Clinical trial NCT04896008: A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Pulmonary Arterial Hypertension
Keywords: Pulmonary, hypertension, sotatercept
Lead sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Sponsor class: INDUSTRY
First posted: 2021-05-21
Enrollment: 173
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Each eligible participant will be randomized in a 1:1 ratio to 1 of the following 2 treatment arms during the double-blind placebo-controlled (DBPC) Treatment Period:

* Arm 1: Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy
* Arm 2: 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 purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to First Confirmed Morbidity or Mortality Event
timeFrame: Up to approximately 31 months
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: Up to approximately 31 months
measure: Transplant-Free Survival
timeFrame: Up to approximately 31 months
measure: Percentage of Participants Who Experienced a Mortality Event
timeFrame: Up to approximately 31 months
measure: Change From Baseline in REVEAL Lite 2 Risk Score at Week 24
timeFrame: Baseline and Week 24
measure: Percentage of Participants Achieving a Low or Intermediate (≤7) REVEAL Lite 2 Risk Score at Week 24
timeFrame: Week 24
measure: Change From Baseline in NT-proBNP levels at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Pulmonary Vascular Resistance (PVR)
timeFrame: Baseline and Week 24
measure: Percentage of Participants Who Improve in WHO FC
timeFrame: Up to approximately 31 months
measure: Change From Baseline in 6-MWD at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in Cardiac Output (CO) at Week 24
timeFrame: Baseline and Week 24
measure: Change From Baseline in EuroQoL-5 Dimensions Scale 5 Levels (EQ-5D-5L) Index Score at Week 24
timeFrame: Baseline and Week 24
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Arizona Pulmonary Specialists ( Site 1010)
state: Arizona
city: Los Angeles
country: United States
facility: David Geffen School of Medicine at UCLA ( Site 1068)
state: California
city: Orange
country: United States
facility: University of California Irvine ( Site 1086)
state: California
city: San Diego
country: United States
facility: University of California San Diego Medical Center ( Site 1002)
state: California
city: San Francisco
country: United States
facility: University of California San Francisco ( Site 1019)
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital ( Site 1013)
state: Colorado
city: Washington
country: United States
facility: The George Washington University Medical Faculty Associates ( Site 1025)
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic Jacksonville - PPDS ( Site 1045)
state: Florida
city: Orlando
country: United States
facility: AdventHealth Medical Group Advanced Lung Disease ( Site 1058)
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital ( Site 1073)
state: Georgia
city: Iowa City
country: United States
facility: University Of Iowa Hospitals and Clinics ( Site 1050)
state: Iowa
city: Kansas City
country: United States
facility: University of Kansas Medical Center ( Site 1020)
state: Kansas
city: Boston
country: United States
facility: Tufts Medical Center - PPDS ( Site 1012)
state: Massachusetts
city: Boston
country: United States
facility: Brigham and Women's Hospital ( Site 1014)
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan ( Site 1011)
state: Michigan
city: Saint Louis
country: United States
facility: Washington University School of Medicine ( Site 1022)
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center ( Site 1053)
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico Health Sciences Center ( Site 1048)
state: New Mexico
city: Rochester
country: United States
facility: University of Rochester Medical Center - PPDS ( Site 1039)
state: New York
city: Durham
country: United States
facility: Duke University Medical Center ( Site 1026)
state: North Carolina
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center ( Site 1035)
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation. ( Site 1065)
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina - PPDS ( Site 1003)
state: South Carolina
city: Knoxville
country: United States
facility: Statcare Pulmonary Consultants - Knoxville ( Site 1031)
state: Tennessee
city: Dallas
country: United States
facility: University Of Texas Southwestern Medical Center ( Site 1038)
state: Texas
city: Milwaukee
country: United States
facility: Medical College of Wisconsin - Froedtert Hospital ( Site 1051)
state: Wisconsin
city: Darlinghurst
country: Australia
facility: St Vincent's Hospital Sydney ( Site 1102)
state: New South Wales
city: New Lambton Heights
country: Australia
facility: John Hunter Hospital ( Site 1101)
state: New South Wales
city: Anderlecht
country: Belgium
facility: Hôpital Erasme ( Site 1402)
state: Bruxelles-Capitale, Region De
city: Leuven
country: Belgium
facility: UZ Leuven Campus Gasthuisberg ( Site 1401)
state: Vlaams-Brabant
city: Calgary
country: Canada
facility: Peter Lougheed Centre ( Site 2102)
state: Alberta
city: Montréal
country: Canada
facility: Jewish General Hospital ( Site 2103)
state: Quebec
city: Strasbourg
country: France
facility: Hôpitaux Universitaires de Strasbourg ( Site 1307)
state: Bas-Rhin
city: Toulouse
country: France
facility: Centre Hospitalier Universitaire de Toulouse. ( Site 1315)
state: Haute-Garonne
city: Vandœuvre-lès-Nancy
country: France
facility: CHU de Nancy - Hôpital de Brabois Adultes ( Site 1308)
state: Meurthe-et-Moselle
city: Lille
country: France
facility: CHRU Lille ( Site 1306)
state: Nord
city: Bron
country: France
facility: Hôpital Louis Pradel ( Site 1317)
state: Rhone
city: Le Kremlin-Bicêtre
country: France
facility: CHU Bicêtre ( Site 1304)
state: Val-de-Marne
city: Poitiers
country: France
facility: CHU de Poitiers ( Site 1316)
state: Vienne
city: Heidelberg
country: Germany
facility: Thoraxklinik-Heidelberg gGmbH ( Site 1509)
state: Baden-Wurttemberg
city: München
country: Germany
facility: Krankenhaus Neuwittelsbach ( Site 1510)
state: Bayern
city: Giessen
country: Germany
facility: Universitaetsklinikum Giessen und Marburg GmbH ( Site 1512)
state: Hessen
city: Hannover
country: Germany
facility: Medizinische Hochschule Hannover ( Site 1505)
state: Niedersachsen
city: Koln
country: Germany
facility: Uniklinik Köln ( Site 1511)
state: Nordrhein-Westfalen
city: Homburg
country: Germany
facility: Universitätsklinikum des Saarlandes ( Site 1513)
state: Saarland
city: Dresden
country: Germany
facility: Universitätsklinikum Carl Gustav Carus an der TU Dresden. ( Site 1501)
state: Sachsen
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Center ( Site 1705)
city: Milan
country: Italy
facility: Ospedale S. Giuseppe Multimedica ( Site 2403)
state: Lombardia
city: Roma
country: Italy
facility: La Sapienza-Università di Roma-Policlinico Umberto I ( Site 2402)
city: Ciudad de Mexico
country: Mexico
facility: Instituto Nacional De Cardiologia Dr. Ignacio Chavez ( Site 2503)
state: Distrito Federal
city: Monterrey
country: Mexico
facility: Hospital Universitario "Dr. Jose Eleuterio Gonzalez" ( Site 2504)
state: Nuevo Leon
city: Monterrey
country: Mexico
facility: Unidad de Investigación Clínica en Medicina, S.C ( Site 2505)
state: Nuevo Leon
city: Amsterdam
country: Netherlands
facility: VU Medisch Centrum ( Site 2601)
state: Noord-Holland
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre ( Site 1603)
city: Cambridge
country: United Kingdom
facility: Royal Papworth Hospital ( Site 1208)
state: Cambridgeshire
city: London
country: United Kingdom
facility: Royal Brompton Hospital ( Site 1206)
state: London, City Of
city: London
country: United Kingdom
facility: Imperial College Healthcare NHS Trust ( Site 1203)
state: London, City Of
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: