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

NCT ID: NCT04896008

Last Updated: 2025-08-22

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 173 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-12-01
• Study Completion Date: 2025-02-18

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.

Detailed Description

This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to 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 WHO FC III PAH or WHO FC IV PAH at high risk of mortality.

Participants with symptomatic PAH (WHO FC III or FC IV at high risk of mortality) 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 defect. Participants must have a Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2.0 risk score of ≥9 and be on maximum tolerated combination background PAH therapy.

Conditions

Pulmonary Arterial Hypertension

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Placebo

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

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: OTHER

Placebo-matched SC injection

Sotatercept

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

Group Type: EXPERIMENTAL

Sotatercept

Intervention Type: DRUG

SC injection

Interventions

Sotatercept

SC injection

Intervention Type: DRUG

Placebo

Placebo-matched SC injection

Intervention Type: OTHER

Other Intervention Names

MK-7962; ACE-011

Eligibility Criteria

Inclusion Criteria

• 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:

• 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
• Ability to adhere to study visit schedule and understand and comply with all protocol requirements
• Ability to understand and provide written informed consent

Exclusion Criteria

• 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
• Personal or family history of long QT syndrome or sudden cardiac death
• Left ventricular ejection fraction <45% on historical echocardiogram within 1 year prior to the screening visit
• Any current or prior history of symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) in the past 6 months prior to the screening visit
• Cerebrovascular accident within 3 months prior to the screening visit
• Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
• Currently on dialysis or anticipated need for dialysis within the next 12 months

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 75 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

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

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Director

Role: STUDY_DIRECTOR

Merck Sharp & Dohme LLC

Locations

Arizona Pulmonary Specialists ( Site 1010)

Phoenix, Arizona, United States

David Geffen School of Medicine at UCLA ( Site 1068)

Los Angeles, California, United States

University of California Irvine ( Site 1086)

Orange, California, United States

University of California San Diego Medical Center ( Site 1002)

San Diego, California, United States

University of California San Francisco ( Site 1019)

San Francisco, California, United States

University of Colorado Hospital ( Site 1013)

Aurora, Colorado, United States

The George Washington University Medical Faculty Associates ( Site 1025)

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

Mayo Clinic Jacksonville - PPDS ( Site 1045)

Jacksonville, Florida, United States

AdventHealth Medical Group Advanced Lung Disease ( Site 1058)

Orlando, Florida, United States

Northside Hospital ( Site 1073)

Atlanta, Georgia, United States

University Of Iowa Hospitals and Clinics ( Site 1050)

Iowa City, Iowa, United States

University of Kansas Medical Center ( Site 1020)

Kansas City, Kansas, United States

Tufts Medical Center - PPDS ( Site 1012)

Boston, Massachusetts, United States

Brigham and Women's Hospital ( Site 1014)

Boston, Massachusetts, United States

University of Michigan ( Site 1011)

Ann Arbor, Michigan, United States

Washington University School of Medicine ( Site 1022)

St Louis, Missouri, United States

University of Nebraska Medical Center ( Site 1053)

Omaha, Nebraska, United States

University of New Mexico Health Sciences Center ( Site 1048)

Albuquerque, New Mexico, United States

University of Rochester Medical Center - PPDS ( Site 1039)

Rochester, New York, United States

Duke University Medical Center ( Site 1026)

Durham, North Carolina, United States

University of Cincinnati Medical Center ( Site 1035)

Cincinnati, Ohio, United States

The Cleveland Clinic Foundation. ( Site 1065)

Cleveland, Ohio, United States

Medical University of South Carolina - PPDS ( Site 1003)

Charleston, South Carolina, United States

Statcare Pulmonary Consultants - Knoxville ( Site 1031)

Knoxville, Tennessee, United States

University Of Texas Southwestern Medical Center ( Site 1038)

Dallas, Texas, United States

Medical College of Wisconsin - Froedtert Hospital ( Site 1051)

Milwaukee, Wisconsin, United States

St Vincent's Hospital Sydney ( Site 1102)

Darlinghurst, New South Wales, Australia

John Hunter Hospital ( Site 1101)

New Lambton Heights, New South Wales, Australia

Hôpital Erasme ( Site 1402)

Anderlecht, Bruxelles-Capitale, Region de, Belgium

UZ Leuven Campus Gasthuisberg ( Site 1401)

Leuven, Vlaams-Brabant, Belgium

Peter Lougheed Centre ( Site 2102)

Calgary, Alberta, Canada

Jewish General Hospital ( Site 2103)

Montreal, Quebec, Canada

Hôpitaux Universitaires de Strasbourg ( Site 1307)

Strasbourg, Bas-Rhin, France

Centre Hospitalier Universitaire de Toulouse. ( Site 1315)

Toulouse, Haute-Garonne, France

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

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

CHRU Lille ( Site 1306)

Lille, Nord, France

Hôpital Louis Pradel ( Site 1317)

Bron, Rhone, France

CHU Bicêtre ( Site 1304)

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

CHU de Poitiers ( Site 1316)

Poitiers, Vienne, France

Thoraxklinik-Heidelberg gGmbH ( Site 1509)

Heidelberg, Baden-Wurttemberg, Germany

Krankenhaus Neuwittelsbach ( Site 1510)

München, Bavaria, Germany

Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)

Giessen, Hesse, Germany

Medizinische Hochschule Hannover ( Site 1505)

Hanover, Lower Saxony, Germany

Uniklinik Köln ( Site 1511)

Cologne, North Rhine-Westphalia, Germany

Universitätsklinikum des Saarlandes ( Site 1513)

Homburg, Saarland, Germany

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

Dresden, Saxony, Germany

Lady Davis Carmel Medical Center ( Site 1705)

Haifa, , Israel

Ospedale S. Giuseppe Multimedica ( Site 2403)

Milan, Lombardy, Italy

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

Roma, , Italy

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

Mexico City, Mexico City, Mexico

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

Monterrey, Nuevo León, Mexico

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

Monterrey, Nuevo León, Mexico

VU Medisch Centrum ( Site 2601)

Amsterdam, North Holland, Netherlands

Hospital Universitario 12 de Octubre ( Site 1603)

Madrid, , Spain

Royal Papworth Hospital ( Site 1208)

Cambridge, Cambridgeshire, United Kingdom

Royal Brompton Hospital ( Site 1206)

London, London, City of, United Kingdom

Imperial College Healthcare NHS Trust ( Site 1203)

London, London, City of, United Kingdom

Countries

United States; Australia; Belgium; Canada; France; Germany; Israel; Italy; Mexico; Netherlands; Spain; United Kingdom

References

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.

Reference Type: RESULT

PMID: 40167274 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Related Links

https://www.merckclinicaltrials.com/

Merck Clinical Trial Information

Other Identifiers

A011-14

Identifier Type: OTHER

Identifier Source: secondary_id

MK-7962-006

Identifier Type: OTHER

Identifier Source: secondary_id

2023-509140-10-00

Identifier Type: REGISTRY

Identifier Source: secondary_id

U1111-1309-6376

Identifier Type: REGISTRY

Identifier Source: secondary_id

2021-001498-21

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

7962-006

Identifier Type: -

Identifier Source: org_study_id