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

Pulmonary Arterial Hypertension Clinical Trial

— ZENITH  

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04896008
• Other study ID #: 7962-006
• Secondary ID: A011-14MK-7962-0
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 1, 2021
• Est. completion date: November 28, 2025

Study information

• Verified date: March 2024
• Source: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 risk score of ≥9 and be on maximum tolerated combination background PAH therapy.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 166
• Est. completion date: November 28, 2025
• Est. primary completion date: September 5, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

Inclusion Criteria:

• Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of World Health Organization (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 diseases (CTD)

• PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair

• Symptomatic PAH classified as WHO functional class (FC) III or IV

• Registry to Evaluate Early and Long-Term PAH Disease Management (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 pulmonary vascular resistance (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

Related Conditions & MeSH terms

• Familial Primary Pulmonary Hypertension
• Hypertension
• Pulmonary Arterial Hypertension

Intervention

Drug:
• Sotatercept
Sotatercept 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.

Other:
• Placebo
Placebo

Locations

Country	Name	City	State
Australia	St Vincent's Hospital Sydney ( Site 1102)	Darlinghurst	New South Wales
Australia	John Hunter Hospital ( Site 1101)	New Lambton Heights	New South Wales
Belgium	Hôpital Erasme ( Site 1402)	Anderlecht	Bruxelles-Capitale, Region De
Belgium	UZ Leuven Campus Gasthuisberg ( Site 1401)	Leuven	Vlaams-Brabant
Canada	Peter Lougheed Centre ( Site 2102)	Calgary	Alberta
Canada	Jewish General Hospital ( Site 2103)	Montréal	Quebec
France	Hôpital Louis Pradel ( Site 1317)	Bron	Rhone
France	CHU Bicêtre ( Site 1304)	Le Kremlin-Bicêtre	Val-de-Marne
France	CHRU Lille ( Site 1306)	Lille	Nord
France	CHU de Poitiers ( Site 1316)	Poitiers	Vienne
France	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
Germany	Universitätsklinikum Carl Gustav Carus an der TU Dresden. ( Site 1501)	Dresden	Sachsen
Germany	Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)	Giessen	Hessen
Germany	Medizinische Hochschule Hannover ( Site 1505)	Hannover	Niedersachsen
Germany	Thoraxklinik-Heidelberg gGmbH ( Site 1509)	Heidelberg	Baden-Wurttemberg
Germany	Universitätsklinikum des Saarlandes ( Site 1513)	Homburg	Saarland
Germany	Uniklinik Köln ( Site 1511)	Koln	Nordrhein-Westfalen
Germany	Krankenhaus Neuwittelsbach ( Site 1510)	München	Bayern
Israel	Lady Davis Carmel Medical Center ( Site 1705)	Haifa
Italy	Ospedale S. Giuseppe Multimedica ( Site 2403)	Milan	Lombardia
Italy	La Sapienza-Università di Roma-Policlinico Umberto I ( Site 2402)	Roma
Mexico	Instituto Nacional De Cardiologia Dr. Ignacio Chavez ( Site 2503)	Ciudad de Mexico	Distrito Federal
Mexico	Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 2504)	Monterrey	Nuevo Leon
Mexico	Unidad de Investigación Clínica en Medicina, S.C ( Site 2505)	Monterrey	Nuevo Leon
Netherlands	VU Medisch Centrum ( Site 2601)	Amsterdam	Noord-Holland
Spain	Hospital Universitario 12 de Octubre ( Site 1603)	Madrid
United Kingdom	Royal Papworth Hospital ( Site 1208)	Cambridge	Cambridgeshire
United Kingdom	Imperial College Healthcare NHS Trust ( Site 1203)	London	London, City Of
United Kingdom	Royal Brompton Hospital ( Site 1206)	London	London, City Of
United States	University of New Mexico Health Sciences Center ( Site 1048)	Albuquerque	New Mexico
United States	University of Michigan ( Site 1011)	Ann Arbor	Michigan
United States	Northside Hospital ( Site 1073)	Atlanta	Georgia
United States	University of Colorado Hospital ( Site 1013)	Aurora	Colorado
United States	Brigham and Women's Hospital ( Site 1014)	Boston	Massachusetts
United States	Tufts Medical Center - PPDS ( Site 1012)	Boston	Massachusetts
United States	Medical University of South Carolina - PPDS ( Site 1003)	Charleston	South Carolina
United States	University of Cincinnati Medical Center ( Site 1035)	Cincinnati	Ohio
United States	The Cleveland Clinic Foundation. ( Site 1065)	Cleveland	Ohio
United States	University Of Texas Southwestern Medical Center ( Site 1038)	Dallas	Texas
United States	Duke University Medical Center ( Site 1026)	Durham	North Carolina
United States	University Of Iowa Hospitals and Clinics ( Site 1050)	Iowa City	Iowa
United States	Mayo Clinic Jacksonville - PPDS ( Site 1045)	Jacksonville	Florida
United States	University of Kansas Medical Center ( Site 1020)	Kansas City	Kansas
United States	Statcare Pulmonary Consultants - Knoxville ( Site 1031)	Knoxville	Tennessee
United States	David Geffen School of Medicine at UCLA ( Site 1068)	Los Angeles	California
United States	Medical College of Wisconsin - Froedtert Hospital ( Site 1051)	Milwaukee	Wisconsin
United States	University of Nebraska Medical Center ( Site 1053)	Omaha	Nebraska
United States	University of California Irvine ( Site 1086)	Orange	California
United States	AdventHealth Medical Group Advanced Lung Disease ( Site 1058)	Orlando	Florida
United States	Arizona Pulmonary Specialists ( Site 1010)	Phoenix	Arizona
United States	University of Rochester Medical Center - PPDS ( Site 1039)	Rochester	New York
United States	Washington University School of Medicine ( Site 1022)	Saint Louis	Missouri
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	The George Washington University Medical Faculty Associates ( Site 1025)	Washington	District of Columbia

Sponsors (1)

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

Countries where clinical trial is conducted

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

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to First Confirmed Morbidity or Mortality Event	Events are defined as all-cause death, lung transplantation, or PAH worsening-related hospitalization of = 24 hours. All events will be adjudicated by a blinded, independent committee of clinical experts.	Up to approximately 43 months
Secondary	Overall survival (OS)	OS is defined as the time from randomization to death due to any cause.	Up to approximately 43 months
Secondary	Transplant-Free Survival	Transplant-free survival is defined as the time from randomization to the first lung transplantation or death due to any cause.	Up to approximately 43 months
Secondary	Percentage of Participants Who Experienced a Mortality Event	Mortality event is defined as death due to any cause throughout the study.	Up to approximately 43 months
Secondary	Change From Baseline in REVEAL Lite 2 Risk Score at Week 24	The REVEAL Lite 2 uses renal insufficiency (by estimated glomerular filtration rate (eGFR)), World Health Organization (WHO) functional class (FC), systolic blood pressure (SBP) and heart rate, 6-Minute Walk Distance (6-MWD), and N-terminal prohormone B-type natriuretic peptide (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.	Baseline and Week 24
Secondary	Percentage of Participants Achieving a Low or Intermediate (=7) REVEAL Lite 2 Risk Score at Week 24	The REVEAL Lite 2 uses renal insufficiency (eGFR), WHO FC, SBP and heart rate, 6-MWD, 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.	Week 24
Secondary	Change From Baseline in NT-proBNP levels at Week 24	Blood samples will be collected at baseline and at Week 24 to measure NT-proBNP levels.	Baseline and Week 24
Secondary	Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24	mPAP was measured by right heart catheterization (RHC) at baseline and at Week 24. mPAP is a hemodynamic parameter used to diagnose PAH.	Baseline and Week 24
Secondary	Change From Baseline in Pulmonary Vascular Resistance (PVR)	PVR is a hemodynamic variable measured by RHC at baseline and at Week 24.	Baseline and Week 24
Secondary	Percentage of Participants Who Improve in WHO FC	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.	Up to approximately 43 months
Secondary	Change From Baseline in 6-MWD at Week 24	6-MWD is a measure of exercise capacity.	Baseline and Week 24
Secondary	Change From Baseline in Cardiac Output (CO) at Week 24	CO is the volume of blood pumped by the heart per minute.	Baseline and Week 24
Secondary	Change From Baseline in EuroQoL-5 Dimensions Scale 5 Levels (EQ-5D-5L) Index Score at Week 24	EQ-5D-5L measures health outcome. It consists of of descriptive system and EQ visual analogue scale (EQ-VAS). EQ-5D-5L system has 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension is divided into 5 levels of perceived problems (Level 1-no problem, Level 2-slight problems, Level 3-moderate problems, Level 4-severe problems, Level 5-extreme problems). Participant selects answer for each of 5 dimensions considering response that best matches his/her health "today". Responses will be used to generate an index score.	Baseline and Week 24

External Links

•   Merck Clinical Trial Information