The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) on time to clinical worsening (TTCW) in participants who are newly diagnosed with PAH and are at intermediate or high risk of disease progression.
This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to background PAH therapy in newly diagnosed intermediate- or high risk PAH participants. Participants enrolled in the study will have a diagnosis within 12 months of study screening of symptomatic PAH (World Health Organization (WHO) Group 1, classified as functional class (FC) II or III) and presentation of idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin- induced PAH, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects. As of Amendment 11, this study will be closed so that all eligible participants can receive sotatercept either on the MK-7962-004 extension study (SOTERIA, NCT04796337,) or by commercial access, if available. All eligible participants will complete the end of treatment visit before enrollment in the extension study or initiation of commercial product. Participants not enrolling into the extension study or initiating commercial product will complete the end of study visit.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
321
Sotatercept (ACE-011) is a recombinant fusion protein consisting of the extracellular domain of the human activin receptor type IIA linked to the Fc piece of human IgG1
Placebo
Time to Clinical Worsening
Time to clinical worsening is defined as time from randomization to the first confirmed morbidity event or death. Clinical worsening events are defined as all-cause death, non-planned PAH-related hospitalization of ≥ 24 hours in duration, atrial septostomy, lung transplant and deterioration in performance in 6-minute walk test from baseline combined with one of the following conditions: worsening of WHO functional class from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the background PAH therapy delivery route to parenteral. All events will be adjudicated by a blinded, independent committee of clinical experts.
Time frame: Up to ~36 months
Percentage of Participants Achieving the Multicomponent Improvement Endpoint of 6-Minute Walk Distance (6MWD), N-terminal prohormone Btype natriuretic peptide (NT-ProBNP) and World Health Organization (WHO) Functional Class (FC)
Multicomponent improvement endpoint measured by the percentage of participants achieving all of the following at Week 24 relative to baseline: * Improvement in 6MWD * Improvement or maintenance/achievement of NT-proBNP * Improvement in WHO FC or maintenance of WHO FC II
Time frame: Baseline and Week 24
Percentage of Participants who Achieved a Low Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 Risk Score
The REVEAL Lite 2 uses renal insufficiency (by estimated glomerular filtration rate (eGFR)), WHO FC, systolic blood pressure (SBP) and heart rate, 6MWD, and NT-proBNP to determine the total risk score. The scores (range: 1-14) can be defined as: low risk as a score of ≤5, intermediate risk as a score of 6 or 7, and high risk as a score of ≥8 for the survival rates.
Time frame: Baseline and Week 24
Percentage of Participants who Maintain or Achieve a Low Simplified French Risk Score
The simplified French Risk Score uses WHO FC, 6MWD, and NT-proBNP to determine the total risk score. A low risk score can be defined as attaining or maintaining all three low-risk criteria: WHO FC I or II, 6MWD \> 440m, and NT-proBNP \< 300 ng/L. The percentage of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator will be reported.
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Arizona Pulmonary Specialists ( Site 1010)
Scottsdale, Arizona, United States
University of Arizona ( Site 1006)
Tucson, Arizona, United States
University of California San Diego ( Site 1002)
La Jolla, California, United States
UCLA Medical Center ( Site 1068)
Los Angeles, California, United States
University of California Irvine ( Site 1086)
Orange, California, United States
Santa Barbara Pulmonary Associates ( Site 1060)
Santa Barbara, California, United States
University of California Davis Medical Center ( Site 1064)
Sherman Oaks, California, United States
University of Colorado Hospital ( Site 1013)
Aurora, Colorado, United States
AdventHealth Medical Group Advanced Lung Disease ( Site 1058)
Orlando, Florida, United States
University of Iowa Hospital and Clinics ( Site 1050)
Iowa City, Iowa, United States
...and 142 more locations
Time frame: Baseline and Week 24
Change from Baseline in NT-proBNP Levels
Blood samples will be collected at baseline and at Week 24 to measure NT-proBNP blood concentration.
Time frame: Baseline and Week 24
Percentage of Participants who Improve in WHO FC or Maintain WHO FC II at 24 Weeks from Baseline
The severity of an individual's PAH symptoms was graded using the WHO FC system. WHO functional classification for PAH range from Class I (no limitation in physical activity, no dyspnea with normal activity), Class II (slight limitation of physical activity), Class III (marked limitation of physical activity) and Class IV (cannot perform a physical activity without any symptoms, dyspnea at rest). The change from baseline in WHO FC is classified into "Improved", "No change" and "Worsened". Improvement = reduction in FC, worsened = increase in FC and no change = no change in FC.
Time frame: Baseline and Week 24
Change from Baseline in 6MWD
The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. Change from baseline in 6MWD at Week 24 will be reported.
Time frame: Baseline and Week 24
Overall Survival (OS)
Overall survival is defined as the time from randomization to date of death due to any cause.
Time frame: Up to ~36 Months
Change from Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT)®
PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported.
Time frame: Baseline and Week 24
Change from Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT®
PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported.
Time frame: Baseline and Week 24
Change from Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT®
PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported
Time frame: Baseline and Week 24
Number of Participants who Experience an Adverse Event (AE)
An AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who experienced an AE are presented.
Time frame: Up to ~36 Months
Number of Participants who Discontinued Study Treatment due to AEs
An AE is any untoward medical occurrence in a clinical investigation participant administered a study drug, which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the study drug whether or not it is considered related to the study drug. The number of participants who discontinued study treatment due to an AE are presented.
Time frame: Up to ~34 months
Incidence of Anti-drug Antibodies (ADAs) to Sotatercept
Blood samples collected at designated timepoints will be used to determine the ADA response to Sotatercept. The incidence of ADAs to Sotatercept over time will be presented.
Time frame: Up to ~36 Months