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Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13) (HYPERION)

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ClinicalTrials.gov Identifier: NCT04811092
Recruitment Status : Recruiting
First Posted : March 23, 2021
Last Update Posted : November 21, 2022
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)

Brief Summary:
The objective of this study is to evaluate the effects of sotatercept (MK-7962, formerly called ACE-011) treatment (plus background pulmonary arterial hypertension (PAH) therapy) versus placebo (plus background PAH therapy) on time to clinical worsening (TTCW) in participants who are newly diagnosed with PAH and are at intermediate or high risk of disease progression.

Condition or disease Intervention/treatment Phase
Pulmonary Arterial Hypertension Drug: Sotatercept Other: Placebo Phase 3

Detailed Description:

This is a phase 3, randomized, double-blind, placebo-controlled study to evaluate sotatercept when added to background PAH therapy in newly diagnosed intermediate- or high risk PAH participants.

Participants enrolled in the study will have a diagnosis within 6 months of study screening of symptomatic PAH (World Health Organization (WHO) Group 1, classified as functional class (FC) II or III) and presentation of idiopathic or heritable PAH, PAH associated with connective tissue diseases (CTD), drug- or toxin- induced PAH, post shunt correction PAH, or PAH presenting at least 1 year following the correction of congenital heart defects.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 662 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description: Double-blind
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-blind, Placebo-controlled Study to Evaluate Sotatercept When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy in Newly Diagnosed Intermediate- and High-risk PAH Patients
Actual Study Start Date : March 18, 2022
Estimated Primary Completion Date : June 30, 2028
Estimated Study Completion Date : August 31, 2028


Arm Intervention/treatment
Placebo Comparator: Placebo plus background PAH therapy
Administered subcutaneously (SC) every 21 days plus background PAH therapy
Other: Placebo
Placebo

Experimental: Sotatercept plus background PAH therapy
Administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously (SC) every 21 days plus background PAH therapy
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 Names:
  • MK-7962
  • ACE-011




Primary Outcome Measures :
  1. Time to Clinical Worsening [ Time Frame: From time of randomization to the time of first clinical worsening event (Up to approximately 56 months) ]
    Time to clinical worsening is defined as time from randomization to the first confirmed morbidity event or death. Clinical worsening events are defined as all-cause death, non-planned PAH-related hospitalization of ≥ 24 hours in duration, atrial septostomy, lung transplant and deterioration in performance in 6-minute walk test from baseline combined with one of the following conditions: worsening of WHO functional class from baseline, signs/symptoms of increased right heart failure, addition of a background PAH therapy or change in the background PAH therapy delivery route to parenteral. All events will be adjudicated by a blinded, independent committee of clinical experts.


Secondary Outcome Measures :
  1. Percentage of Participants Achieving the Multicomponent Improvement Endpoint of 6-Minute Walk Distance (6MWD), N-terminal prohormone Btype natriuretic peptide (NT-ProBNP) and World Health Organization (WHO) Functional Class (FC) [ Time Frame: Baseline and Week 24 ]

    Multicomponent improvement endpoint measured by the percentage of participants achieving all of the following at Week 24 relative to baseline:

    • Improvement in 6MWD
    • Improvement or maintenance/achievement of NT-proBNP
    • Improvement in WHO FC or maintenance of WHO FC II

  2. Percentage of Participants who Achieved a Low Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 Risk Score [ Time Frame: Baseline and Week 24 ]
    The REVEAL Lite 2 uses renal insufficiency (by estimated glomerular filtration rate (eGFR)), WHO FC, systolic blood pressure (SBP) and heart rate, 6MWD, 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.

  3. Percentage of Participants who Maintain or Achieve a Low Simplified French Risk Score [ Time Frame: Baseline and Week 24 ]
    The simplified French Risk Score uses WHO FC, 6MWD, and NT-proBNP to determine the total risk score. A low risk score can be defined as attaining or maintaining all three low-risk criteria: WHO FC I or II, 6MWD > 440m, and NT-proBNP < 300 ng/L. The percentage of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator will be reported.

  4. Change from Baseline in NT-proBNP Levels [ Time Frame: Baseline and Week 24 ]
    Blood samples will be collected at baseline and at Week 24 to measure NT-proBNP blood concentration.

  5. Percentage of Participants who Improve in WHO FC or Maintain WHO FC II at 24 Weeks from Baseline [ Time Frame: Baseline and Week 24 ]
    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.

  6. Change from Baseline in 6MWD [ Time Frame: Baseline and Week 24 ]
    The 6MWD tests the distance walked in 6 minutes as a measure of functional capacity. Change from baseline in 6MWD at Week 24 will be reported.

  7. Change from Baseline in the Physical Impacts Domain Score of Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT)® [ Time Frame: Baseline and Week 24 ]
    PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported.

  8. Change from Baseline in the Cardiopulmonary Symptoms Domain Score of PAH-SYMPACT® [ Time Frame: Baseline and Week 24 ]
    PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported.

  9. Change from Baseline in the Cognitive/Emotional Impacts Domain Score of PAH-SYMPACT® [ Time Frame: Baseline and Week 24 ]
    PAH SYMPACT is a self-rating questionnaire to assess symptoms and their physical and cognitive/emotional impact. The PAH-SYMPACT® questionnaire consists of consists of 16 symptom and 25 impact items. A higher score indicates worse symptoms. Change from baseline in responses in PAH-SYMPACT questionnaire at Week 24 will be reported



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

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

  1. Age ≥ 18 years
  2. Documented diagnostic right heart catheterization (RHC) within 6 months of screening documenting a minimum PVR of ≥ 4 Wood units and pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure (LVEDP) of ≤ 15 mmHg, with the diagnosis of WHO PAH Group 1 in any of the following subtypes:

    • Idiopathic PAH
    • Heritable PAH
    • Drug/toxin-induced PAH
    • PAH associated with connective tissue disease
    • PAH associated with simple, congenital systemic to pulmonary shunts at least 1 year following repair
  3. Symptomatic PAH classified as WHO FC II or III
  4. REVEAL Lite 2 Risk Score ≥ 6
  5. Diagnosis of PAH within 12 months of screening and on stable doses of a double combination of background PAH therapies and diuretics for at least 90 days prior to screening
  6. Six-minute walk distance ≥ 150 m repeated twice at screening at least 4 hours apart, but no longer than 1 week apart, and both values are within 15% of each other (calculated from the highest value)
  7. Females of childbearing potential must meet the following criteria:

    • Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study drug administration; she 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 highly effective contraception without interruption, for at least 28 days prior to starting the investigational product AND agreed to use the same highly effective contraception in combination with a barrier method 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 meet the following criteria:

    • 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:

Participants will be excluded from the study if any of the following criteria are met:

  1. Diagnosis of pulmonary hypertension (PH) WHO Groups 2, 3, 4, or 5
  2. Diagnosis of the following PAH Group 1 subtypes: human immunodeficiency virus (HIV)-associated PAH and PAH associated with portal hypertension, schistosomiasis-associated PAH, pulmonary veno occlusive disease, and pulmonary capillary hemangiomatosis
  3. Hemoglobin at screening above gender-specific upper limit of normal (ULN), per local laboratory test
  4. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic BP > 100 mmHg during the Screening Visit after a period of rest
  5. Baseline systolic BP < 90 mmHg at screening
  6. Pregnant or breastfeeding women
  7. Any of the following clinical laboratory values at the Screening Visit:

    • Estimated glomerular filtration rate < 30 mL/min/m2 (as defined by MDRD equation)
    • Serum alanine aminotransferase, aspartate aminotransferase, and total bilirubin levels > 3 × ULN
    • Platelet count < 50,000/mm3 (< 50.0 × 109 /L)
  8. Currently enrolled in or have completed any other investigational product study within 30 days for small molecule drugs or within 5 half-lives for investigational biologics prior to the date of documented informed consent
  9. Known allergic reaction to sotatercept (ACE-011), its excipients, or luspatercept
  10. History of pneumonectomy
  11. Pulmonary function test values of forced vital capacity < 60% predicted within 1 year prior to the Screening Visit
  12. Stopped receiving any PH chronic general supportive therapy (e.g., diuretics, oxygen, anticoagulants, and digoxin) within 60 days prior to the Screening Visit
  13. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days prior to the Screening Visit or planned initiation during the study (participants who are stable in the maintenance phase of a program and who will continue for the duration of the study are eligible)
  14. Untreated more than mild obstructive sleep apnea
  15. History of known pericardial constriction
  16. History of restrictive or congestive cardiomyopathy
  17. History of atrial septostomy within 180 days prior to the Screening Visit
  18. 18. Electrocardiogram with Fridericia's corrected QT interval > 500 ms during the Screening Period
  19. Personal or family history of long QT syndrome or sudden cardiac death
  20. Left ventricular ejection fraction < 50% on historical echocardiogram (ECHO) within 1 year prior to the Screening Visit
  21. 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
  22. Cerebrovascular accident within 3 months prior to the Screening Visit
  23. Acutely decompensated heart failure within 30 days prior to the Screening Visit, as per investigator assessment
  24. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease
  25. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, and vasopressin) within 30 days prior to the Screening Visit

Information from the National Library of Medicine

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): NCT04811092


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

Locations
Show Show 122 study locations
Sponsors and Collaborators
Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
Investigators
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Study Director: Medical Director Merck Sharp & Dohme LLC
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Responsible Party: Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.)
ClinicalTrials.gov Identifier: NCT04811092    
Other Study ID Numbers: 7962-005
A011-13 ( Other Identifier: Acceleronpharma )
MK-7962-005 ( Other Identifier: Merck )
2021-000199-12 ( EudraCT Number )
First Posted: March 23, 2021    Key Record Dates
Last Update Posted: November 21, 2022
Last Verified: November 2022
Individual Participant Data (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

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Acceleron Pharma Inc. (a wholly owned subsidiary of Merck Sharp and Dohme, a subsidiary of Merck & Co., Inc.):
Pulmonary
Hypertension
Sotatercept
Additional relevant MeSH terms:
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Pulmonary Arterial Hypertension
Familial Primary Pulmonary Hypertension
Hypertension
Vascular Diseases
Cardiovascular Diseases
Hypertension, Pulmonary
Lung Diseases
Respiratory Tract Diseases