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    Summary
    EudraCT Number:2020-004142-11
    Sponsor's Protocol Code Number:A011-11
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2021-01-19
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2020-004142-11
    A.3Full title of the trial
    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
    Eine randomisierte, doppelblinde, placebokontrollierte Phase-III-Studie zum Vergleich der Wirksamkeit und Sicherheit von Sotatercept gegenüber Placebo, wenn es der Hintergrundtherapie der pulmonal arteriellen Hypertonie (PAH) bei der Behandlung von PAH hinzugefügt wird
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 Study of Sotatercept for the Treatment of PAH
    A.3.2Name or abbreviated title of the trial where available
    A Phase 3 Study of Sotatercept for the Treatment of PAH
    A.4.1Sponsor's protocol code numberA011-11
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAcceleron Pharma Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAcceleron Pharma Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAcceleron Pharma Inc.
    B.5.2Functional name of contact pointJohn Butler
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave.
    B.5.3.2Town/ cityRahway
    B.5.3.3Post codeNJ 07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1503964-9504
    B.5.6E-mailjohn.butler2@merck.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/20/2369
    D.3 Description of the IMP
    D.3.1Product nameSotatercept
    D.3.2Product code ACE-011
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNSOTATERCEPT
    D.3.9.1CAS number 1001080-50-7
    D.3.9.2Current sponsor codeACE-011
    D.3.9.3Other descriptive nameActRIIA-IgG1Fc
    D.3.9.4EV Substance CodeSUB179718
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Pulmonary Arterial Hypertension (PAH)
    E.1.1.1Medical condition in easily understood language
    Cardiovascular Disease
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.1
    E.1.2Level PT
    E.1.2Classification code 10064911
    E.1.2Term Pulmonary arterial hypertension
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age ≥ 18 years
    2. Documented diagnostic right heart catheterization (RHC) at any time 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 pulmonary hypertension classified as WHO FC II or III
    4. Baseline RHC performed during the Screening Period documenting a minimum PVR of ≥ 5 WU and a pulmonary capillary wedge pressure (PCWP) or left ventricular end-diastolic pressure of = 15 mmHg
    5. At stable doses of background PAH therapy and diuretics (i.e., patientspecific 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.
    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 drug administration; she must agree to ongoing 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 non-latex 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 112 days (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
    E.4Principal 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 associated PAH and pulmonary veno-occlusive disease
    3. Hemoglobin (Hgb) at screening above gender-specific upper limit of normal, per local laboratory test
    4. Baseline platelet count < 50,000/mm3 (< 50.0 × 109/L) at screening
    5. Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure (BP) > 160 mmHg or sitting diastolic blood pressure > 100 mmHg during screening visit after a period of rest
    6. Baseline systolic blood pressure < 90 mmHg at screening
    7. Pregnant or breastfeeding women
    8. Any of the following clinical laboratory values at the screening visit:
    • eGFR < 30 mL/min/m2 (as defined by the Modification of Diet in Renal Disease (MDRD) equation)
    • Serum alanine aminotransferase, aspartate aminotransferase levels or total bilirubin
    levels > 3 x ULN (bilirubin criterion waived if there is a documented history of Gilbert's syndrome)
    9. Currently enrolled in or have completed any other investigational product study within 30 days for small-molecule drugs or within 5 halflives for biologics prior to the date of signed informed consent
    10. Prior exposure to sotatercept (ACE-011) or luspatercept (ACE-536) or known allergic reaction to either one
    11. History of partial pneumonectomy
    12. 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 more than mild interstitial lung disease at the screening visit or 1 years prior to it
    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. History of more than mild obstructive sleep apnea that is untreated
    15. 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).
    16. History of restrictive, constrictive or congestive cardiomyopathy
    17. History of atrial septostomy within 180 days prior to the screening visit
    18. Electrocardiogram (ECG) with Fridericia's corrected QT interval (QTcF) > 500 ms during Screening Period
    19. Personal or family history of long QT syndrome (LQTS) or sudden cardiac death
    20. Left ventricular ejection fraction (LVEF) < 45% on historical ECHO
    within 6 months prior to the screening visit
    21. Any symptomatic coronary disease (prior myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, or cardiac anginal chest pain) within 6 months prior to the screening visit. Note: Anginal pain can be ignored as an exclusion criterion if coronary angiography shows no obstructions
    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, vasopressin) within 30 days prior to the screening visit.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change from baseline in 6MWD at Week 24 versus baseline
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    1. Multicomponent improvement endpoint measured by the proportion of participants achieving all of the following:
    • 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 PVR
    3. Change from baseline in NT-proBNP levels
    4. Proportion of participants who improve in WHO FC
    5. Time to death or the first occurrence of any of the following clinical worsening events
    • 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
    • Hospitalization for worsening of PAH (≥ 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
    7. Change from baseline in the Physical Impacts domain score of Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT®) at Week 24
    8. Change from baseline in the Cardiopulmonary Symptoms domain score of PAH-SYMPACT® at Week 24
    9. Change from baseline in the Cognitive/Emotional Impacts domain score of PAH-SYMPACT® at Week 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned10
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA83
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Israel
    Korea, Republic of
    Mexico
    New Zealand
    United States
    Austria
    France
    Poland
    Sweden
    Netherlands
    Spain
    Switzerland
    Czechia
    Germany
    Italy
    Belgium
    Ireland
    United Kingdom
    Serbia
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    A participant is considered to have completed the study if he/she has completed all phases of the study, including the EOT and/or EOS visits. The EOS visits are only required for participants who discontinue the study early or decline transition to a future sotatercept LTFU study. The EOS is defined as when the last participant completes the last visit
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 142
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 142
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state19
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 130
    F.4.2.2In the whole clinical trial 284
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Patients who completed the study will be able to participate in a LTFU study
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-05-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-12-06
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