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    The EU Clinical Trials Register currently displays   43977   clinical trials with a EudraCT protocol, of which   7312   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2016-000302-12
    Sponsor's Protocol Code Number:BUC-CLIN-303
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-17
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2016-000302-12
    A.3Full title of the trial
    GENETIC-AF – A Genotype-Directed Comparative Effectiveness Trial of Bucindolol and Toprol-XL for Prevention of Symptomatic Atrial Fibrillation/Atrial Flutter in Patients with Heart Failure
    GENETIC-AF: Badanie Ukierunkowane Genotypowo, Porównujące Skuteczność Bucindololu i Toprolu-XL w Zapobieganiu Objawowemu Migotaniu Przedsionków/Trzepotaniu Przedsionków u Pacjentów z Niewydolnością Serca.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Genetically Targeted Therapy for the Prevention of Symptomatic Atrial Fibrillation in Patients With Heart Failure (GENETIC-AF)
    Terapia celowana genetycznie w zapobieganiu objawowemu migotaniu Przedsionków u Pacjentów z Niewydolnością Serca (GENETIC-AF)
    A.3.2Name or abbreviated title of the trial where available
    GENETIC-AF
    A.4.1Sponsor's protocol code numberBUC-CLIN-303
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01970501
    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 SponsorARCA biopharma, 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 supportARCA biopharma, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationARCA biopharma, Inc.
    B.5.2Functional name of contact pointGENETIC-AF helpdesk
    B.5.3 Address:
    B.5.3.1Street Address11080 CirclePoint Road, Suite 140
    B.5.3.2Town/ cityWestminster, Colorado
    B.5.3.3Post code80020
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1720940 2291
    B.5.5Fax number+1720208 9262
    B.5.6E-mailhelpdesk@genetic-af.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 nameBucindolol hydrochloride (bucindolol)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUCINDOLOL HYDROCHLORIDE
    D.3.9.1CAS number 70369-47-0
    D.3.9.4EV Substance CodeSUB00886MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6.25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 2
    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 nameBucindolol hydrochloride (bucindolol)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUCINDOLOL HYDROCHLORIDE
    D.3.9.1CAS number 70369-47-0
    D.3.9.4EV Substance CodeSUB00886MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number12.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 3
    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 nameBucindolol hydrochloride (bucindolol)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUCINDOLOL HYDROCHLORIDE
    D.3.9.1CAS number 70369-47-0
    D.3.9.4EV Substance CodeSUB00886MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 4
    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 nameBucindolol hydrochloride (bucindolol)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUCINDOLOL HYDROCHLORIDE
    D.3.9.1CAS number 70369-47-0
    D.3.9.4EV Substance CodeSUB00886MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 5
    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 nameBucindolol hydrochloride (bucindolol)
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBUCINDOLOL HYDROCHLORIDE
    D.3.9.1CAS number 70369-47-0
    D.3.9.4EV Substance CodeSUB00886MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name TOPROL-XL
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca LP
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETOPROLOL SUCCINATE
    D.3.9.3Other descriptive nameMETOPROLOL SUCCINATE
    D.3.9.4EV Substance CodeSUB03274MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name TOPROL-XL
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca LP
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETOPROLOL SUCCINATE
    D.3.9.3Other descriptive nameMETOPROLOL SUCCINATE
    D.3.9.4EV Substance CodeSUB03274MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 8
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name TOPROL-XL
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca LP
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETOPROLOL SUCCINATE
    D.3.9.3Other descriptive nameMETOPROLOL SUCCINATE
    D.3.9.4EV Substance CodeSUB03274MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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.IMP: 9
    D.1.2 and D.1.3IMP RoleComparator
    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 Yes
    D.2.1.1.1Trade name TOPROL-XL
    D.2.1.1.2Name of the Marketing Authorisation holderAstra Zeneca LP
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNMETOPROLOL SUCCINATE
    D.3.9.3Other descriptive nameMETOPROLOL SUCCINATE
    D.3.9.4EV Substance CodeSUB03274MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    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 placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Atrial Fibrillation
    E.1.1.1Medical condition in easily understood language
    Atrial Fibrillation (an abnormal, rapid heart rhythm)
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10003658
    E.1.2Term Atrial fibrillation
    E.1.2System Organ Class 10007541 - Cardiac disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to compare the effects of bucindolol and metoprolol on the recurrence of symptomatic Atrial Fibrillation (AF)/Atrial Flutter (AFL) in patients with HFREF (heart failure with reduced left ventricle ejection fraction) who have a β1389 arginine homozygous (β1389Arg/Arg) genotype.
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study are to compare the effects of bucindolol and metoprolol on clinical outcomes and other electrocardiographic parameters, and to assess the effects on rate control in patients who have developed recurrent AF/AFL. The safety and tolerability of bucindolol and metoprolol will also be evaluated.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    1. AF Burden Substudy (cardiac rhythm monitored
    continuously via a Medtronic implanted device) - part of the Clinical Study Protocol Version 4.0, Date: 29 January 2016
    2. Optional Genetic Analyses (DNA Bank) - part of the Clinical Study Protocol Version 4.0, Date: 29 January 2016
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for randomization in this study.
    1. Age ≥ 18 years and ≤ 85 years at the Screening Visit.
    2. Weight ≥ 40 kg at the Randomization Visit.
    3. Possess the β1389Arg/Arg genotype.
    4. History of heart failure with reduced left ventricle ejection fraction (HFREF).
    a. LVEF < 0.50 assessed at any time during the previous 12 months of the Screening Visit.
    5. At least one symptomatic paroxysmal or persistent AF episode ≤ 180 days of the Screening Visit.
    a. Qualifying AF episode may be documented by ECG, Holter, TTM, or implanted device. AF documented by implanted device must be a single episode ≥ 60 minutes in duration. Atrial flutter is not considered a qualifying AF episode.
    b. Must have experienced AF symptoms ≤ 180 days of the Screening Visit, but these symptoms may overlap with HF symptoms, i.e. may be “arrhythmic” (e.g. palpitations, dizziness) or “heart failure” (e.g. breathlessness, fatigability) in nature.
    6. Clinically appropriate for ECV if AF/AFL is present at the Week 0 Visit, including:
    a. Patients with AF/AFL at randomization determined by the Investigator to require ECV.
    b. Patients in SR at randomization determined by the Investigator to require ECV if AF/AFL recurs.
    7. Receiving guideline indicated oral anticoagulation therapy at the Randomization Visit, which is considered optimal for stroke prevention in the opinion of the Investigator.
    8. Systolic blood pressure > 90 mmHg and < 150 mmHg at the Randomization Visit.
    9. Female of childbearing potential must have a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at the Randomization Visit.
    a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be of childbearing potential.
    10. Female of childbearing potential must agree to use a highly effective contraception for the duration of the trial and for at least 30 days following the last dose of study drug.
    a. Female who is surgically sterile or post-menopausal for at least 12 months is not considered to be of childbearing potential.
    11. Must agree not to participate in a clinical study involving another investigational drug or device throughout the duration of this study.
    12. Must be competent to understand the information given in the Institutional Review Board (IRB) or Independent Ethics Committee (IEC) approved ICF. Must sign the ICF prior to the initiation of any study procedure and not withdraw consent prior to the Randomization Visit.
    E.4Principal exclusion criteria
    1. NYHA Class IV symptoms at the Randomization Visit.
    2. Significant fluid overload at the Randomization Visit, in the opinion of the Investigator. Evidence of significant fluid overload may include:
    a. Mean jugular venous pressure above the clavicle at 90°.
    b. Liver congestion.
    c. Moist pulmonary rales post-cough.
    d. Peripheral edema beyond 1+ pedal not explained by local factors.
    3. Permanent AF at the Screening Visit.
    a. Permanent AF is defined as an ongoing AF event 1 year or longer in duration in which there is no intervening evidence of SR.
    4. More than two ECV procedures within 6 months of the Randomization Visit or if the most recent ECV within 6 months of the Randomization Visit failed to produce SR.
    5. Use of any of the following < 7 days of the randomization Visit:
    a. Amiodarone, disopyramide, dofetilide, dronedarone, flecainide, propafenone, sotalol, non-dihydropyridine calcium channel blockers, daily NSAIDS (e.g., ibuprofen, celecoxib), thiazolidinediones, or frequent use of short acting nitroglycerin (e.g., > 6 sublingual tablets/week).
    b. Note: Amiodarone and dofetilide can be restarted after the start of follow-up if the patient experiences an AF/AFL event or after failure to convert to SR following ECV (see protocol Section 5.8).
    6. The presence of a left ventricular assist device (LVAD) or a condition that is likely to require LVAD placement within 6 months of the Randomization Visit.
    7. History of a successful atrioventricular node ablation.
    8. History of an AF ablation or AFL ablation within 30 days of the Randomization Visit.
    9. History of untreated second degree Mobitz II or third degree heart block.
    10. History of untreated symptomatic bradycardia or if symptomatic bradycardia is likely on full dose of study drug in the opinion of the Investigator.
    11. Heart rate < 60 beats per minute at the Randomization Visit for patients who were not receiving β-blocker therapy during the screening period.
    12. Heart rate > 180 beats per minute at the Randomization Visit.
    13. Contraindication or previous history of intolerance to β-blocker therapy (e.g., untreated valvular disease) or Toprol-XL (e.g., inability to tolerate at least 25mg QD).
    14. Myocardial infarction, unstable angina, acute coronary syndrome, cardiac surgery (including PTCA or stent placement), or evidence of new ischemic changes as assessed by ECG ≤ 90 days of the Randomization Visit.
    15. Moderate to severe asthma or other obstructive lung disease requiring chronic use (> 2 days/week) of an inhaled β2-selective adrenergic agonist < 7 days of the Randomization Visit.
    16. History of pulmonary hypertension, defined as a systolic pulmonary arterial pressure ≥ 70 mmHg at rest as assessed by echocardiography or right heart catheterization.
    17. Known reversible causes of AF such as alcohol intoxication, pulmonary embolism, hyperthyroidism, acute pericarditis, or hypoxemia.
    18. Evidence of an appropriate firing of an ICD device for ventricular tachycardia (VT) or ventricular fibrillation (VF) ≤ 90 days of the Randomization Visit.
    a. Exception: does not include anti-tachycardia pacing.
    19. Untreated thyroid disease, in the opinion of the Investigator, at the Randomization Visit.
    20. Serum potassium < 3.5 mmol/L at the Screening Visit.
    a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results must be corrected prior to randomization as documented by either the central or local lab.
    21. Renal failure requiring dialysis, serum creatinine > 2.5 mg/dL or an estimated creatinine clearance < 30 mL/min (Cockcroft-Gault) at the Screening Visit.
    a. Lab values will be assessed by the central lab at the Screening Visit and any exclusionary results must be corrected prior to randomization as documented by either the central or local lab.
    22. Significant intrinsic liver disease or a total bilirubin > 2.5 mg/dL at the Screening Visit.
    a. Lab value will be assessed by the central lab at the Screening Visit and any exclusionary results must be corrected prior to randomization as documented by either the central or local lab.
    23. Use of strong inhibitors of cytochrome P450 2D6 (e.g., fluoxetine, paroxetine, propafenone, quinidine, or ritonavir) < 7 days prior to the Randomization Visit for patients who are not receiving β-blocker therapy at screening.
    24. Participation in a clinical study or treatment with an investigational drug or device within 30 days of the Screening Visit (or 5 half-lives of the investigational agent, whichever is longer).
    25. Comorbid condition or illness which, in the opinion of the Investigator, may limit life expectancy to less than 1 year.
    26. Serious or active medical or psychiatric condition
    27. Treatment for a malignancy ≤ 2 years prior to randomization, the presence of a treated malignancy that has evidence of disease progression
    28. History of alcohol, drug or chemical abuse
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is elapsed time to first event of symptomatic atrial fibrillation/atrial flutter (AF/AFL) or all cause mortality (ACM) during the 24-week Follow-up Period. This is a time to event endpoint censored at 24 weeks of follow-up after establishment of stable SR on study drug. Both calculations will be stratified by the pre-specified randomization strata: HF etiology (ischemic/non-ischemic); LVEF (< 0.35 / ≥ 0.35); type of Medtronic device (Reveal/Non-Reveal/No Device), and; rhythm status at randomization (SR vs. AF/AFL). The analysis methodology will also be applied separately to each component of this compound endpoint (i.e., time to first event of symptomatic AF/AFL and time to ACM).
    The following definitions apply to this endpoint:
    - Stable SR on study drug is defined as any of the following:
    o SR confirmed ≥ 1 hour after ECV.
    o SR confirmed ≥ 1 hour after spontaneous conversion from AF/AFL.
    o SR confirmed ≥ 1 hour at the Week 0 Visit for patients randomized in SR.
    - An AF/AFL event is defined as AF or AFL observed on two consecutive measures separated by at least 10 minutes as assessed by ECG.
    - A symptomatic AF/AFL event is defined as an AF/AFL event that is associated with a clinically relevant change in patient-reported symptoms, as determined by the Clinical Events Committee (CEC) examination of blinded data.
    E.5.1.1Timepoint(s) of evaluation of this end point
    - in Phase 2b of the study: during the 24-Week Follow-up Period
    - in Phase 3 of the study: during the Treatment Extension Period
    E.5.2Secondary end point(s)
    The following endpoints will be tested for superiority of bucindolol benefit relative to metoprolol by fixed sequence provided that bucindolol meets the superiority criteria on the primary endpoint.
    1. Time to first event of AF/AFL (i.e., symptomatic or asymptomatic) or ACM during the 24-week Follow-up Period. A supportive analysis will involve the same analysis methodology applied to each component (i.e., AF, AFL and ACM). Supportive analysis will also be conducted to
    examine this endpoint and its components for the Total Follow-up Period.
    2. Proportion of patients with ventricular tachycardia (VT), ventricular fibrillation (VF), or symptomatic supraventricular tachycardia (SVT) during the 24-week Follow-up Period. Includes VF and symptomatic SVT events of any duration, VT events of ≥ 15 seconds, and VT events that result in appropriate firing of an ICD. This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification variables. The components will also be examined individually with the same methodology. A supportive analysis will also be conducted to examine this endpoint and its components for the Total Follow-up Period.
    3. Total number of hospitalization days per patient (all-cause) during the Total Study Period. This count will be normalized for the total number of days of follow-up prior to testing with the Wilcoxon Rank Sum statistic. A supportive analysis for this endpoint will also be conducted that compares patients who are in AF at the EOS Visit and have VRR control to patients who are in
    AF at the EOS Visit without VRR control. A supportive analysis for this endpoint will also be conducted for the subset of heart-failure related hospitalization days per patient during the Total Study Period.
    4. Time to first event of AF/AFL (i.e., symptomatic or asymptomatic), HF hospitalization (as assessed by the Investigator), or ACM during the Total Study Period. Supportive analyses will also be performed for the 24-week Follow-up Period only, for each endpoint component, and for each endpoint combination (i.e., AF/AFL+ACM, AF/AFL+HFH, HFH+ACM).
    5. Proportion of patients with adequate ventricular rate control in the setting of AF/AFL. These patients will be identified by the CEC and the condition will be defined by (a) a ventricular response rate (VRR) between 40 and 80 beats per minute at rest on the last tracing demonstrating
    AF/AFL during the 24-week Follow-up Period and (b) the absence of symptoms associated with bradycardia. This endpoint will be tested with a Cochran-Mantel-Haenszel statistic to control for the four stratification variables. A supportive analysis will also be performed to evaluate this
    endpoint at the time of study drug discontinuation.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
    2. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
    3. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
    4. during the Total Follow-up Period (24-Week Follow-up Period + Treatment Extension Period)
    5. during the 24-Week Follow-up Period and at the time of study drug discontinuation
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) 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 Yes
    E.8.1.7.1Other trial design description
    genotype-directed, adaptive-design, superiority study
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 EEA60
    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
    Bulgaria
    Canada
    Czech Republic
    Hungary
    Netherlands
    Poland
    Serbia
    United States
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months7
    E.8.9.1In the Member State concerned days21
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days15
    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: 155
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 465
    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 state100
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 620
    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)
    At the end of the study, patients will discontinue study drug and should transition to commercially-available β-blocker therapy per Investigator discretion. Transition to commercial β-blocker therapy is recommended to occur in a similar manner as described for initiation of blinded β-blocker therapy.
    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 Decision2016-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-09-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-12-28
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