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

A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sotatercept When Added to Maximum Tolerated Background Therapy in Participants With Pulmonary Arterial Hypertension (PAH) World Health Organization (WHO) Functional Class (FC) III or FC IV at High Risk Mortality

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.

Study Overview

• Status: Completed
• Conditions: Pulmonary Arterial Hypertension
• Intervention / Treatment: Other: Placebo; Drug: Sotatercept

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 who were eligible for this study presented with symptomatic PAH that was classified as idiopathic, heritable, drug- or toxin-induced, associated with connective tissue disease, or post-shunt correction.

• Study Type: Interventional
• Enrollment (Actual): 173
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Darlinghurst, New South Wales, Australia, 2010
      • St Vincent's Hospital Sydney ( Site 1102)
    • New Lambton Heights, New South Wales, Australia, 2305
      • John Hunter Hospital ( Site 1101)
• Belgium
  • Bruxelles-Capitale, Region de
    • Anderlecht, Bruxelles-Capitale, Region de, Belgium, 1070
      • Hopital Erasme ( Site 1402)
  • Vlaams-Brabant
    • Leuven, Vlaams-Brabant, Belgium, 3000
      • UZ Leuven Campus Gasthuisberg ( Site 1401)
• Canada
  • Alberta
    • Calgary, Alberta, Canada, T1Y 6J4
      • Peter Lougheed Centre ( Site 2102)
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital ( Site 2103)
• France
  • Bas-Rhin
    • Strasbourg, Bas-Rhin, France, 67000
      • Hopitaux Universitaires de Strasbourg ( Site 1307)
  • Haute-Garonne
    • Toulouse, Haute-Garonne, France, 31059
      • Centre Hospitalier Universitaire de Toulouse. ( Site 1315)
  • Meurthe-et-Moselle
    • Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France, 54511
      • CHU de Nancy - Hôpital de Brabois Adultes ( Site 1308)
  • Nord
    • Lille, Nord, France, 59037
      • CHRU Lille ( Site 1306)
  • Rhone
    • Bron, Rhone, France, 69500
      • Hôpital Louis Pradel ( Site 1317)
  • Val-de-Marne
    • Le Kremlin-Bicêtre, Val-de-Marne, France, 94275
      • CHU Bicêtre ( Site 1304)
  • Vienne
    • Poitiers, Vienne, France, 86021
      • CHU de Poitiers ( Site 1316)
• Germany
  • Baden-Wurttemberg
    • Heidelberg, Baden-Wurttemberg, Germany, 69126
      • Thoraxklinik-Heidelberg gGmbH ( Site 1509)
  • Bavaria
    • München, Bavaria, Germany, 80639
      • Krankenhaus Neuwittelsbach ( Site 1510)
  • Hesse
    • Giessen, Hesse, Germany, 35392
      • Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)
  • Lower Saxony
    • Hanover, Lower Saxony, Germany, 30625
      • Medizinische Hochschule Hannover ( Site 1505)
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Uniklinik Köln ( Site 1511)
  • Saarland
    • Homburg, Saarland, Germany, 66424
      • Universitatsklinikum des Saarlandes ( Site 1513)
  • Saxony
    • Dresden, Saxony, Germany, 01307
      • Universitätsklinikum Carl Gustav Carus an der TU Dresden. ( Site 1501)
• Israel
  • Haifa, Israel, 34362
    • Lady Davis Carmel Medical Center ( Site 1705)
• Italy
  • Roma, Italy, 161
    • La Sapienza-Università di Roma-Policlinico Umberto I ( Site 2402)
  • Lombardy
    • Milan, Lombardy, Italy, 20123
      • Ospedale S. Giuseppe Multimedica ( Site 2403)
• Mexico
  • Mexico City
    • Mexico City, Mexico City, Mexico, 14080
      • Instituto Nacional De Cardiologia Dr. Ignacio Chavez ( Site 2503)
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 2504)
    • Monterrey, Nuevo León, Mexico, 64718
      • Unidad de Investigación Clínica en Medicina, S.C ( Site 2505)
• Netherlands
  • North Holland
    • Amsterdam, North Holland, Netherlands, 1081 HV
      • VU Medisch Centrum ( Site 2601)
• Spain
  • Madrid, Spain, 28041
    • Hospital Universitario 12 de Octubre ( Site 1603)
• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB23 3RE
      • Royal Papworth Hospital ( Site 1208)
  • London, City of
    • London, London, City of, United Kingdom, SW3 6JY
      • Royal Brompton Hospital ( Site 1206)
    • London, London, City of, United Kingdom, W2 1NY
      • Imperial College Healthcare NHS Trust ( Site 1203)
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85013
      • Arizona Pulmonary Specialists ( Site 1010)
  • California
    • Los Angeles, California, United States, 90095
      • David Geffen School of Medicine at UCLA ( Site 1068)
    • Orange, California, United States, 92868-2994
      • University of California Irvine ( Site 1086)
    • San Diego, California, United States, 92037
      • University of California San Diego Medical Center ( Site 1002)
    • San Francisco, California, United States, 94118
      • University of California San Francisco ( Site 1019)
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado Hospital ( Site 1013)
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20037
      • The George Washington University Medical Faculty Associates ( Site 1025)
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic Jacksonville - PPDS ( Site 1045)
    • Orlando, Florida, United States, 32804
      • AdventHealth Medical Group Advanced Lung Disease ( Site 1058)
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Northside Hospital ( Site 1073)
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University Of Iowa Hospitals and Clinics ( Site 1050)
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center ( Site 1020)
  • Massachusetts
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center - PPDS ( Site 1012)
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital ( Site 1014)
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan ( Site 1011)
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine ( Site 1022)
  • Nebraska
    • Omaha, Nebraska, United States, 68105
      • University Of Nebraska Medical Center ( Site 1053)
  • New Mexico
    • Albuquerque, New Mexico, United States, 87131
      • University of New Mexico Health Sciences Center ( Site 1048)
  • New York
    • Rochester, New York, United States, 14642-0001
      • University of Rochester Medical Center - PPDS ( Site 1039)
  • North Carolina
    • Durham, North Carolina, United States, 27713
      • Duke University Medical Center ( Site 1026)
  • Ohio
    • Cincinnati, Ohio, United States, 45267-0558
      • University of Cincinnati Medical Center ( Site 1035)
    • Cleveland, Ohio, United States, 44103-3736
      • The Cleveland Clinic Foundation. ( Site 1065)
  • South Carolina
    • Charleston, South Carolina, United States, 29425
      • Medical University of South Carolina - PPDS ( Site 1003)
  • Tennessee
    • Knoxville, Tennessee, United States, 37909
      • Statcare Pulmonary Consultants - Knoxville ( Site 1031)
  • Texas
    • Dallas, Texas, United States, 75390
      • University of Texas Southwestern Medical Center ( Site 1038)
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin - Froedtert Hospital ( Site 1051)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Participants on background PAH therapy will be administered placebo by SC injection every 21 days	Other: Placebo; Placebo-matched SC injection
Experimental: 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	Drug: Sotatercept; SC injection; Other Names: ACE-011; MK-7962

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in European Quality of Life (EuroQoL)-5 Dimensions-5 Levels (EQ-5D-5L) Index Score at Week 24	EQ-5D-5L is a standardized measure of health status, consisting of 5 health dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression), each assessed on a 5-point scale (1=no problem, 2=slight problems, 3=moderate problems, 4=severe problems, 5=extreme problems). Participants score each dimension based on their health that day and their responses are used to generate a health index score. Index scores could range from <0 (a health state equivalent to dead with negative values representing a state worse than dead) to 1 (full health). Higher scores indicated better health and a positive change in score indicated improved overall health. Per SAP, multiple imputation was used to impute missing data at Week 24 for reasons other than death or a non-fatal clinical worsening event. Range was based on the minimum and maximum of median scores across the imputed dataset (100 repetitions). The change from baseline to Week 24 in EQ-5D-5L index score is reported.	Baseline and Week 24
Overall Survival (OS)	OS was defined as the time from randomization to death due to any cause. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. The OS for participants, calculated using the non-parametric Kaplan-Meier method, is reported.	Up to approximately 31 months
Transplant-free Survival	Transplant-free survival was defined as the time from randomization to the first lung transplantation or death due to any cause. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. Transplant-free survival for participants, calculated using the non-parametric Kaplan-Meier method, is reported.	Up to approximately 31 months
Percentage of Participants Who Experienced a Mortality Event	Mortality events were defined as death due to any cause throughout the study. As pre-specified in the SAP, all deaths up to data cutoff, including among participants who completed or discontinued the study, were included except for those that occurred after enrollment in the long-term follow-up study (MK-7962-004) or after lung transplantation. The percent of participants who experienced a mortality event is reported.	Up to approximately 31 months
Change From Baseline in REVEAL Lite 2.0 Risk Score at Week 24	REVEAL Lite 2.0 risk scoring is used to guide PAH treatment decisions. Total score uses 6 variables with each assessed based on contribution to mortality risk. Variables and sub-score ranges: eGFR (0, +1), WHO FC (-1, 0, +1, +2), SBP (0, +1), heart rate (0, +1), 6MWD (-2, -1, 0, +1), and NT-proBNP (-2, 0, +2). Sub-scores are added to a base score of +6 and a total score of 1 to 14 is obtained (≤5=low risk; 6,7=intermediate risk; ≥8=high risk). A higher score = higher risk. Median change and full ranges are reported based on observed data.	Baseline and Week 24
Percentage of Participants Achieving a Low or Intermediate (≤7) REVEAL Lite 2 Risk Score at Week 24	REVEAL Lite 2.0 risk scoring is used to guide PAH treatment decisions. Total score uses 6 variables with each assessed based on contribution to mortality risk. Variables and sub-score ranges: eGFR (0, +1), WHO FC (-1, 0, +1, +2), SBP (0, +1), heart rate (0, +1), 6MWD (-2, -1, 0, +1), and NT-proBNP (-2, 0, +2). Sub-scores are added to a base score of +6 and a total score of 1 to 14 is obtained (≤5=low risk; 6,7=intermediate risk; ≥8=high risk). A higher score = higher risk. Per SAP, participants who did not have a REVEAL risk score at Week 24 were considered as non-responders and multiple imputation was not conducted for this endpoint. Comparisons between this analysis reporting non-imputed data should not be made to other REVEAL analyses which included imputation of missing Week 24 data. The percentage of participants who achieved a low or intermediate REVEAL Lite 2.0 score at Week 24 is reported.	Week 24
Change From Baseline in NT-proBNP Levels at Week 24	NT-proBNP is secreted by cardiomyocytes in response to ventricular stretch and is an established noninvasive marker of ventricular dysfunction in patients with PAH. Blood samples were collected at baseline and at Week 24 to measure NT-proBNP levels. Median change and full ranges are reported based on observed data.	Baseline and Week 24
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24	mPAP is a hemodynamic variable associated with PAH severity and was measured measured at baseline and at Week 24 by right heart catheterization (RHC). Median change and full ranges are reported based on observed data.	Baseline and Week 24
Change From Baseline in Pulmonary Vascular Resistance (PVR)	PVR is a hemodynamic variable associated with PAH severity and was measured at baseline and at Week 24 by right heart catheterization (RHC). Median change and full ranges are reported based on observed data.	Baseline and Week 24
Percentage of Participants Who Improve in WHO FC	The severity of a participant's PAH symptoms was graded using the WHO FC system. WHO functional classification for PAH ranges 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). Participants who improve in WHO FC were classified into "Improved", "No change", or "Worsened" (Improved = reduction in FC; Worsened = increase in FC; No change = no change in FC). The percentage of participants who had improvement from baseline in WHO FC at the end of the treatment period is reported.	Baseline and up to approximately 31 months
Change From Baseline in 6MWD at Week 24	6MWD was measured using the 6-Minute Walk Test (6MWT). The 6MWT measures the distance covered in 6 minutes and is intended to measure changes in functional exercise capacity. Each participant's 6MWD was measured at baseline and at 24 weeks. An increase in the distance walked during the 6MWT indicated improvement in functional exercise capacity. Median change and full ranges are reported based on observed data.	Baseline and Week 24
Change From Baseline in Cardiac Output (CO) at Week 24	CO is a prognostic hemodynamic parameter measured at baseline and at Week 24 by RHC. Median change and full ranges are reported based on observed data.	Baseline and Week 24

Collaborators and Investigators

• Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Investigators: Study Director: Medical Director, Merck Sharp & Dohme LLC

Publications and helpful links

General Publications

• 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.

Helpful Links

• Merck Clinical Trial Information
• Plain Language Summary

Study record dates

Study Major Dates

• Study Start (Actual): December 1, 2021
• Primary Completion (Actual): July 26, 2024
• Study Completion (Actual): February 18, 2025

Study Registration Dates

• First Submitted: May 13, 2021
• First Submitted That Met QC Criteria: May 17, 2021
• First Posted (Actual): May 21, 2021

Study Record Updates

• Last Update Posted (Actual): May 29, 2026
• Last Update Submitted That Met QC Criteria: May 27, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Pulmonary, hypertension, sotatercept
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Respiratory Tract Diseases; Lung Diseases; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Hypertension; ACE-011
• Other Study ID Numbers: 7962-006; A011-14 (Other Identifier: Acceleronpharma); MK-7962-006 (Other Identifier: MSD); 2021-001498-21 (EudraCT Number); U1111-1309-6376 (Registry Identifier: UTN); 2023-509140-10-00 (Registry Identifier: EU CT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: https://trialstransparency.msdclinicaltrials.com/pdf/ProcedureAccessClinicalTrialData.pdf

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No