A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality (MK-7962-006/ZENITH) (ZENITH)
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|ClinicalTrials.gov Identifier: NCT04896008|
Recruitment Status : Recruiting
First Posted : May 21, 2021
Last Update Posted : December 28, 2022
|Condition or disease||Intervention/treatment||Phase|
|Pulmonary Arterial Hypertension||Drug: Sotatercept Other: Placebo||Phase 3|
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 IV PAH or WHO FC III 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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||200 participants|
|Intervention Model:||Parallel Assignment|
|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:
|Masking:||Triple (Participant, Care Provider, Investigator)|
|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|
|Actual Study Start Date :||December 1, 2021|
|Estimated Primary Completion Date :||November 30, 2025|
|Estimated Study Completion Date :||December 31, 2026|
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
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.
- Time to First Confirmed Morbidity or Mortality Event [ Time Frame: Up to approximately 46 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.
- Overall survival (OS) [ Time Frame: Up to approximately 46 months ]OS is defined as the time from randomization to death due to any cause.
- Transplant-Free Survival [ Time Frame: Up to approximately 46 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 [ Time Frame: Up to approximately 46 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: Up to approximately 46 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 [ Time Frame: Baseline and Week 24 ]6-MWD is a measure of exercise capacity.
- Change From Baseline in Cardiac Output (CO) at Week 24 [ Time Frame: 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 [ Time Frame: 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.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04896008
|Contact: Toll Free Number||1-888-577-8839||Trialsites@merck.com|
|Study Director:||Medical Director||Merck Sharp & Dohme LLC|