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

• ClinicalTrials.gov Identifier: NCT04896008
• Recruitment Status: Recruiting
• First Posted: May 21, 2021
• Last Update Posted: June 13, 2022
• Sponsor: Acceleron Pharma Inc.
• Information provided by (Responsible Party): Acceleron Pharma Inc.

Tracking Information

• First Submitted Date: May 13, 2021
• First Posted Date: May 21, 2021
• Last Update Posted Date: June 13, 2022
• Actual Study Start Date: October 13, 2021
• Estimated Primary Completion Date: November 30, 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 17, 2021)

Time to first confirmed morbidity or mortality event. [ Time Frame: From randomization to first event, 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.

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: May 17, 2021)

• Overall survival [ Time Frame: Through study completion, estimated up to 46 months ]
  Time from randomization to death from any cause.
• Transplant-free survival. [ Time Frame: Through study completion, estimated up to 46 months ]
  Time from randomization to lung transplantation or death from any cause.
• Proportion of participants who experienced a mortality event. [ Time Frame: Through study completion, estimated up to 46 months ]
  Death from any cause is tracked throughout the study.
• Change from baseline in REVEAL Lite 2 risk score. [ Time Frame: From screening to Week 24. ]
  REVEAL Lite 2 risk score in each participant was measured at Week 24 versus baseline.
• Proportion of participants achieving a low or intermediate (≤ 7) REVEAL Lite 2 risk score at Week 24. [ Time Frame: From screening to Week 24. ]
  REVEAL Lite 2 risk score in each participant was measured at Week 24.
• Change from baseline in NT-proBNP levels. [ Time Frame: From screening to Week 24. ]
  NT-proBNP was measured at baseline and Week 24.
• Change from baseline in mean pulmonary artery pressure (mPAP) at Week 24. [ Time Frame: From screening to Week 24. ]
  mPAP was measured by right heart catheterization (RHC) during screening and Week 24.
• Change from baseline in pulmonary vascular resistance (PVR). [ Time Frame: From screening to Week 24. ]
  PVR is a hemodynamic variable measured by RHC during screening and Week 24.
• Proportion of participants who improve in WHO FC. [ Time Frame: From randomization to the end of the double-blind, placebo-controlled (DBPC) treatment period (EOT). ]
  The severity of an individual's PAH symptoms was graded using the WHO FC system at baseline and at the end of treatment (EOT).
• Change from baseline in 6MWD. [ Time Frame: From randomization to Week 24. ]
  6-minute walk test is a clinical exercise test to assess the functional capacity. 6MWD at baseline and Week 24 were measured.
• Change from baseline in cardiac output (CO) at Week 24. [ Time Frame: From screening to Week 24. ]
  CO is a component of the PVR calculation, and reduced CO reflects increased risk of morbidity and mortality.
• Change from baseline in EuroQoL-5 dimensions scale 5 levels (EQ-5D-5L) index score at Week 24. [ Time Frame: From randomization to Week 24. ]
  EQ 5D 5L index score measures health-related quality of life states in adults. The EQ 5D 5L questionnaire is designed for self-completion and captures information directly from the respondent. EQ 5D 5L index scores at baseline and Week 24 were measured.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Sotatercept in Participants With PAH WHO FC III or FC IV at High Risk of Mortality
• 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
• Brief Summary: The objective of this study is to evaluate the effects of sotatercept treatment (plus maximum tolerated background 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 WHO FC III or FC IV PAH at high risk of mortality.

Detailed Description

Study A011-14 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 ≥ 10 and be on maximum tolerated combination background PAH therapy.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
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 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 (Participant, Care Provider, Investigator)
Primary Purpose: Treatment

• Condition: Pulmonary Arterial Hypertension

Intervention

• Drug: Sotatercept
  Sotatercept (ACE-011) 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 Name: ACE-011
• Other: Placebo
  Placebo

Study Arms

• Placebo Comparator: Placebo plus background PAH therapy
  Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy
  Intervention: Other: Placebo
• 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
  Intervention: Drug: Sotatercept

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: May 17, 2021): 166
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 31, 2026
• Estimated Primary Completion Date: November 30, 2025 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

Eligible participants must meet all of the following inclusion criteria to be enrolled in the study:

1. Age 18 to 75 years, inclusive

2. Documented diagnostic right heart catheterization prior to screening confirming the diagnosis of WHO PAH Group 1 in any of the following subtypes:

   • Idiopathic PAH
   • Heritable PAH
   • Drug/toxin-induced PAH
   • PAH associated with CTD
   • PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
3. Symptomatic PAH classified as WHO FC III or IV
4. REVEAL Lite 2 risk score of ≥ 10
5. Right heart catheterization performed during screening (or within 2 weeks prior to screening, if done at the clinical study site) documenting a minimum PVR of ≥ 5 Wood units and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤ 15 mmHg
6. 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

7. 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, have used, and agree to use highly effective contraception without interruption; 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

8. 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
9. Ability to adhere to study visit schedule and understand and comply with all protocol requirements
10. Ability to understand and provide written informed consent

Exclusion Criteria:

1. Diagnosis of PAH WHO Groups 2, 3, 4, or 5
2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus-associated PAH and PAH associated with portal hypertension
3. Diagnosis of pulmonary veno-occlusive diseases or pulmonary capillary hemangiomatosis or overt signs of capillary and/or venous involvement
4. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
5. Baseline platelet count < 50,000/mm3 (< 50.0 x 109/L) at screening
6. Baseline systolic blood pressure < 85 mmHg at screening
7. Pregnant or breastfeeding women

8. Any of the following clinical laboratory values at the Screening Visit:

   • Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease Study equation)
   • Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 2.0 × ULN
9. 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
10. Prior exposure to or known allergic reaction to sotatercept (ACE 011) or luspatercept (ACE-536)
11. History of pneumonectomy
12. Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
13. Untreated obstructive sleep apnea
14. History of known pericardial constriction
15. History of restrictive or congestive cardiomyopathy
16. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 450 ms (or > 500 ms if right bundle branch block is present) during the Screening Period
17. Personal or family history of long QT syndrome or sudden cardiac death
18. Left ventricular ejection fraction < 50% on historical echocardiogram within 1 year prior to the Screening Visit
19. 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
20. Cerebrovascular accident within 3 months prior to the Screening Visit
21. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Australia, Belgium, France, Germany, Italy, Mexico, Netherlands, Spain, United States

Administrative Information

• NCT Number: NCT04896008
• Other Study ID Numbers: 7962-006; A011-14 ( Other Identifier: Acceleronpharma ); 2020-005061-13 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Current Responsible Party: Acceleron Pharma Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Acceleron Pharma Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Acceleron Pharma Inc.
• Verification Date: June 2022