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Study of Sotatercept in Newly Diagnosed Intermediate- and High-risk PAH Patients (HYPERION)

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ClinicalTrials.gov Identifier: NCT04811092
Recruitment Status : Recruiting
First Posted : March 23, 2021
Last Update Posted : August 12, 2021
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma Inc.

Brief Summary:
The objective of this study is to evaluate the effects of sotatercept treatment (plus background 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:

Study A011-13 is 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 patients.

Participants enrolled in the study will have a diagnosis within 6 months of study screening of symptomatic PAH (WHO Group 1, classified as 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 : July 28, 2021
Estimated Primary Completion Date : June 2028
Estimated Study Completion Date : August 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 Name: ACE-011




Primary Outcome Measures :
  1. Time to Clinical Worsening, defined as the first confirmed morbidity event or death. [ Time Frame: From screening to the first clinical worsening event, up to 56 months. ]
    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 composition of PAH background therapy, including an increase in parenteral prostacyclin of ≥ 10%. All events will be adjudicated by a blinded, independent committee of clinical experts.


Secondary Outcome Measures :
  1. Multicomponent improvement endpoint of 6-minute walk distance (6MWD), NT-proBNP and WHO functional class (FC). [ Time Frame: From initiation of treatment to Week 24 ]

    Multicomponent improvement endpoint measured by the proportion 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. Proportion of participants who achieved a low Registry to Evaluate Early and Long Term PAH Disease Management (REVEAL) Lite 2 risk score. [ Time Frame: From initiation of treatment to Week 24 ]
    REVEAL Lite 2 risk score in each participant was measured at Week 24 versus baseline.

  3. Proportion of participants who maintain or achieve a low simplified French risk score (FC) [ 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 was measured.

  4. Change from baseline in NT-proBNP levels. [ Time Frame: From initiation of treatment to Week 24 ]
    NT-proBNP was measured at baseline and Week 24.

  5. 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 ]
    The severity of an individual's PAH symptoms was graded using WHO FC system at baseline and Week 24.

  6. Change in 6MWD. [ Time Frame: From initiation of treatment 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.

  7. Change in EuroQol - 5 dimensions scale 5 levels (EQ 5D 5L) index score. [ Time Frame: From initiation of treatment 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.

  8. Change in Pulmonary Arterial Hypertension Symptoms and Impact (PAH-SYMPACT)® [ Time Frame: From initiation of treatment to 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. Responses in PAH-SYMPACT questionnaire at baseline and Week 24 were recorded.



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 6 months of screening and on stable doses of a double combination of background PAH therapies for at least 90 days prior to screening. A triple combination of therapies, with stable doses for 90 days, may be allowed per local standard-of-care guidelines, but is restricted to 10% of the study population.
  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, 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 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 PAH 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
  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 or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 1.5 × 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 biologics prior to the date of signed informed consent
  9. Known allergic reaction to sotatercept (ACE-011)
  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 pulmonary hypertension 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 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 > 450 ms (or > 500 ms if right bundle branch abnormality is present) 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 within 1 year prior to the Screening Visit or pulmonary capillary wedge pressure > 15 mmHg as determined by historical RHC within 6 months 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: Clinical Trial Manager 617-649-9200 Clinicaltrials011@acceleronpharma.com

Locations
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United States, Kansas
University of Kansas Medical Center Recruiting
Kansas City, Kansas, United States, 66160
Contact: Luigi Boccardi    918-588-4022    lboccardi@kumc.edu   
Contact: Kimberly Cyan    (918) 588 - 0046    kcygan@kumc.edu   
Principal Investigator: Leslie A. Spikes, MD         
United States, Michigan
Cardiovascular Center Not yet recruiting
Ann Arbor, Michigan, United States, 48109
Principal Investigator: Victor Moles, MD         
Sponsors and Collaborators
Acceleron Pharma Inc.
Investigators
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Study Director: John Butler, MD Acceleron Pharma Inc.
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Responsible Party: Acceleron Pharma Inc.
ClinicalTrials.gov Identifier: NCT04811092    
Other Study ID Numbers: A011-13
First Posted: March 23, 2021    Key Record Dates
Last Update Posted: August 12, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Acceleron is committed to sharing clinical trial data following completion of a clinical study. All data provided are de-identified to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.
Time Frame: Data will be shared after the primary publication or 2 years after the study has ended for market authorized products and indications.
Access Criteria: Data from eligible studies will be shared according to the criteria and process to be posted on Acceleron's website
URL: http://acceleronpharma.com

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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.:
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