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

• ClinicalTrials.gov Identifier: NCT04811092
• Recruitment Status: Recruiting
• First Posted: March 23, 2021
• Last Update Posted: April 8, 2024
• Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Information provided by (Responsible Party): Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA

Tracking Information

• First Submitted Date: March 16, 2021
• First Posted Date: March 23, 2021
• Last Update Posted Date: April 8, 2024
• Actual Study Start Date: March 18, 2022
• Estimated Primary Completion Date: August 27, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 15, 2023)

Time to Clinical Worsening [ Time Frame: From time of randomization to the time of first clinical worsening event (Up to approximately 47 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.

Original Primary Outcome Measures (submitted: March 19, 2021)

• All-cause death [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
• Non-planned PAH-related hospitalization of ≥ 24 hours in duration [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
• Number of participants completing atrial septostomy [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
• Number of participants with lung transplant [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
• Worsening of World Health Organization functional class (WHO FC) from baseline [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
  Deterioration in performance in exercise testing due to PAH, defined as a decrease in 6MWD from baseline on 2 consecutive tests (which must be at least 4 hours apart)
• Signs/symptoms of increased right heart failure [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
  Deterioration in performance in exercise testing due to PAH, defined as a decrease in 6MWD from baseline on 2 consecutive tests (which must be at least 4 hours apart)
• Addition of a background PAH therapy or change in the composition of PAH background therapy, including an increase in parenteral prostacyclin of ≥ 10% [ Time Frame: From initiation of treatment to last clinical worsening event, up to 100 weeks ]
  Deterioration in performance in exercise testing due to PAH, defined as a decrease in 6MWD from baseline on 2 consecutive tests (which must be at least 4 hours apart)

Current Secondary Outcome Measures (submitted: November 11, 2022)

• 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
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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

Original Secondary Outcome Measures (submitted: March 19, 2021)

• Improvement in 6MWD (increase ≥ 30 m) [ Time Frame: From initiation of treatment to Week 24 ]
  Multicomponent improvement endpoint(s) will be measured by the proportion of participants achieving improvement in 6MWD
• Improvement in NT-proBNP or maintenance/achievement of NT-proBNP level < 300 ng/L [ Time Frame: From initiation of treatment to Week 24 ]
  Multicomponent improvement endpoint(s) will be measured by the proportion of participants achieving improvement in NT-proBNP (decrease in NT-proBNP ≥ 30%) or maintenance/achievement of NT-proBNP level < 300 ng/L
• Improvement in WHO FC or maintenance of WHO FC II [ Time Frame: From initiation of treatment to Week 24 ]
  Multicomponent improvement endpoint(s) will be measured by the proportion of participants achieving improvement in WHO FC or maintenance of WHO FC II
• Proportion of participants who achieve a low Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) Lite 2 Risk Score at Week 24 versus baseline [ Time Frame: From initiation of treatment to Week 24 ]
• Proportion of participants who maintain or achieve a low risk score at Week 24 versus baseline using the simplified French Risk score calculator [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in NT-proBNP levels at Week 24 [ Time Frame: From initiation of treatment to Week 24 ]
• Proportion of participants who improve in WHO FC or maintain WHO FC II at 24 weeks from baseline [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in 6MWD at Week 24 [ Time Frame: From initiation of treatment to Week 24 ]
• Change from baseline in EuroQoL - 5 dimensions scale 5 levels (EQ-5D-5L) index score at Week 24 [ Time Frame: From initiation of treatment to Week 24 ]
  The EQ-5D-5L questionnaire is designed for self-completion and captures information directly from the respondent. The EQ-5D questionnaire has 2 components, health state description and evaluation. Health status is measured in terms of 5 dimensions (5D): mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Respondents self-rate their level of severity for each dimension using the 5-level (EQ-5D-5L) scale. In the evaluation part: the respondents evaluate their overall health status using the visual analog scale (EQ-VAS).
• Change from baseline in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH SYMPACT®) at Week 24 [ Time Frame: From initiation of treatment to Week 24 ]
  PAH SYMPACT® (Pulmonary Arterial Hypertension-Symptoms and Impact) 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.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Sotatercept in Newly Diagnosed Intermediate- and High-Risk PAH Participants (MK-7962-005/A011-13)
• 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
• 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.

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 12 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.

• Study Type: Interventional
• Study Phase: Phase 3

Study Design

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Masking Description:

Double-blind

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 Names:

  • MK-7962
  • ACE-011
• Other: Placebo
  Placebo

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: November 15, 2023): 444
• Original Estimated Enrollment (submitted: March 19, 2021): 662
• Estimated Study Completion Date: December 27, 2029
• Estimated Primary Completion Date: August 27, 2026 (Final data collection date for primary outcome measure)

Eligibility 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 12 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. Either Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) Lite 2 Risk Score ≥ 6 or Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA) 2.0 risk score ≥2 (intermediate to-low-risk or above)
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) > 180 mmHg or sitting diastolic BP > 110 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/1.73 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. 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
26. Has an active malignancy with the exception of fully excised or treated basal cell carcinoma, cervical carcinoma in-situ, or prostate cancer that is not currently or expected, during the study, to be treated with radiation therapy, chemotherapy, and/or surgical intervention, or hormonal treatment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

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

• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Canada, Colombia, Croatia, Czechia, Denmark, France, Germany, Greece, Israel, Italy, Korea, Republic of, Netherlands, New Zealand, Poland, Portugal, Serbia, Spain, Sweden, Switzerland, Taiwan, United Kingdom, United States

Administrative Information

• NCT Number: NCT04811092
• Other Study ID Numbers: 7962-005; A011-13 ( Other Identifier: Acceleronpharma ); MK-7962-005 ( Other Identifier: Merck ); 2021-000199-12 ( 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., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Original Responsible Party: Same as current
• Current Study Sponsor: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

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

• PRS Account: Acceleron Pharma, Inc., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ USA
• Verification Date: April 2024