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A Study of Sotatercept for the Treatment of Pulmonary Arterial Hypertension (STELLAR)

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ClinicalTrials.gov Identifier: NCT04576988
Recruitment Status : Recruiting
First Posted : October 6, 2020
Last Update Posted : September 13, 2021
Sponsor:
Information provided by (Responsible Party):
Acceleron Pharma Inc.

Brief Summary:
The objectives of this study are to evaluate the efficacy and safety of sotatercept treatment (plus background PAH therapy) versus placebo (plus background PAH therapy) at 24 weeks in adults with PAH.

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

Detailed Description:

This is a Phase 3, randomized, double-blind, placebo-controlled, multicenter, parallel-group study in subjects with symptomatic Pulmonary Arterial Hypertension (PAH) 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 defects (CHDs), and currently on background PAH therapy.

The primary efficacy endpoint of the study is exercise capacity, as measured by the 6-minute walk distance (6MWD) measured at 24 week following initiation of treatment.

Approximately 284 participants will be enrolled and randomized 1:1 to receive either sotatercept or placebo on the background of stable standard-of-care PAH mediation. Study duration will be approximately 2 years A stratified Wilcoxon test will be used for analysis of the primary endpoint, with appropriate imputation for missing data, as detailed in the Statistical Analysis Plan. An unblinded, external, independent Data Monitoring Committee (DMC) will monitor participant safety throughout the course of the study. Participants completing this study will be eligible to receive sotatercept in a separate, open-label extension study.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 284 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants will be randomized to one of two treatment arms to receive either sotatercept (0.7 mg/kg) by subcutaneous administration once every 3 weeks, or placebo. All participants will be on concurrent, stable background PAH therapy. Randomization will be stratified by baseline WHO Functional Class (Class II or III) and by background PAH therapy (mono/double or triple therapy)
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Masking Description: Study participants, care providers. Investigators and outcomes assessor will be masked to the study intervention until the final participant complete the 24-week efficacy assessment.
Primary Purpose: Treatment
Official Title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Compare the Efficacy and Safety of Sotatercept Versus Placebo When Added to Background Pulmonary Arterial Hypertension (PAH) Therapy for the Treatment of PAH
Actual Study Start Date : January 25, 2021
Estimated Primary Completion Date : December 2022
Estimated Study Completion Date : December 2022


Arm Intervention/treatment
Experimental: Sotatercept plus background PAH theraphy
Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy
Drug: Sotatercept
Sotatercept at a starting dose of 0.3 mg/kg with a target dose of 0.7 mg/kg administered subcutaneously (SC) every 21 days plus background PAH therapy.

Placebo Comparator: Placebo plus background PAH therapy
Placebo administered (SC) every 21 days plus background PAH therapy
Drug: Placebo
Placebo administered subcutaneously (SC) every 21 days plus background PAH therapy.




Primary Outcome Measures :
  1. Change from baseline in 6MWD. [ Time Frame: From initiation of treatment to Week 24 ]

Secondary Outcome Measures :
  1. The proportion of participants achieving the multicomponent improvement endpoint, consisting of all of the following: [ Time Frame: From initiation of treatment to Week 24 ]
    • Improvement in 6MWD (increase ≥ 30 m)
    • 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

  2. Change from baseline in pulmonary vascular resistance (PVR). [ Time Frame: From initiation of treatment to Week 24 ]
  3. Proportion of participants who improve in WHO FC. [ Time Frame: From initiation of treatment to Week 24 ]
  4. Change from baseline in NT-proBNP levels. [ Time Frame: From initiation of treatment to Week 24 ]
  5. Time to death or the first occurrence of any of the following clinical worsening events (TTCW): [ Time Frame: From initiation of treatment to through study completion, an average of 1 year. ]
    • Worsening-related listing for lung and/or heart transplant
    • Need to initiate rescue therapy with an approved background PAH therapy or the need to increase the dose of infusion prostacyclin by 10% or more
    • Need for atrial septostomy
    • PAH-specific hospitalization (≥ 24 hours)
    • Deterioration of PAH defined by both of the following events occurring at any time, even if they began at different times, as compared to their baseline values:

      • Worsened WHO FC
      • Decrease in 6MWD by ≥ 15% confirmed by 2 tests at least 4 hours apart, but no more than 1 week

  6. Proportion of participants who maintain or achieve a low risk score using the simplified French Risk score calculator. [ Time Frame: From initiation of treatment to Week 24 ]
  7. Change from baseline in EuroQol 5 dimension 5 level (EQ-5D-5L) index score. [ Time Frame: From initiation of treatment to Week 24 ]
  8. Change from baseline in Pulmonary Arterial Hypertension - Symptoms and Impact (PAH-SYMPACT®). [ Time Frame: From initiation of treatment to Week 24 ]


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

Key Inclusion Criteria:

  1. Age ≥ 18 years
  2. Documented diagnostic right heart catheterization (RHC) at any time prior to screening confirming the diagnosis of WHO pulmonary arterial hypertension (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 Functional Class II or III
  4. Baseline RHC performed during the Screening Period documenting a minimum pulmonary vascular resistance (PVR) of ≥ 5 Wood units (WU)
  5. On stable doses of background PAH therapy and diuretics (i.e., patient-specific dose goal for each therapy already achieved) for at least 90 days prior to screening; for infusion prostacyclins, dose adjustment within 10% of optimal dose is allowed per medical practice. Background PAH therapy is defined in Section 7.2
  6. 6MWD ≥ 150 and ≤ 500 m repeated twice at screening (measured at least 4 hours apart, but no longer than 1 week), and both values are within 15% of each other (calculated from the highest value)
  7. Females of childbearing potential must:

    • Have 2 negative urine or serum pregnancy tests as verified by the investigator prior to starting study therapy; she must agree to ongoing urine or serum pregnancy testing during 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

Key Exclusion Criteria:

  1. Diagnosis of pulmonary hypertension 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. Exclusions in PAH Group I should also include schistosomiasis APAH and pulmonary veno occlusive disease
  3. Hemoglobin (Hgb) 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 > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during 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 (eGFR) < 30 mL/min/m2 (as defined by MDRD equation)
    • Serum alanine aminotransferase or aspartate aminotransferase levels > 3 × ULN or total bilirubin > 1.5 × ULN
  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. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE 536) and/or excipients or known allergic reaction to either one
  10. Have full or partial pneumonectomy
  11. Pulmonary function test (PFT) values of forced vital capacity (FVC) < 60% predicted at the screening visit or within 6 months prior to the screening visit. If PFT is not available, a chest CT scan showing no more than mild interstitial lung disease (ILD) performed at the screening visit or 1 year to it.
  12. 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).
  13. History of more than mild obstructive sleep apnea that is untreated
  14. Known history of portal hypertension or chronic liver disease, including hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), defined as mild to severe hepatic impairment (Child-Pugh Class A-C)
  15. History of restrictive, constrictive or congestive cardiomyopathy
  16. History of atrial septostomy within 180 days prior to the screening visit
  17. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during the screening period
  18. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
  19. Left ventricular ejection fraction < 45% on historical echocardiogram within 6 months prior to the screening visit or pulmonary capillary wedge pressure > 15 mmHg as determined in the Screening Period RHC
  20. Any symptomatic coronary disease events" within 6 months (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months of the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions.
  21. Cerebrovascular accident within 3 months prior to the screening visit
  22. Acutely decompensated heart failure within 30 days prior to the screening visit, as per investigator assessment
  23. Significant (≥ 2+ regurgitation) mitral regurgitation or aortic regurgitation valvular disease, mitral stenosis and more than mild aortic valve stenosis
  24. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, 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): NCT04576988


Contacts
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Contact: Clinical Trials Manger 617-649-9200 Clinicaltrials011@acceleronpharma.com

Locations
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Sponsors and Collaborators
Acceleron Pharma Inc.
Investigators
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Study Director: Janethe de Oliveira Pena, MD Acceleron Pharma Inc.
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Responsible Party: Acceleron Pharma Inc.
ClinicalTrials.gov Identifier: NCT04576988    
Other Study ID Numbers: A011-11
First Posted: October 6, 2020    Key Record Dates
Last Update Posted: September 13, 2021
Last Verified: September 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.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
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