A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH)
- Conditions
- Pulmonary Arterial Hypertension
- Interventions
- Other: Placebo
- Registration Number
- NCT04896008
- Lead Sponsor
- Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
- 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 risk score of ≥9 and be on maximum tolerated combination background PAH therapy.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 173
-
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
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo plus background PAH therapy Placebo Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy Sotatercept plus background PAH therapy Sotatercept Sotatercept at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, SC every 21 days plus background PAH therapy
- Primary Outcome Measures
Name Time Method Time to First Confirmed Morbidity or Mortality Event Up to approximately 31 months 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.
- Secondary Outcome Measures
Name Time Method Overall survival (OS) Up to approximately 31 months OS is defined as the time from randomization to death due to any cause.
Transplant-Free Survival Up to approximately 31 months Transplant-free survival is defined as the time from randomization to the first lung transplantation or death due to any cause.
Percentage of Participants Who Experienced a Mortality Event Up to approximately 31 months Mortality event is defined as death due to any cause throughout the study.
Change From Baseline in REVEAL Lite 2 Risk Score at Week 24 Baseline and 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.
Percentage of Participants Achieving a Low or Intermediate (≤7) REVEAL Lite 2 Risk Score at Week 24 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.
Change From Baseline in NT-proBNP levels at Week 24 Baseline and Week 24 Blood samples will be collected at baseline and at Week 24 to measure NT-proBNP levels.
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24 Baseline and 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.
Change From Baseline in Pulmonary Vascular Resistance (PVR) Baseline and Week 24 PVR is a hemodynamic variable measured by RHC at baseline and at Week 24.
Percentage of Participants Who Improve in WHO FC Up to approximately 31 months 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.
Change From Baseline in 6-MWD at Week 24 Baseline and Week 24 6-MWD is a measure of exercise capacity.
Change From Baseline in Cardiac Output (CO) at Week 24 Baseline and Week 24 CO is the volume of blood pumped by the heart per minute.
Change From Baseline in EuroQoL-5 Dimensions Scale 5 Levels (EQ-5D-5L) Index Score at Week 24 Baseline and 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.
Trial Locations
- Locations (57)
Uniklinik Köln ( Site 1511)
🇩🇪Koln, Nordrhein-Westfalen, Germany
Thoraxklinik-Heidelberg gGmbH ( Site 1509)
🇩🇪Heidelberg, Baden-Wurttemberg, Germany
Hôpital Louis Pradel ( Site 1317)
🇫🇷Bron, Rhone, France
Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)
🇩🇪Giessen, Hessen, Germany
Medizinische Hochschule Hannover ( Site 1505)
🇩🇪Hannover, Niedersachsen, Germany
Krankenhaus Neuwittelsbach ( Site 1510)
🇩🇪München, Bayern, Germany
CHU de Nancy - Hôpital de Brabois Adultes ( Site 1308)
🇫🇷Vandœuvre-lès-Nancy, Meurthe-et-Moselle, France
La Sapienza-Università di Roma-Policlinico Umberto I ( Site 2402)
🇮🇹Roma, Italy
Universitätsklinikum Carl Gustav Carus an der TU Dresden. ( Site 1501)
🇩🇪Dresden, Sachsen, Germany
University of Rochester Medical Center - PPDS ( Site 1039)
🇺🇸Rochester, New York, United States
Lady Davis Carmel Medical Center ( Site 1705)
🇮🇱Haifa, Israel
Statcare Pulmonary Consultants - Knoxville ( Site 1031)
🇺🇸Knoxville, Tennessee, United States
St Vincent's Hospital Sydney ( Site 1102)
🇦🇺Darlinghurst, New South Wales, Australia
University Of Texas Southwestern Medical Center ( Site 1038)
🇺🇸Dallas, Texas, United States
University of California Irvine ( Site 1086)
🇺🇸Orange, California, United States
University of New Mexico Health Sciences Center ( Site 1048)
🇺🇸Albuquerque, New Mexico, United States
Instituto Nacional De Cardiologia Dr. Ignacio Chavez ( Site 2503)
🇲🇽Ciudad de Mexico, Distrito Federal, Mexico
Royal Brompton Hospital ( Site 1206)
🇬🇧London, London, City Of, United Kingdom
David Geffen School of Medicine at UCLA ( Site 1068)
🇺🇸Los Angeles, California, United States
Mayo Clinic Jacksonville - PPDS ( Site 1045)
🇺🇸Jacksonville, Florida, United States
Northside Hospital ( Site 1073)
🇺🇸Atlanta, Georgia, United States
University Of Iowa Hospitals and Clinics ( Site 1050)
🇺🇸Iowa City, Iowa, United States
Washington University School of Medicine ( Site 1022)
🇺🇸Saint Louis, Missouri, United States
Medical University of South Carolina - PPDS ( Site 1003)
🇺🇸Charleston, South Carolina, United States
John Hunter Hospital ( Site 1101)
🇦🇺New Lambton Heights, New South Wales, Australia
Jewish General Hospital ( Site 2103)
🇨🇦Montréal, Quebec, Canada
Hospital Universitario 12 de Octubre ( Site 1603)
🇪🇸Madrid, Spain
University of California San Diego Medical Center ( Site 1002)
🇺🇸San Diego, California, United States
University of Cincinnati Medical Center ( Site 1035)
🇺🇸Cincinnati, Ohio, United States
The Cleveland Clinic Foundation. ( Site 1065)
🇺🇸Cleveland, Ohio, United States
Duke University Medical Center ( Site 1026)
🇺🇸Durham, North Carolina, United States
University of Kansas Medical Center ( Site 1020)
🇺🇸Kansas City, Kansas, United States
Universitätsklinikum des Saarlandes ( Site 1513)
🇩🇪Homburg, Saarland, Germany
Ospedale S. Giuseppe Multimedica ( Site 2403)
🇮🇹Milan, Lombardia, Italy
Hôpital Erasme ( Site 1402)
🇧🇪Anderlecht, Bruxelles-Capitale, Region De, Belgium
Centre Hospitalier Universitaire de Toulouse. ( Site 1315)
🇫🇷Toulouse, Haute-Garonne, France
Brigham and Women's Hospital ( Site 1014)
🇺🇸Boston, Massachusetts, United States
Hôpitaux Universitaires de Strasbourg ( Site 1307)
🇫🇷Strasbourg, Bas-Rhin, France
Tufts Medical Center - PPDS ( Site 1012)
🇺🇸Boston, Massachusetts, United States
UZ Leuven Campus Gasthuisberg ( Site 1401)
🇧🇪Leuven, Vlaams-Brabant, Belgium
Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 2504)
🇲🇽Monterrey, Nuevo Leon, Mexico
VU Medisch Centrum ( Site 2601)
🇳🇱Amsterdam, Noord-Holland, Netherlands
Peter Lougheed Centre ( Site 2102)
🇨🇦Calgary, Alberta, Canada
CHU de Poitiers ( Site 1316)
🇫🇷Poitiers, Vienne, France
Unidad de Investigación Clínica en Medicina, S.C ( Site 2505)
🇲🇽Monterrey, Nuevo Leon, Mexico
The George Washington University Medical Faculty Associates ( Site 1025)
🇺🇸Washington, District of Columbia, United States
Royal Papworth Hospital ( Site 1208)
🇬🇧Cambridge, Cambridgeshire, United Kingdom
CHRU Lille ( Site 1306)
🇫🇷Lille, Nord, France
CHU Bicêtre ( Site 1304)
🇫🇷Le Kremlin-Bicêtre, Val-de-Marne, France
Imperial College Healthcare NHS Trust ( Site 1203)
🇬🇧London, London, City Of, United Kingdom
Arizona Pulmonary Specialists ( Site 1010)
🇺🇸Phoenix, Arizona, United States
University of California San Francisco ( Site 1019)
🇺🇸San Francisco, California, United States
University of Nebraska Medical Center ( Site 1053)
🇺🇸Omaha, Nebraska, United States
Medical College of Wisconsin - Froedtert Hospital ( Site 1051)
🇺🇸Milwaukee, Wisconsin, 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 Michigan ( Site 1011)
🇺🇸Ann Arbor, Michigan, United States