A Phase 2 Study of Sotatercept for Combined Postcapillary and Precapillary Pulmonary Hypertension Treatment

Phase 1

• Conditions: Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved EjectionFraction (HFpEF); MedDRA version: 21.1Level: PTClassification code 10037400Term: Pulmonary hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders; Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

• Registration Number: EUCTR2021-003020-32-DE
• Lead Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2021-10-15
• Last Update Posted: 26 August 2024

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

Participants must meet the following criteria to be enrolled in this 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 2 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 = 320 dyn•sec/cm5 (4 wood units) (see Section 9.2.1 for historic RHC requirements)
• Mean pulmonary arterial pressure > 20 mmHg
• Pulmonary capillary wedge pressure > 15 mmHg but < 30 mmHg
4. New York Heart Association FC of II or III
5. Six minute Walk Distance = 100 meters repeated twice during Screening and both values
within 15% of each other, calculated from the highest value (see Section 9.3.2 for details)
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 (defined in Appendix 2) 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
See Appendix 2 for additional contraceptive information.
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 WOCBP 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 (see Appendix 2 for additional contraceptive information)
• 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 informed consent for participation
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 37
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 113

Exclusion Criteria

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 comorbidities, which include any of the following:
-History of more than mild mitral or aortic stenosis (corrected mitral or
aortic stenosis by a surgical or transcatheter method within 12 months
from Visit 1 and no more than mild residual stenosis may be allowed
after the Medical Monitor's review)
-Ongoing more than mild mitral or aortic regurgitation (corrected mitral
or aortic regurgitation by a surgical or transcatheter method within 12
months from Visit 1 and no more than mild residual regurgitation may be allowed after the Medical Monitor's review). NOTE: if an imaging report reads 'mild-to-moderate mitral regurgitation', the participant may still be enrolled if, in the opinion of the
investigator, the mitral regurgitation is no more than mild.
-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 (e.g.,
from endocarditis, carcinoid, or mechanical destruction).
- 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
- 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 (including atrial
fibrillation)
- 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 subject's
ECG shows a normal QTc
- Arrhythmogenic right ventricular dysplasia (ARVD) unless the subject
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

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: Efficacy: This study is designed to evaluate the efficacy, measured by change from baseline in<br>PVR (primary endpoint) and 6MWD (key secondary endpoint) of sotatercept versus placebo in<br>adults with Cpc-PH due to HFpEF.<br>Safety: The safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to<br>HFpEF will be assessed by the safety endpoints listed below.;Secondary Objective: Not Applicable;Primary end point(s): Efficacy Endpoints<br>Primary Efficacy Endpoint<br>• Change from baseline in PVR at Week 24<br>;Timepoint(s) of evaluation of this end point: From baseline at Week 24