Trial Review

Registering a new trial?

To achieve prospective registration, we recommend submitting your trial for registration at the same time as ethics submission.

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04896008




Registration number
NCT04896008
Ethics application status
Date submitted
13/05/2021
Date registered
21/05/2021
Date last updated
22/03/2024

Titles & IDs
Public title
A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH)
Scientific 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
Secondary ID [1] 0 0
A011-14
Secondary ID [2] 0 0
7962-006
Universal Trial Number (UTN)
Trial acronym
ZENITH
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary Arterial Hypertension 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Human Genetics and Inherited Disorders 0 0 0 0
Other human genetics and inherited disorders
Cardiovascular 0 0 0 0
Hypertension

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Sotatercept
Other interventions - Placebo

Placebo comparator: Placebo plus background PAH therapy - Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy

Experimental: Sotatercept plus background PAH therapy - 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


Treatment: Drugs: 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 interventions: Placebo
Placebo
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Time to First Confirmed Morbidity or Mortality Event
Timepoint [1] 0 0
Up to approximately 43 months
Secondary outcome [1] 0 0
Overall survival (OS)
Timepoint [1] 0 0
Up to approximately 43 months
Secondary outcome [2] 0 0
Transplant-Free Survival
Timepoint [2] 0 0
Up to approximately 43 months
Secondary outcome [3] 0 0
Percentage of Participants Who Experienced a Mortality Event
Timepoint [3] 0 0
Up to approximately 43 months
Secondary outcome [4] 0 0
Change From Baseline in REVEAL Lite 2 Risk Score at Week 24
Timepoint [4] 0 0
Baseline and Week 24
Secondary outcome [5] 0 0
Percentage of Participants Achieving a Low or Intermediate (=7) REVEAL Lite 2 Risk Score at Week 24
Timepoint [5] 0 0
Week 24
Secondary outcome [6] 0 0
Change From Baseline in NT-proBNP levels at Week 24
Timepoint [6] 0 0
Baseline and Week 24
Secondary outcome [7] 0 0
Change From Baseline in Mean Pulmonary Artery Pressure (mPAP) at Week 24
Timepoint [7] 0 0
Baseline and Week 24
Secondary outcome [8] 0 0
Change From Baseline in Pulmonary Vascular Resistance (PVR)
Timepoint [8] 0 0
Baseline and Week 24
Secondary outcome [9] 0 0
Percentage of Participants Who Improve in WHO FC
Timepoint [9] 0 0
Up to approximately 43 months
Secondary outcome [10] 0 0
Change From Baseline in 6-MWD at Week 24
Timepoint [10] 0 0
Baseline and Week 24
Secondary outcome [11] 0 0
Change From Baseline in Cardiac Output (CO) at Week 24
Timepoint [11] 0 0
Baseline and Week 24
Secondary outcome [12] 0 0
Change From Baseline in EuroQoL-5 Dimensions Scale 5 Levels (EQ-5D-5L) Index Score at Week 24
Timepoint [12] 0 0
Baseline and Week 24

Eligibility
Key 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
Minimum age
18 Years
Maximum age
75 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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 design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s

The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
1/12/2021
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
28/11/2025
Actual
Sample size
Target
166
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
St Vincent's Hospital Sydney ( Site 1102) - Darlinghurst
Recruitment hospital [2] 0 0
John Hunter Hospital ( Site 1101) - New Lambton Heights
Recruitment postcode(s) [1] 0 0
2010 - Darlinghurst
Recruitment postcode(s) [2] 0 0
2305 - New Lambton Heights
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Arizona
Country [2] 0 0
United States of America
State/province [2] 0 0
California
Country [3] 0 0
United States of America
State/province [3] 0 0
Colorado
Country [4] 0 0
United States of America
State/province [4] 0 0
District of Columbia
Country [5] 0 0
United States of America
State/province [5] 0 0
Florida
Country [6] 0 0
United States of America
State/province [6] 0 0
Georgia
Country [7] 0 0
United States of America
State/province [7] 0 0
Iowa
Country [8] 0 0
United States of America
State/province [8] 0 0
Kansas
Country [9] 0 0
United States of America
State/province [9] 0 0
Massachusetts
Country [10] 0 0
United States of America
State/province [10] 0 0
Michigan
Country [11] 0 0
United States of America
State/province [11] 0 0
Missouri
Country [12] 0 0
United States of America
State/province [12] 0 0
Nebraska
Country [13] 0 0
United States of America
State/province [13] 0 0
New Mexico
Country [14] 0 0
United States of America
State/province [14] 0 0
New York
Country [15] 0 0
United States of America
State/province [15] 0 0
North Carolina
Country [16] 0 0
United States of America
State/province [16] 0 0
Ohio
Country [17] 0 0
United States of America
State/province [17] 0 0
South Carolina
Country [18] 0 0
United States of America
State/province [18] 0 0
Tennessee
Country [19] 0 0
United States of America
State/province [19] 0 0
Texas
Country [20] 0 0
United States of America
State/province [20] 0 0
Wisconsin
Country [21] 0 0
Belgium
State/province [21] 0 0
Bruxelles-Capitale, Region De
Country [22] 0 0
Belgium
State/province [22] 0 0
Vlaams-Brabant
Country [23] 0 0
Canada
State/province [23] 0 0
Alberta
Country [24] 0 0
Canada
State/province [24] 0 0
Quebec
Country [25] 0 0
France
State/province [25] 0 0
Bas-Rhin
Country [26] 0 0
France
State/province [26] 0 0
Haute-Garonne
Country [27] 0 0
France
State/province [27] 0 0
Meurthe-et-Moselle
Country [28] 0 0
France
State/province [28] 0 0
Nord
Country [29] 0 0
France
State/province [29] 0 0
Rhone
Country [30] 0 0
France
State/province [30] 0 0
Val-de-Marne
Country [31] 0 0
France
State/province [31] 0 0
Vienne
Country [32] 0 0
Germany
State/province [32] 0 0
Baden-Wurttemberg
Country [33] 0 0
Germany
State/province [33] 0 0
Bayern
Country [34] 0 0
Germany
State/province [34] 0 0
Hessen
Country [35] 0 0
Germany
State/province [35] 0 0
Niedersachsen
Country [36] 0 0
Germany
State/province [36] 0 0
Nordrhein-Westfalen
Country [37] 0 0
Germany
State/province [37] 0 0
Saarland
Country [38] 0 0
Germany
State/province [38] 0 0
Sachsen
Country [39] 0 0
Israel
State/province [39] 0 0
Haifa
Country [40] 0 0
Italy
State/province [40] 0 0
Lombardia
Country [41] 0 0
Italy
State/province [41] 0 0
Roma
Country [42] 0 0
Mexico
State/province [42] 0 0
Distrito Federal
Country [43] 0 0
Mexico
State/province [43] 0 0
Nuevo Leon
Country [44] 0 0
Netherlands
State/province [44] 0 0
Noord-Holland
Country [45] 0 0
Spain
State/province [45] 0 0
Madrid
Country [46] 0 0
United Kingdom
State/province [46] 0 0
Cambridgeshire
Country [47] 0 0
United Kingdom
State/province [47] 0 0
London, City Of

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/study/NCT04896008
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04896008