Purpose

The objectives of this study are to evaluate the efficacy and safety of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH.

Condition

Eligibility

Eligible Ages
Over 18 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

  1. Age ≥ 18 years 2. Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO pulmonary arterial hypertension (PAH) Group 1 in any of the following subtypes: - Idiopathic PAH - Heritable PAH - Drug/toxin-induced PAH - PAH associated with connective tissue disease - PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair 3. Symptomatic PAH classified as WHO Functional Class II or III 4. Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of ≥ 5 Wood units (WU) 5. On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice. Background PAH therapy is defined in Section 7.2 6. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value) 7. Females of childbearing potential must: - Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during the study and until 8 weeks after the last dose of the study drug - If sexually active, have used, and agree 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 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 treatment 8. Male participants must: - Agree to use a condom, defined as a male latex condom or nonlatex 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 treatment 9. Ability to adhere to study visit schedule and understand and comply with all protocol requirements 10. Ability to understand and provide written informed consent

Exclusion Criteria

  1. Diagnosis of pulmonary hypertension WHO Groups 2, 3, 4, or 5 2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension. Exclusions in PAH Group I should also include schistosomiasis APAH and pulmonary veno occlusive disease 3. Hemoglobin (Hgb) at screening above gender-specific upper limit of normal (ULN), per local laboratory test 4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest 5. Baseline systolic BP < 90 mmHg at screening 6. Pregnant or breastfeeding women 7. Any of the following clinical laboratory values at the screening visit: - Estimated glomerular filtration rate (eGFR) < 30 mL/min/m2 (as defined by MDRD equation) - Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 1.5 × ULN 8. 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 9. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE 536) and/or excipients or known allergic reaction to either one 10. Have full or partial pneumonectomy 11. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing no more than mild interstitial lung disease (ILD) performed at the screening visit or 1 year to it. 12. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the screening visit 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). 13. History of more than mild obstructive sleep apnea that is untreated 14. Known history of portal hypertension or chronic liver disease, including 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-C) 15. History of restrictive, constrictive or congestive cardiomyopathy 16. History of atrial septostomy within 180 days prior to the screening visit 17. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during the screening period 18. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death 19. Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months prior to the screening visit or pulmonary capillary wedge pressure > 15 mmHg as determined in the Screening Period RHC 20. Any symptomatic coronary disease events" within 6 months (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months of the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions. 21. Cerebrovascular accident within 3 months prior to the screening visit 22. Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment 23. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, mitral stenosis and more than mild aortic valve stenosis 24. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin) within 30 days prior to the screening visit

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Intervention Model Description
Participants will be randomized to one of two treatment arms to receive either sotatercept (0.7 mg/kg) by subcutaneous administration once every 3 weeks, or placebo. All participants will be on concurrent, stable background PAH therapy. Randomization will be stratified by baseline WHO Functional Class (Class II or III) and by background PAH therapy (mono/double or triple therapy)
Primary Purpose
Treatment
Masking
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description
Study participants, care providers. Investigators and outcomes assessor will be masked to the study intervention until the final participant complete the 24-week efficacy assessment.

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Sotatercept plus background PAH theraphy
Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy
  • Drug: Sotatercept
    Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.
Placebo Comparator
Placebo plus background PAH therapy
Placebo administered (SC) every 21 days plus background PAH therapy
  • Drug: Placebo
    Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy.

Recruiting Locations

University of Kansas Medical Center
Kansas City, Kansas 66160
Contact:
Luigi Boccardi
lboccardi@kumc.edu

More Details

Status
Recruiting
Sponsor
Acceleron Pharma Inc.

Study Contact

Clinical Trials Manger
617-649-9200
Clinicaltrials011@acceleronpharma.com

Detailed Description

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study in subjects with symptomatic Pulmonary Arterial Hypertension (PAH) who present with idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug or toxin induced, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects (CHDs), and currently on background PAH therapy. The primary efficacy endpoint of the study is exercise capacity, as measured by the 6-minute walk distance (6MWD) measured at 24 week following initiation of treatment. Approximately 284 participants will be enrolled and randomized 1:1 to receive either sotatercept or placebo on the background of stable standard-of-care PAH mediation. Study duration will be approximately 2 years A stratified Wilcoxon test will be used for analysis of the primary endpoint, with appropriate imputation for missing data, as detailed in the Statistical Analysis Plan. An unblinded, external, independent Data Monitoring Committee (DMC) will monitor participant safety throughout the course of the study. Participants completing this study will be eligible to receive sotatercept in a separate, open-label extension study.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.