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

• ClinicalTrials.gov Identifier: NCT04945460
• Recruitment Status: Recruiting
• First Posted: June 30, 2021
• Last Update Posted: May 20, 2024
• Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Information provided by (Responsible Party): Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Tracking Information

• First Submitted Date: June 11, 2021
• First Posted Date: June 30, 2021
• Last Update Posted Date: May 20, 2024
• Actual Study Start Date: December 29, 2021
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 6, 2022)

Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 24 [ Time Frame: Baseline and Week 24 ]

PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).

Original Primary Outcome Measures (submitted: June 22, 2021)

Change in Pulmonary Vascular Resistance (PVR) at 24 weeks from baseline [ Time Frame: From screening to Week 24. ]

PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization (RHC).

Current Secondary Outcome Measures (submitted: May 16, 2024)

• Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 24 [ Time Frame: Baseline and Week 24 ]
  The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity.
• Time to First Clinical Worsening Event (TTCW) at Weeks 24 [ Time Frame: Week 24 ]
  Clinical Worsening events are defined as the number of weeks from first dose date to 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 or subcutaneous (SC) furosemide
  • 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.
• Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 24 [ Time Frame: Baseline and Week 24 ]
  mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization.
• Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 24 [ Time Frame: Baseline and Week 24 ]
  PCWP is an indirect estimate of left atrial pressure measured in right heart catheterization.
• Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 24 [ Time Frame: Baseline and Week 24 ]
  TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function.
• Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 24 [ Time Frame: Baseline and 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.
• Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 24 [ Time Frame: Baseline and 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.
• Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 24 [ Time Frame: Baseline and 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.
• Change From Baseline in ratio of mitral inflow velocity I to mitral annular velocity'(e') (E/e' ratio) at Week 24 [ Time Frame: Baseline and Week 24 ]
  E/e' is a ratio measured in echocardiography as an indicator of diastolic function.
• 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 [ Time Frame: Baseline and Week 24 ]
  E/A is a ratio measured in echocardiography as an indicator of diastolic function.
• Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 24 [ Time Frame: Baseline and Week 24 ]
  NT-proBNP is a circulating biomarker that reflects myocardial stretch.
• Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 24 [ Time Frame: Baseline and Week 24 ]
  NYHA FC classifies the extent of heart failure.
• Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 24 [ Time Frame: Baseline and 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.
• Change From Baseline in the 6-Minute Walk Distance (6MWD) at Week 48 [ Time Frame: Baseline and Week 48 ]
  The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity.
• Change From Baseline in Pulmonary Vascular Resistance (PVR) at Week 48 [ Time Frame: Baseline and Week 48 ]
  PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization.
• Change From Baseline in Mean Pulmonary Arterial Pressure (mPAP) at Week 48 [ Time Frame: Baseline and Week 48 ]
  mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization.
• Change From Baseline in Pulmonary Capillary Wedge Pressure (PCWP) at Week 48 [ Time Frame: Baseline and Week 48 ]
  PCWP is an indirect estimate of left atrial pressure measured in right heart catheterization.
• Change From Baseline in Tricuspid Annular Plane Systolic Excursion (TAPSE) at Week 48 [ Time Frame: Baseline and Week 48 ]
  TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function.
• Change From Baseline in Right Ventricular Fractional Area Change (RVFAC) at Week 48 [ Time Frame: Baseline and 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.
• Change From Baseline in Left Ventricular Ejection Fraction (LVEF) at Week 48 [ Time Frame: Baseline and 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.
• Change From Baseline in Isovolumic Relaxation Time (IVRT) at Week 48 [ Time Frame: Baseline and 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.
• Change From Baseline in E/e' (Early Mitral Inflow Velocity E and Mitral Annular Early Diastolic Velocity e') Ratio at Week 48 [ Time Frame: Baseline and Week 48 ]
  E/e' is a ratio measured in echocardiography as an indicator of diastolic function.
• 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 [ Time Frame: Baseline and Week 48 ]
  E/A is a ratio measured in echocardiography as an indicator of diastolic function.
• Change From Baseline in N-terminal Pro-hormone Brain Natriuretic Peptide (NT-proBNP) at Week 48 [ Time Frame: Baseline and Week 48 ]
  NT-proBNP is a circulating biomarker that reflects myocardial stretch.
• Change From Baseline in New York Heart Association Functional Class (NYHA FC) at Week 48 [ Time Frame: Baseline and Week 48 ]
  NYHA FC classifies the extent of heart failure.
• Change From Baseline in Myocardial Contraction Fraction (MCF) at Week 48 [ Time Frame: Baseline and 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.
• Change From Baseline in Pulmonary Vascular Resistance (PVR) for the Placebo Crossed Over to Sotatercept Cohorts at Week 48 of the Extension Period [ Time Frame: Baseline and Week 48 of the Extension Period ]
  PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization.
• 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 [ Time Frame: Baseline and Week 48 of the Extension Period ]
  The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity.
• 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 [ Time Frame: Baseline and Week 48 of the Extension Period ]
  NYHA FC classifies the extent of heart failure.
• Change in Pulmonary Vascular Resistance (PVR) for the Placebo Crossed Over to Sotatercept Cohorts From Week 24 to Week 48 of the Extension Period [ Time Frame: From Week 24 to Week 48 of the Extension Period ]
  PVR, a hemodynamic variable of pulmonary circulation, is measured by right heart catheterization.
• 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 [ Time Frame: 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.
• 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 [ Time Frame: From Week 24 to Week 48 of the Extension Period ]
  NYHA FC classifies the extent of heart failure.

Original Secondary Outcome Measures (submitted: June 22, 2021)

• Change in 6MWD (6 minute walk distance) [ Time Frame: 24 weeks from baseline. ]
  This tests the distance walked in 6 minutes, to assess functional capacity.
• Number of Clinical Worsening events. [ Time Frame: From initiation of treatment to 24 weeks. ]
  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
• Number of Clinical Worsening events at 48 weeks [ Time Frame: From initiation of treatment to 48 weeks. ]
  Clinical Worsening events, defined as above, is measured at 48 weeks.
• Number of participants with first Clinical Worsening event at 24 weeks [ Time Frame: From initiation of treatment to 24 weeks. ]
  Number of patients with Clinical Worsening events, defined as above, is measured at 24 weeks.
• Number of participants with first Clinical Worsening event at 48 weeks [ Time Frame: From initiation of treatment to 48 weeks. ]
  Number of patients with Clinical Worsening events, defined as above, is measured at 48 weeks.
• Time to Clinical Worsening [ Time Frame: From initiation of treatment to the time of Clinical Worsening event, up to 110 weeks. ]
  Time to Clinical Worsening events, defined as above, is measured.
• Change in Dyspnea Score (assessed by Borg Category Ratio 10 scale®) [ Time Frame: From initiation of treatment to Week 24 . ]
  This scale assesses subject's perceived severity of shortness of breath. The scale is from 0-10, higher number indicate more severe dyspnea.
• Change in mean pulmonary arterial pressure (mPAP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  mPAP is calculated from systolic and diastolic pulmonary artery pressure measured by right heart catheterization.
• Change in pulmonary capillary wedge pressure (PCWP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  PCWP is indirect estimate of left atrial pressure measured in right heart catheterization.
• Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) [ Time Frame: 24 weeks from baseline. ]
  TAPSE is an echocardiographic measurement of tricuspid valve annulus movement, as an indicator of right heart function.
• Change in right ventricular fractional area change (RVFAC) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  RVFAC is an echocardiographic measurement of percent change between right ventricular area during diastole and systole, as an indicator of right heart function.
• Change in left ventricular ejection fraction (LVEF) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  LVEF is an echocardiographic measurement of percent change between left ventricular volume during diastole and systole, as an indicator of left heart function.
• Change in isovolumic relaxation time (IVRT) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  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.
• Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 24 weeks from baseline. [ Time Frame: 24 weeks from baseline. ]
  E/e' is a ratio measured in echocardiography as an indicator of diastolic function
• Change in 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) weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  E/A is a ratio measured in echocardiography as an indicator of diastolic function
• Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  NT-proBNP is a circulating biomarker that reflects myocardial stretch
• Change in New York Heart Association Functional Class (NYHA FC) at 24 weeks from baseline [ Time Frame: 24 weeks from baseline. ]
  NYHA FC classifies the extent of heart failure
• Change in 6MWD at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in Pulmonary Vascular Resistance (PVR) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in mean pulmonary arterial pressure (mPAP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in pulmonary capillary wedge pressure (PCWP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in Tricuspid Annular Plane Systolic Excursion (TAPSE) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in right ventricular fractional area change (RVFAC) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in left ventricular ejection fraction (LVEF) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in isovolumic relaxation time (IVRT) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in E/e' (early mitral inflow velocity E and mitral annular early diastolic velocity e') ratio at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in A wave in late diastole (E/A) ratio at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in New York Heart Association Functional Class (NYHA FC) at 48 weeks from baseline [ Time Frame: 48 weeks from baseline. ]
• Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [ Time Frame: Week 48 from baseline in the Extension Period ]
• Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [ Time Frame: Week 48 from baseline in the Extension Period ]
• Change in New York Heart Association Functional Class (NYHA FC) [ Time Frame: Week 48 from baseline in the Extension Period. ]
• Change in Pulmonary Vascular Resistance (PVR) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]
• Change in 6MWD (6 minute walk distance) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]
• Change in New York Heart Association Functional Class (NYHA FC) in the placebo crossed Treatment Group [ Time Frame: Week 24 to Week 48 in the Extension Period. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

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

Brief Summary

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: 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.
• Study Type: Interventional
• Study Phase: Phase 2

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention 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 (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Hypertension, Pulmonary

Intervention

• Drug: Sotatercept 0.3 mg/kg
  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.
  Other Name: ACE-011
• Drug: Placebo
  Administered by subcutaneous injection
• Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg
  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.
  Other Name: ACE-011

Study Arms

• Placebo Comparator: Placebo
  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.
  Intervention: Drug: Placebo
• Experimental: Sotatercept 0.3 mg/kg
  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.
  Intervention: Drug: Sotatercept 0.3 mg/kg
• Experimental: Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg
  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.
  Intervention: Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg
• Experimental: Extension Period: Placebo Crossed Over to Sotatercept 0.3 mg/kg
  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.
  Intervention: Drug: Sotatercept 0.3 mg/kg
• Experimental: Extension Period: Placebo Crossed Over to Sotatercept 0.3 mg/kg, escalating to 0.7 mg.kg
  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.
  Intervention: Drug: Sotatercept 0.3 mg/kg escalating to 0.7 mg/kg

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 6, 2022): 150
• Original Estimated Enrollment (submitted: June 22, 2021): 180
• Estimated Study Completion Date: February 20, 2027
• Estimated Primary Completion Date: October 31, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

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

1. Age 18 to 85 years

2. 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

3. 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
4. New York Heart Association FC of II or III
5. Six-minute Walk Distance ≥100 m repeated twice during Screening and both values within 15% of each other, calculated from the highest value
6. 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.

7. 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

8. 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
9. Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
10. Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
11. 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:

1. A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5

2. 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)

3. 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
4. Hospitalization for any worsening of medical conditions or any significant surgery per investigator within 30 days of Visit 1.
5. 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.
6. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin,or levosimendan) within 30 days of Visit 1
7. Received erythropoietin within 6 months of Visit 1.
8. 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)
9. Prior exposure to sotatercept or luspatercept.
10. 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.
11. 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).

12. 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
13. History of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in the investigational product .
14. Major surgery within 60 days of Visit 1. Participants must have completely recovered from any previous surgery prior to Visit 1.
15. Prior organ transplantation (e.g., heart, lung, liver, kidney), bone marrow transplantation, or life expectancy of < 12 months.
16. Pregnancy or breastfeeding in females.
17. 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.
18. 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.
19. Body mass index ≥50 kg/m2.
20. More than mild obstructive sleep apnea (treated or untreated).
21. Any non-cardiopulmonary condition or acute/chronic impairment(s) (other than dyspnea) that limits the ability to perform 6-minute walk test (6MWT).

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Belgium, Canada, France, Germany, Israel, Italy, Poland, Spain, Sweden, United Kingdom, United States

Administrative Information

• NCT Number: NCT04945460
• Other Study ID Numbers: 7962-007; A011-16 ( Other Identifier: Acceleronpharma ); MK-7962-007 ( Other Identifier: Merck ); 2021-003020-32 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Original Responsible Party: Same as current
• Current Study Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Verification Date: May 2024