Evaluation of Sotatercept in Adults with Combined Postcapillary and Precapillary Pulmonary Hypertension Due to Heart Failure with Preserved Ejection Fraction

Trial ID: 2023-509141-12-00
Protocol: A011-16
Sponsor: Acceleron Pharma Inc.

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Diseases & Conditions

Pulmonary hypertension

Objectives

The primary objective of this Phase 2, double-blind, randomized, placebo-controlled study is to evaluate the **efficacy** of **sotatercept** compared to placebo in adults with Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved Ejection Fraction (HFpEF). The efficacy will be measured by the change from baseline in pulmonary vascular resistance (PVR), which serves as the primary endpoint. This is clinically relevant as PVR is a critical parameter in assessing the severity and progression of pulmonary hypertension, and its reduction could indicate a therapeutic benefit. Additionally, the study will assess the safety and tolerability of sotatercept versus placebo, which is crucial for determining the risk-benefit profile of the treatment in this patient population.

Participants

The clinical trial involves a total of **69 participants** diagnosed with **Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH)** due to **Heart Failure with Preserved Ejection Fraction (HFpEF)**. The study population includes both male and female subjects, aged between 18 and 85 years. Participants were selected based on their ability to provide informed consent and their clinical diagnosis of HFpEF, with specific hemodynamic criteria confirmed by right heart catheterization. The trial includes individuals who are on stable chronic medication for heart failure or any underlying condition, with exceptions for diuretics and anticoagulants. Participants are required to have a New York Heart Association functional class of II or III and a six-minute walk distance of at least 100 meters. The study population is not limited by gender, and both male and female participants are included, with specific contraceptive requirements for women of childbearing potential and male participants. The trial does not exclude vulnerable populations, ensuring a comprehensive assessment of the investigational product's efficacy and safety across a diverse group of individuals.

Plans and Procedures

The clinical trial is a **Phase 2, double-blind, randomized, placebo-controlled** study designed to evaluate the efficacy and safety of **sotatercept** in adults with **Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH)** due to **Heart Failure with Preserved Ejection Fraction (HFpEF)**. The primary objective is to assess the change from baseline in pulmonary vascular resistance (PVR) at Week 24, while secondary endpoints include time to clinical worsening and changes in hemodynamic and echocardiographic parameters, NT-proBNP levels, and New York Heart Association Functional Class (NYHA FC) at Week 24. The trial is expected to last until November 2025, with participant recruitment having commenced in November 2021.

Participants will be involved in the study for a maximum treatment period of 114 days, with the investigational product administered as a **solution for injection** via the subcutaneous route. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, clinical diagnosis, and medication stability; baseline assessments; and regular follow-up visits to monitor safety and efficacy outcomes. The end-of-study visit will conclude the participant's involvement, with assessments to ensure safety and collect final data.

Inclusion criteria require participants to be between 18 and 85 years old, with a clinical diagnosis of HFpEF and demonstrated Cpc-PH. Participants must agree not to participate in other investigational trials during the study and must adhere to contraceptive guidelines if applicable. Conditions for early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The study aims to provide valuable insights into the potential benefits of sotatercept for this specific patient population.

Treatment

The clinical trial involves the administration of **sotatercept**, a **biological** agent, as the experimental medication. Sotatercept is provided in a **solution for injection** form and is administered via the **subcutaneous** route. The dosing regimen for sotatercept is based on body weight, with a maximum daily dose of 0.7 mg/kg and a total maximum dose of 105 mg over the treatment period. The treatment duration is set for a maximum of 114 days. The administration of sotatercept is facilitated by a pre-filled syringe containing sterile water for injection, accompanied by a syringe and needle, ensuring precise and sterile delivery of the medication. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the protocol.

The study also includes a **placebo** group, which serves as the comparator treatment. The placebo is designed to match the experimental treatment in appearance and administration method, ensuring the double-blind nature of the trial. Participants in the placebo group receive an injection that mimics the administration of sotatercept, without containing the active substance. This allows for an unbiased comparison of the efficacy and safety of sotatercept against a control group. The placebo is administered following the same schedule and route as the experimental medication, maintaining consistency across the study arms.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the change from baseline in **Pulmonary Vascular Resistance (PVR)**, which serves as the primary endpoint. This measurement will be taken at Week 24 to determine the effectiveness of sotatercept compared to placebo in adults with Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved Ejection Fraction (HFpEF). Additionally, a key secondary endpoint involves assessing the change in the six-minute walk distance (6MWD) from baseline, also at Week 24. These endpoints are designed to provide a comprehensive evaluation of the treatment's impact on the condition.

Secondary endpoints include the time to clinical worsening at Week 24, which encompasses hospitalization for cardiopulmonary indications, administration of intravenous diuretics or subcutaneous furosemide, death, and a decrease in 6MWD by 15% or more from baseline. Other secondary measures include changes from baseline in hemodynamic and echocardiographic parameters, NT-proBNP levels, and New York Heart Association Functional Class (NYHA FC) at Week 24. These parameters will be collected and analyzed to provide further insights into the treatment's efficacy.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Age 18 to 85 years
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
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
New York Heart Association FC of II or III
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)
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 (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.
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
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 informed consent for participation

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Exclusion Criteria

1.-8. Diagnosis of PH in WHO Group 1, 3, 4 or 5 2. Clinically significant, active lung disease: -COPD w/post-bronchodilator FEV1 < 60% predicted -Restrictive lung disease w/total lung capacity < 70% predicted -More than mild ILD w/FVC < 70% or FEV1 < 60% predicted (unless absence of > mild ILD, fibrosis, or COPD on CT imaging) 3. CV comorbidities, any: -Hx of more than mild mitral or aortic stenosis, corrected mitral or aortic stenosis by surgical or transcatheter method w/in 12 months of Visit 1 -Ongoing more than mild mitral or aortic regurg, corrected mitral or aortic regurg by surgical or transcatheter method w/in 12 months of Visit 1 -More than 1 valve replacement or repair or any anticipated valve replacement or repair -Severe tricuspid regurgitation due to primary valvular disease -MI, ACS, CABG or PCI w/in 180 days of Visit 1 -Hx of serious life-threatening or hemodynamically significant arrhythmia -Hx of or anticipated heart transplant or ventricular assist device implantation -Hx of implantable cardioverter defibrillator placement, anticipated pacemaker implant, or pacemaker implant w/in 30 days of Scrning -Hx of pericardial constriction, hypertrophic cardiomyopathy, sarcoidosis, or amyloid cardiomyopathy -Uncontrolled systemic hypertension (SBP > 160 mmHg or DBP > 110 mmHg during Scrning at rest) -Systemic hypotension (SBP < 90 mmHg or DBP < 50 mmHg during Scrning) -Resting HR < 45 bpm or > 115 bpm (including afib) -Stroke w/in 90 days of Visit 1 -Acutely decompensated HF requiring hospitalization w/in 30 days of Visit 1 -ECG during Scrning with QTcF > 470 msec if male, > 480 msec if female, or > 500 msec if ventricular conduction defect (RBBB/LBBBB or interventricular conduction delay) is present -Personal/family Hx of Brugada synd, sudden cardiac arrest or unexplained SCD or arrest -Personal/family Hx of long QT synd unless subject ECG shows normal QTcARVD unless recent cardiac MRI shows no evidence of diagnosis 4. Hospitalization for worsening of medical conditions/ significant surgery per PI w/in 30 days of Visit 1 5. Received any approved PAH-specific therapies (ERA, prostacyclin analogs, PDE-5 inhibitors, sGC stimulators) w/in 30 days of Visit 1. Oral PDE-5 inhibitor for ED permitted if not administered w/in 48 hours of visit or procedure. 6. Received IV inotropes w/in 30 days of Visit 1 7. Received EPOw/in 6 months of Visit 1 8. Hx of chronic liver disease, including untreated hepatitis B or C (with evidence of recent infection or active virus replication), with severe hepatic impairment or cirrhosis
9.-21. Prior exposure to sotatercept or luspatercept 10. Currently enrolled in or completed IP study w/in 30 days for small-molecule drugs or w/in 5 halflives for biologics prior to documented consent date 11. Initiation of cardiopulm rehab exercise program w/in 90 days of Visit 1 or planned initiation during study 12. Lab values, any of: -Hgb > gender-specific ULN or < 10 g/dL per local lab w/in 28 days of Visit 1 -Serum ALT, AST, or total bilirubin > 3×ULN w/in 28 days of Visit 1 -eGFR < 30 mL/min/1.73 m2 (4-variable MDRD equation) w/in 28 days of Visit 1 or required renal replacement w/in 90 days of Visit 1 - HbA1c > 10% w/in 28 days of Visit 1 - PLT < 75,000/mm3 w/in 28 days of Visit 1 13. Hx of severe allergic or anaphylactic reaction or hypersensitivity to recombinant proteins or excipients in investigational product 14. Major surgery w/in 60 days of Visit 1 or incomplete recovery from any surgery prior to Visit 1 15. Prior solid organ or bone marrow transplant, or life expectancy of < 12 months 16. Pregnancy/ breastfeeding 17. Active malignancy, except fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or ≤ 2 squamous cell carcinomas of the skin 18. Hx of clinically significant (per investigator) disease that may limit study participation 19. BMI ≥ 50 kg/m2 20. More than mild OSA 21. Any non-cardiopul condition or impairment (except dyspnea) that limits ability to perform 6MWT
Cont. 8. Polish translation (due to size limit)

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	30 Nov 2021	1
France	Not Recruiting	30 Nov 2021	40
Germany	Not Recruiting	30 Nov 2021	35
Italy	Not Recruiting	30 Nov 2021	37
Poland	Not Recruiting	30 Nov 2021	30
Spain	Not Recruiting	30 Nov 2021	30
Sweden	Not Recruiting	30 Nov 2021	1