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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Acceleron Pharma Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

28 Apr 2022 → 9 Apr 2026

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA

External identifiers

EU CT number

2023-509141-12-00

EudraCT number

2021-003020-32

WHO UTN

U1111-1309-6433

ClinicalTrials.gov

NCT04945460

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Pharmacokinetic, Efficacy, Pharmacodynamic

Efficacy: This study is designed to evaluate the efficacy, measured by change from baseline in PVR (primary endpoint) and 6MWD (key secondary endpoint) of sotatercept versus placebo in adults with Cpc-PH due to HFpEF. Safety: The safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to HFpEF will be assessed by the safety endpoints listed below.

Conditions and MedDRA coding

Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved Ejection Fraction (HFpEF)

Study design 4 periods

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

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

Exclusion criteria 3

1. 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
2. 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
3. Cont. 8. Polish translation (due to size limit)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Change from baseline in PVR at Week 24

Secondary endpoints 2

1. Time to clinical worsening at Wk 24: −Hospitalization cardiopulmonary indication −Administration IV diuretics or SC furosemide −Death −Decrease 6MWD by ≥ 15% from baseline • Change from baseline in: -hemodynamic and ECHO parameters at Wk 24 -NT-proBNP at Wk 24 - -NYHA FC at Wk 24
2. Cont. translations

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Acceleron Pharma Inc.

Sponsor organisation

Acceleron Pharma Inc.

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Acceleron Pharma Inc.

Contact name

Alexandra Cornell

Public contact point

Organisation

Acceleron Pharma Inc.

Contact name

Alexandra Cornell

Third parties 11

Locations

7 EU/EEA countries · 31 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 119 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications