed Over to Sotatercept 0.3 mg/kg<br>After the placebo-controlled treatment period, placebo participants will cross over to receive sotatercept SC at a dose of 0.3 mg/kg Q3W for up to 18 months in an extension period. | Drug: Sotatercept 0.3 mg/kg<br>* Administered by subcutaneous injection. Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;|
| Experimental: Extension Period: Placebo Crossed Over to Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg<br>After the placebo-controlled treatment period, placebo participants will cross over to receive 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 then Q3W for up to 18 months in an extension period. | Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg<br>* Administered by subcutaneous injection. Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1.<br>* Other names: ACE-011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24 | PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC). | Baseline and Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 24 | The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. | Baseline and Week 24 | 
| Number of Clinical Worsening Events at Week 24 | Clinical Worsening events are defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week apart. | Week 24 | 
| Number of Clinical Worsening Events at Week 48 | Clinical Worsening events are defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week apart. | Week 48 | 
| Number of Participants With First Clinical Worsening Event at Week 24 | Number of patients with clinical worsening events defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week apart. | Week 24 | 
| Number of Participants With First Clinical Worsening Event at Week 48 | Number of patients with clinical worsening events defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week apart. | Week 48 | 
| Time to Clinical Worsening | Time to clinical worsening events defined as any of the following: Hospitalization due to a cardiopulmonary indication (a non-elective hospitalization lasting at least 24 hours in duration caused by clinical conditions directly related to Pulmonary Hypertension and/or Heart Failure) Administration of intravenous diuretics Death (all causes) Decrease in 6 minute walk distance (6MWD) by ≥ 15% from baseline confirmed by 2 tests at least 4 hours, but no more than 1 week apart. | From initiation of treatment to the time of clinical worsening event (up to 110 weeks) | 
| Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 24 | mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization. | Baseline and Week 24 | 
| Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 24 | PCWP is an indirect estimate of left atrial pressure measured in right heart catheterization. | Baseline and Week 24 | 
| Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 24 | TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function. | Baseline and Week 24 | 
| Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 24 | RVFAC is an echocardiographic measurement of percent change between right ventricular area during diastole and systole, as an indicator of right heart function. | Baseline and Week 24 | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24 | LVEF is an echocardiographic measurement of percent change between left ventricular volume during diastole and systole, as an indicator of left heart function. | Baseline and Week 24 | 
| Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 24 | IVRT is an echocardiographic measurement of the interval between closure of the aortic valve, to onset of filling by opening of the mitral valve. It is used as an indicator of diastolic dysfunction. | Baseline and Week 24 | 
| Change From Baseline in E/e' (Early Mitral Inflow Velocity E and Mitral Annular Early Diastolic Velocity e') Ratio at Week 24 | E/e' is a ratio measured in echocardiography as an indicator of diastolic function. | 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 | E/A is a ratio measured in echocardiography as an indicator of diastolic function. | Baseline and Week 24 | 
| Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 24 | NT-proBNP is a circulating biomarker that reflects myocardial stretch. | Baseline and Week 24 | 
| Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 24 | NYHA FC classifies the extent of heart failure. | Baseline and Week 24 | 
| Change From Baseline in Dyspnea Score As Assessed by Borg Category Ratio 10 Scale® at Week 24 | The Borg Category Ratio 10 Scale assesses the severity of shortness of breath as perceived by the participant. The scale is from 0-10 with a higher number indicating more severe dyspnea. | Baseline and Week 24 | 
| Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 24 | MCF is an echocardiographic measurement that determines the ratio of left ventricular stroke volume to myocardial volume and is an indicator of left ventricular systolic function. | Baseline and Week 24 | 
| Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 48 | The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. | Baseline and Week 48 | 
| Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 48 | PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization. | Baseline and Week 48 | 
| Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 48 | mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization. | Baseline and Week 48 | 
| Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 48 | PCWP is an indirect estimate of left atrial pressure measured in right heart catheterization. | Baseline and Week 48 | 
| Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 48 | TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function. | Baseline and Week 48 | 
| Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 48 | RVFAC is an echocardiographic measurement of percent change between right ventricular area during diastole and systole, as an indicator of right heart function. | Baseline and Week 48 | 
| Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 48 | LVEF is an echocardiographic measurement of percent change between left ventricular volume during diastole and systole, as an indicator of left heart function. | Baseline and Week 48 | 
| Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 48 | IVRT is an echocardiographic measurement of the interval between closure of the aortic valve, to onset of filling by opening of the mitral valve. It is used as an indicator of diastolic dysfunction. | Baseline and Week 48 | 
| Change From Baseline in E/e' (Early Mitral Inflow Velocity E and Mitral Annular Early Diastolic Velocity e') Ratio at Week 48 | E/e' is a ratio measured in echocardiography as an indicator of diastolic function. | Baseline and Week 48 | 
| 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 48 | E/A is a ratio measured in echocardiography as an indicator of diastolic function. | Baseline and Week 48 | 
| Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 48 | NT-proBNP is a circulating biomarker that reflects myocardial stretch. | Baseline and Week 48 | 
| Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 48 | NYHA FC classifies the extent of heart failure. | Baseline and Week 48 | 
| Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 48 | MCF is an echocardiographic measurement that determines the ratio of left ventricular stroke volume to myocardial volume and is an indicator of left ventricular systolic function. | Baseline and Week 48 | 
| Change From Baseline in Pulmonary Vascular Resistance (PVR) for the Placebo Crossed Over to Sotatercept Cohorts at Week 48 of the Extension Period | PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization. | Baseline and Week 48 of the Extension Period | 
| Change From Baseline in the 6-minute walk distance (6MWD) for the Placebo Crossed Over to Sotatercept Cohorts at Week 48 of the Extension Period | The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. | Baseline and Week 48 of the Extension Period | 
| Change From Baseline in New York Heart Association Functional Class (NYHA FC) for the Placebo Crossed Over to Sotatercept Cohorts at Week 48 of the Extension Period | NYHA FC classifies the extent of heart failure. | Baseline and Week 48 of the Extension Period | 
| Change in Pulmonary Vascular Resistance (PVR) for the Placebo Crossed Over to Sotatercept Cohorts From Week 24 to Week 48 of the Extension Period | PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization. | From Week 24 to Week 48 of the Extension Period | 
| Change in 6-minute Walk Distance (6MWD) for the Placebo Crossed Over to Sotatercept Cohorts From Week 24 to Week 48 of the Extension Period | The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. | From Week 24 to Week 48 of the Extension Period | 
| Change in New York Heart Association Functional Class (NYHA FC) for the Placebo Crossed Over to Sotatercept Cohorts From Week 24 to Week 48 of the Extension Period | NYHA FC classifies the extent of heart failure. | From Week 24 to Week 48 of the Extension Period | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary, hypertension, Cpc PH, HFpEF, sotatercept