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    Summary
    EudraCT Number:2021-003020-32
    Sponsor's Protocol Code Number:A011-16
    National Competent Authority:Sweden - MPA
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-11-10
    Trial 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 ConcernedSweden - MPA
    A.2EudraCT number2021-003020-32
    A.3Full title of the trial
    Phase 2, Double-blind, Randomized, Placebo-controlled Study to Evaluate the Effects of Sotatercept versus Placebo-Controlled for the Treatment of Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved Ejection Fraction (HFpEF)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 2 Study of Sotatercept for Combined Postcapillary and Precapillary Pulmonary Hypertension Treatment
    A.3.2Name or abbreviated title of the trial where available
    A Phase 2 Study of Sotatercept for Cpc-PH Treatment
    A.4.1Sponsor's protocol code numberA011-16
    A.5.4Other Identifiers
    Name:IND Number:154471
    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., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
    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., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
    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., a wholly-owned subsidiary of Merck & Co., Inc., Rahway, NJ, USA
    B.5.2Functional name of contact pointAlexandra Cornell
    B.5.3 Address:
    B.5.3.1Street Address126 East Lincoln Ave., P.O. Box 2000
    B.5.3.2Town/ cityRahway
    B.5.3.3Post codeNJ 07065
    B.5.3.4CountryUnited States
    B.5.4Telephone number001617992 3648
    B.5.6E-mailalexandra.cornell@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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSotatercept
    D.3.2Product code ACE-011 / MK-7962
    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 / MK-7962
    D.3.9.3Other descriptive nameSOTATERCEPT
    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 placeboPowder 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
    Combined Postcapillary and Precapillary Pulmonary Hypertension (Cpc-PH) due to Heart Failure with Preserved Ejection
    Fraction (HFpEF)
    E.1.1.1Medical condition in easily understood language
    Combined Postcapillary and Precapillary Pulmonary Hypertension due to Heart Failure
    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 10037400
    E.1.2Term Pulmonary 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
    Efficacy: This study is designed to evaluate the efficacy, measured by change from baseline in
    PVR (primary endpoint) and 6MWD (key secondary endpoint) of sotatercept versus placebo in
    adults with Cpc-PH due to HFpEF.
    Safety: The safety and tolerability of sotatercept versus placebo in adults with Cpc-PH due to
    HFpEF will be assessed by the safety endpoints listed below.
    E.2.2Secondary objectives of the trial
    Not Applicable
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Participants must meet the following criteria to be enrolled in this study:
    1. Age 18 to 85 years
    2. Clinical diagnosis of HFpEF:
    • Left ventricular ejection fraction ≥ 50%, with no history of LVEF below 45% in more than 2 consecutive measurements under stable conditions
    3. Demonstrated Cpc-PH by all of the following:
    • Baseline RHC performed within 28 days of randomization documenting a minimum PVR ≥ 320 dyn•sec/cm5 (4 wood units) (see Section 9.2.1 for historic RHC requirements)
    • Mean pulmonary arterial pressure > 20 mmHg
    • Pulmonary capillary wedge pressure > 15 mmHg but < 30 mmHg
    4. New York Heart Association FC of II or III
    5. Six minute Walk Distance ≥ 100 meters repeated twice during Screening and both values within 15% of each other, calculated from the highest value (see Section 9.3.2 for details)
    6. Chronic medication for HF or for any underlying condition, administered at a stable (per investigator) dose for ≥ 30 days prior to Visit 1. Diuretics and/or anticoagulants are excepted from this rule but should not be newly started or stopped within 30 days of Visit 1, and a prescribed dose change should not occur within 7 days of Visit 1.
    Anticoagulation may be suspended for RHC if necessary.
    7. Women of childbearing potential (defined in Appendix 2) must:
    • Have 2 negative urine or serum pregnancy tests as verified by the investigator during the Screening Period; 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, with a male partner:
    - Use highly effective contraception without interruption, for at least 28 days prior to starting the investigational product, AND
    - Agree 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 drug
    See Appendix 2 for additional contraceptive information.
    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 WOCBP 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 (see Appendix 2 for additional contraceptive information)
    • Refrain from donating blood or sperm for the duration of the study and for 16 weeks (112 days) after the last dose of study drug
    9. Ability to adhere to the study visit schedule and understand and comply with all protocol requirements
    10. Agreement to not participate in any other trials of investigational drugs/devices while enrolled in the A011-16 study
    11. Ability to understand and provide documented informed consent for participation
    E.4Principal exclusion criteria
    1. A diagnosis of PH in WHO Group 1, WHO Group 3, WHO Group 4, or WHO Group 5
    2. Documented significant lung disease:
    - Chronic obstructive pulmonary disease with post-bronchodilator forced expiratory volume in the first second (FEV1) < 60% predicted
    - Restrictive lung disease with total lung capacity < 70% predicted
    - More than mild interstitial lung disease (ILD), with FVC< 70% or FEV1< 60% predicted (still appropriate if absence of more than mild ILD, fibrosis, or COPD on computed tomography [CT] imaging)
    3. Cardiovascular comorbidities, which include any of the following:
    -History of more than mild mitral or aortic stenosis (corrected mitral or aortic stenosis by a surgical or transcatheter method within 12 months from Visit 1 and no more than mild residual stenosis may be allowed after the Medical Monitor’s review)
    -Ongoing more than mild mitral or aortic regurgitation (corrected mitral or aortic regurgitation by a surgical or transcatheter method within 12 months from Visit 1 and no more than mild residual regurgitation may be allowed after the Medical Monitor’s review). NOTE: if an imaging report reads ‘mild-to-moderate mitral regurgitation', the participant may still be enrolled if, in the opinion of the
    investigator, the mitral regurgitation is no more than mild.
    -More than one valve replacement or repair (mechanical or biomechanical) or anticipation of any valve replacement or repair.
    -Severe tricuspid regurgitation due to primary valvular disease (e.g., from endocarditis, carcinoid, or mechanical destruction).
    - Occurrence of myocardial infarction, acute coronary syndrome, coronary artery bypass graft or percutaneous coronary intervention within 180 days of Visit 1
    - History of serious life-threatening or hemodynamically significant arrhythmia
    - History of or anticipated heart transplant or ventricular assist device implantation
    - History of implantable cardioverter defibrillator placement or anticipated implantation of pacemaker, pacemaker implantation within 30 days of Screening
    - History of known pericardial constriction, hypertrophic cardiomyopathy, sarcoidosis, or amyloid cardiomyopathy
    - Uncontrolled systemic hypertension as evidenced by sitting systolic blood pressure > 160 mmHg or sitting diastolic blood pressure > 110 mmHg during Screening after a period of rest
    - Systemic hypotension as evidenced by sitting systolic blood pressure < 90 mmHg or sitting diastolic blood pressure < 50 mmHg during Screening
    - Resting heart rate of < 45 bpm or > 115 bpm (including atrial fibrillation)
    - Stroke within 90 days of Visit 1
    - Acutely decompensated HF that required hospitalization within 30 days of Visit 1
    - Electrocardiogram during Screening Period with Fridericia’s corrected QT interval (QTcF) > 470 msec for males or > 480 msec for females, or > 500 msec if a ventricular conduction defect (right bundle branch block; left bundle branch block; or interventricular conduction delay) is present
    - Personal or family history of Brugada syndrome, sudden cardiac arrest or unexplained sudden cardiac death or arrest
    - Personal or family history of long QT syndrome unless the subject’s ECG shows a normal QTc
    - Arrhythmogenic right ventricular dysplasia (ARVD) unless the subject has a recent cardiac MRI that shows no evidence of this diagnosis.
    4. Hospitalization for any worsening of medical conditions or any significant surgery per investigator within 30 days of Visit 1
    5. Received any approved PAH-specific therapies (i.e., endothelin receptor antagonists, prostacyclin analogs, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators) within 30 days of Visit 1. The use of an oral phosphodiesterase type 5 inhibitor, if only indicated for erectile dysfunction, is permitted, if not administered within 48 hours of a study visit or procedure.
    6. Received intravenous inotropes (e.g., dobutamine, dopamine, norepinephrine, vasopressin, or levosimendan) within 30 days of Visit 1
    7. Received erythropoietin within 6 months of Visit 1
    8. Known history of chronic liver disease, including untreated hepatitis B and/or hepatitis C (with evidence of recent infection and/or active virus replication), with severe hepatic impairment and/or cirrhosis (e.g., hepatic encephalopathy)
    9. Prior exposure to sotatercept or luspatercept
    10. 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 consent
    11. Initiation of an exercise program for cardiopulmonary rehabilitation within 90 days of Visit 1 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)

    Please refer to the study protocol Section 7.2 for all exclusion criteria
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy Endpoints
    Primary Efficacy Endpoint
    • Change from baseline in PVR at Week 24
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline at Week 24
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoint
    • Change from baseline in 6MWD at Week 24
    Secondary Endpoints
    • Time to first clinical worsening event (TTCW) assessed at Week 24 and separately for all available follow-up after Week 24, defined as the number of weeks from first dose date to any
    of the following:
    − Hospitalization due to a cardiopulmonary indication (a non-elective
    hospitalization lasting at least 24 hours in duration caused by clinical conditions
    directly related to PH and/or HF)
    − Administration of intravenous diuretics or SC furosemide
    − Death (all causes)
    − Decrease in 6MWD by ≥ 15% from baseline confirmed by 2 tests at least 4 hours,
    but no more than 1 week apart
    • Change from baseline in hemodynamic and echocardiography (ECHO) parameters, including but
    not limited to PVR, mean pulmonary arterial pressure (mPAP), pulmonary capillary
    wedge pressure (PCWP), TAPSE, right ventricular fractional area change (RVFAC),
    LVEF, IVRT, ratio of mitral inflow velocity I to mitral annular velocity’(e') (E/e’ ratio), ratio of the peak velocity flow of the E wave in early diastole to peak velocity flow of the A wave in late diastole (E/A ratio) and myocardial contraction fraction (MCF) at Week 24
    • Change from baseline in NT-proBNP at Week 24
    • Change from baseline in NYHA FC at Week 24
    • Change from baseline in 6MWD at Week 48
    • Change from baseline in hemodynamic and ECHO parameters, including but not limited to PVR, mPAP, PCWP, TAPSE, RVFAC, LVEF, IVRT, E/e' ratio, E/A ratio and MCF at Week 48
    • Change from baseline in NT-proBNP at Week 48
    •Change from baseline in NYHA FC at Week 48
    • Change from baseline in PVR, 6MWD, and NYHA FC at Week 48 in the Extension Period in the placebo-crossed Treatment Group
    • Change from Week 24 in PVR, 6MWD, and NYHA FC at Week 48 in the Extension Period in the placebo-crossed Treatment Group
    E.5.2.1Timepoint(s) of evaluation of this end point
    From baseline in 6MWD at 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 No
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 No
    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 trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    Canada
    Israel
    Mexico
    United Kingdom
    United States
    Belgium
    France
    Germany
    Italy
    Poland
    Spain
    Sweden
    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
    LPLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months3
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days0
    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: 37
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 113
    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 state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 65
    F.4.2.2In the whole clinical trial 150
    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)
    None
    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 Decision2022-01-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-04-27
    P. End of Trial
    P.End of Trial StatusOngoing
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