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 (ZENITH)

  • STATUS
    Recruiting
  • End date
    Dec 31, 2026
  • participants needed
    200
  • sponsor
    Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
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Updated on 22 October 2022
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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.

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 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), drugor 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.

Details
Condition Pulmonary Arterial Hypertension
Treatment Placebo, Sotatercept
Clinical Study IdentifierNCT04896008
SponsorAcceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Last Modified on22 October 2022

Eligibility

 Yes No Not Sure

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
PAH associated with connective tissue diseases (CTD)
Heritable PAH
PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
Drug/toxin-induced PAH
Symptomatic PAH classified as WHO functional class (FC) III or IV
Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 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
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
Females of childbearing potential must
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
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
Male participants must
Ability to understand and provide written informed consent
Ability to adhere to study visit schedule and understand and comply with all protocol
requirements

Exclusion Criteria

Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
Diagnosis of PAH WHO Groups 2, 3, 4, or 5
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
Serum alanine aminotransferase or aspartate aminotransferase levels or total bilirubin >3.0×ULN
Pregnant or breastfeeding women
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
Untreated more than mild obstructive sleep apnea
History of pneumonectomy
Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) >500 ms during the screening period
Left ventricular ejection fraction <45% on historical echocardiogram within 1 year prior to the screening visit
History of known pericardial constriction
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
History of restrictive or congestive cardiomyopathy
Cerebrovascular accident within 3 months prior to the screening visit
Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
Personal or family history of long QT syndrome or sudden cardiac death
Currently on dialysis or anticipated need for dialysis within the next 12 months
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