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 10064911Term: Pulmonary arterial hypertensionSystem Organ Class: 10038738 - Respiratory, thoracic and mediastinal disorders
Therapeutic area: Diseases [C] - Cardiovascular Diseases [C14]

Registration Number: EUCTR2021-003020-32-ES

Lead Sponsor: Acceleron Pharma Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: Authorised-recruitment may be ongoing or finished

Sex: All

Target Recruitment: 180

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%
3. Demonstrated Cpc-PH by all of the following:
• Baseline RHC performed within 10 days prior to Visit 1 (during the Screening
Period) documenting a minimum PVR = 320 dyn•sec/cm5 (4 wood units)
• 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
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. Females of childbearing potential (defined in Appendix 2) must:
• Have a negative pregnancy test as verified by the investigator prior to starting study
drug administration; she 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, have used, and agree to continue to use highly effective
contraception without interruption, for at least 28 days prior to starting the
investigational product, 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
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 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 (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 written 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 45
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 135

Exclusion Criteria

1. A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
2. Significant parenchymal lung disease (e.g., chronic obstructive pulmonary disease with
Global Initiative for Obstructive Lung Disease (GOLD) criteria III and IV, moderate or
severe restrictive lung disease, diffuse interstitial fibrosis or alveolitis, pulmonary
thromboembolism)
3. Cardiovascular co-morbidities, which include any of the following:
• Any history of greater than mild mitral regurgitation or aortic regurgitation valvular
disease or greater than mild aortic or mitral stenosis
• 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
• History of or anticipated implantation of pacemaker or implantable cardioverter
defibrillator
• Occurrence of myocardial infarction within 90 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
>1 60 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
• Cerebrovascular accident within 90 days of Visit 1
• Acutely decompensated HF within 45 days prior to Visit 1, as per investigator
assessment
• Electrocardiogram during Screening Period with Fridericia’s corrected QT interval
(QTcF) > 480 msec 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 long corrected QT syndrome or sudden cardiac death in
first-degree relative
4. Hospitalization for any indication within 30 days of Visit 1
5. Received any approved PAH-specific therapies, i.e., endothelin receptor antagonists,
prostacyclin analogs, phosphodiesterase-5 inhibitors, or a soluble guanylate cyclase
stimulator, within 30 days prior to Visit 1
6. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine,
vasopressin) within 30 days prior to Visit 1
7. Received erythropoietin within 6 months prior to 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), defined as mild to
severe hepatic impairment (Child-Pugh Class A to C)
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 biologics prior to the date of
signed informed consent
11. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior
to 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 above the gender-specific upper limit of normal (ULN) per local
laboratory te

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 in PVR at 24 weeks from baseline;Timepoint(s) of evaluation of this end point: 24 weeks from baseline

Secondary Outcome Measures

Name	Time	Method

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