A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH)

NCT04896008 | Completed Phase 3 Results DMC FDA Drug

• 6 other identifiers: 7962-006A011-14MK-7962-0062023-509140-10-00U1111-1309-63762021-001498-21
• Study Type: interventional
• Target: 173
• Locations: 12 countries
• Sites: 57

Brief Summary

The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus maximum tolerated background pulmonary arterial hypertension \[PAH\] therapy) versus placebo (plus maximum tolerated background PAH therapy) on time to first event of all cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours, in participants with World Health Organization (WHO) functional class (FC) III or FC IV PAH at high risk of mortality.

Conditions

Pulmonary Arterial Hypertension

Keywords

Pulmonary, hypertension, sotatercept

Outcome Measures

Primary Outcomes (1)

• Time to First Confirmed Morbidity or Mortality Event

  Morbidity or mortality events were defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of ≥24 hours. All events were adjudicated by a blinded, independent committee of clinical experts. Only adjudication-confirmed lung transplantation and PAH worsening-related hospitalization of ≥24 hours were included in the primary analysis. All deaths that are a first event for a participant were included regardless of adjudication. The time from randomization to the first confirmed morbidity or mortality event, calculated using the non-parametric Kaplan-Meier method, is presented.

  Up to approximately 31 months

Secondary Outcomes (12)

• Overall Survival (OS)

  Up to approximately 31 months

• Transplant-free Survival

  Up to approximately 31 months

• Percentage of Participants Who Experienced a Mortality Event

  Up to approximately 31 months

• Change From Baseline in REVEAL Lite 2.0 Risk Score at Week 24

  Baseline and Week 24

• Percentage of Participants Achieving a Low or Intermediate (≤7) REVEAL Lite 2 Risk Score at Week 24

  Week 24

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Participants on background PAH therapy will be administered placebo by SC injection every 21 days

Other: Placebo

Sotatercept

EXPERIMENTAL

Participants on background PAH therapy will be administered sotatercept by SC injection at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, every 21 days

Drug: Sotatercept

Interventions

Placebo OTHER

Placebo-matched SC injection

Placebo

Sotatercept DRUG

SC injection

Also known as: MK-7962, ACE-011

Sotatercept

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:
• Idiopathic PAH
• Heritable PAH
• Drug/toxin-induced PAH
• PAH associated with CTD
• PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
• Symptomatic PAH classified as WHO FC III or IV
• REVEAL Lite 2.0 risk score of ≥9
• Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum PVR of ≥5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤15 mmHg
• Clinically stable and on stable doses of maximum tolerated (per investigator's judgment) double or triple background PAH therapies for at least 30 days prior to screening
• Females of childbearing potential must:
• Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; must agree to ongoing urine or serum 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, have used, and agree to use highly effective contraception without interruption per protocol; 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
• Male participants must:

You may not qualify if:

• Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
• Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
• Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
• Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
• Baseline platelet count \<50,000/mm3 (\<50.0 x 109/L) at screening
• Baseline systolic blood pressure \<85 mmHg at screening
• Pregnant or breastfeeding women
• Serum alanine aminotransferase or aspartate aminotransferase levels or total bilirubin \>3.0×ULN
• 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
• Prior exposure to sotatercept or known allergic reaction to sotatercept, its excipients or luspatercept
• History of pneumonectomy
• Untreated more than mild obstructive sleep apnea
• History of known pericardial constriction
• History of restrictive or congestive cardiomyopathy
• Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) \>500 ms during the screening period

Sponsors & Collaborators

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

Study Sites (57)

Arizona Pulmonary Specialists ( Site 1010)

Phoenix, Arizona, 85013, United States

Location

David Geffen School of Medicine at UCLA ( Site 1068)

Los Angeles, California, 90095, United States

Location

University of California Irvine ( Site 1086)

Orange, California, 92868-2994, United States

Location

University of California San Diego Medical Center ( Site 1002)

San Diego, California, 92037, United States

Location

University of California San Francisco ( Site 1019)

San Francisco, California, 94118, United States

Location

University of Colorado Hospital ( Site 1013)

Aurora, Colorado, 80045, United States

Location

The George Washington University Medical Faculty Associates ( Site 1025)

Washington D.C., District of Columbia, 20037, United States

Location

Mayo Clinic Jacksonville - PPDS ( Site 1045)

Jacksonville, Florida, 32224, United States

Location

AdventHealth Medical Group Advanced Lung Disease ( Site 1058)

Orlando, Florida, 32804, United States

Location

Northside Hospital ( Site 1073)

Atlanta, Georgia, 30342, United States

Location

University Of Iowa Hospitals and Clinics ( Site 1050)

Iowa City, Iowa, 52242, United States

Location

University of Kansas Medical Center ( Site 1020)

Kansas City, Kansas, 66160, United States

Location

Tufts Medical Center - PPDS ( Site 1012)

Boston, Massachusetts, 02111, United States

Location

Brigham and Women's Hospital ( Site 1014)

Boston, Massachusetts, 02115, United States

Location

University of Michigan ( Site 1011)

Ann Arbor, Michigan, 48109, United States

Location

Washington University School of Medicine ( Site 1022)

St Louis, Missouri, 63110, United States

Location

University of Nebraska Medical Center ( Site 1053)

Omaha, Nebraska, 68105, United States

Location

University of New Mexico Health Sciences Center ( Site 1048)

Albuquerque, New Mexico, 87131, United States

Location

University of Rochester Medical Center - PPDS ( Site 1039)

Rochester, New York, 14642-0001, United States

Location

Duke University Medical Center ( Site 1026)

Durham, North Carolina, 27713, United States

Location

University of Cincinnati Medical Center ( Site 1035)

Cincinnati, Ohio, 45267-0558, United States

Location

The Cleveland Clinic Foundation. ( Site 1065)

Cleveland, Ohio, 44103-3736, United States

Location

Medical University of South Carolina - PPDS ( Site 1003)

Charleston, South Carolina, 29425, United States

Location

Statcare Pulmonary Consultants - Knoxville ( Site 1031)

Knoxville, Tennessee, 37909, United States

Location

University Of Texas Southwestern Medical Center ( Site 1038)

Dallas, Texas, 75390, United States

Location

Medical College of Wisconsin - Froedtert Hospital ( Site 1051)

Milwaukee, Wisconsin, 53226, United States

Location

St Vincent's Hospital Sydney ( Site 1102)

Darlinghurst, New South Wales, 2010, Australia

Location

John Hunter Hospital ( Site 1101)

New Lambton Heights, New South Wales, 2305, Australia

Location

Hôpital Erasme ( Site 1402)

Anderlecht, Bruxelles-Capitale, Region de, 1070, Belgium

Location

UZ Leuven Campus Gasthuisberg ( Site 1401)

Leuven, Vlaams-Brabant, 3000, Belgium

Location

Peter Lougheed Centre ( Site 2102)

Calgary, Alberta, T1Y 6J4, Canada

Location

Jewish General Hospital ( Site 2103)

Montreal, Quebec, H3T 1E2, Canada

Location

Hôpitaux Universitaires de Strasbourg ( Site 1307)

Strasbourg, Bas-Rhin, 67000, France

Location

Centre Hospitalier Universitaire de Toulouse. ( Site 1315)

Toulouse, Haute-Garonne, 31059, France

Location

CHU de Nancy - Hôpital de Brabois Adultes ( Site 1308)

Vandœuvre-lès-Nancy, Meurthe-et-Moselle, 54511, France

Location

CHRU Lille ( Site 1306)

Lille, Nord, 59037, France

Location

Hôpital Louis Pradel ( Site 1317)

Bron, Rhone, 69500, France

Location

CHU Bicêtre ( Site 1304)

Le Kremlin-Bicêtre, Val-de-Marne, 94275, France

Location

CHU de Poitiers ( Site 1316)

Poitiers, Vienne, 86021, France

Location

Thoraxklinik-Heidelberg gGmbH ( Site 1509)

Heidelberg, Baden-Wurttemberg, 69126, Germany

Location

Krankenhaus Neuwittelsbach ( Site 1510)

München, Bavaria, 80639, Germany

Location

Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)

Giessen, Hesse, 35392, Germany

Location

Medizinische Hochschule Hannover ( Site 1505)

Hanover, Lower Saxony, 30625, Germany

Location

Uniklinik Köln ( Site 1511)

Cologne, North Rhine-Westphalia, 50937, Germany

Location

Universitätsklinikum des Saarlandes ( Site 1513)

Homburg, Saarland, 66424, Germany

Location

Universitätsklinikum Carl Gustav Carus an der TU Dresden. ( Site 1501)

Dresden, Saxony, 01307, Germany

Location

Lady Davis Carmel Medical Center ( Site 1705)

Haifa, 34362, Israel

Location

Ospedale S. Giuseppe Multimedica ( Site 2403)

Milan, Lombardy, 20123, Italy

Location

La Sapienza-Università di Roma-Policlinico Umberto I ( Site 2402)

Roma, 161, Italy

Location

Instituto Nacional De Cardiologia Dr. Ignacio Chavez ( Site 2503)

Mexico City, Mexico City, 14080, Mexico

Location

Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 2504)

Monterrey, Nuevo León, 64460, Mexico

Location

Unidad de Investigación Clínica en Medicina, S.C ( Site 2505)

Monterrey, Nuevo León, 64718, Mexico

Location

VU Medisch Centrum ( Site 2601)

Amsterdam, North Holland, 1081 HV, Netherlands

Location

Hospital Universitario 12 de Octubre ( Site 1603)

Madrid, 28041, Spain

Location

Royal Papworth Hospital ( Site 1208)

Cambridge, Cambridgeshire, CB23 3RE, United Kingdom

Location

Royal Brompton Hospital ( Site 1206)

London, London, City of, SW3 6JY, United Kingdom

Location

Imperial College Healthcare NHS Trust ( Site 1203)

London, London, City of, W2 1NY, United Kingdom

Location

Related Publications (1)

• Humbert M, McLaughlin VV, Badesch DB, Ghofrani HA, Gibbs JSR, Gomberg-Maitland M, Preston IR, Souza R, Waxman AB, Moles VM, Savale L, Vizza CD, Rosenkranz S, Shi Y, Miller B, Mackenzie HS, Kim SS, Loureiro MJ, Patel MJ, Koglin J, Cornell AG, Hoeper MM; ZENITH Trial Investigators. Sotatercept in Patients with Pulmonary Arterial Hypertension at High Risk for Death. N Engl J Med. 2025 May 29;392(20):1987-2000. doi: 10.1056/NEJMoa2415160. Epub 2025 Mar 31.

  PMID: 40167274 RESULT

Related Links

• Merck Clinical Trial Information

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Hypertension

Interventions

ACE-011

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme LLC

ClinicalTrialsDisclosure@MSD.com

1-800-672-6372

Study Officials

• Medical Director

  Merck Sharp & Dohme LLC

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Each eligible participant will be randomized in a 1:1 ratio to 1 of the following 2 treatment arms during a double-blind placebo-controlled treatment period: * Sotatercept at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously (SC) every 21 days plus background PAH therapy; or * Placebo administered SC every 21 days plus background PAH therapy.

Study Record Dates

• First Submitted: May 13, 2021
• First Posted: May 21, 2021
• Study Start: December 1, 2021
• Primary Completion: July 26, 2024
• Study Completion: February 18, 2025
• Last Updated: March 2, 2026
• Results First Posted: August 22, 2025

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share

Locations

AU (2); CA (2); IT (2); BE (2); ES (1); GB (3); ME (3); NL (1); DE (7); FR (7); US (26); IL (1)