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

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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Pulmonary Arterial Hypertension

Intervention / Treatment
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* Drug: Sotatercept
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional 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
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo plus background PAH therapy<br>Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy | Other: Placebo<br>* Placebo<br>|
| Experimental: Sotatercept plus background PAH therapy<br>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 | Drug: Sotatercept<br>* 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.<br>* Other names: ACE-011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | OS is defined as the time from randomization to death due to any cause. | Up to approximately 43 months | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Change From Baseline in 6-MWD at Week 24 | 6-MWD is a measure of exercise capacity. | Baseline and Week 24 | 
| 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 | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pulmonary, hypertension, sotatercept