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    Summary
    EudraCT Number:2015-005043-13
    Sponsor's Protocol Code Number:RG_14-187
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-08-09
    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 ConcernedUK - MHRA
    A.2EudraCT number2015-005043-13
    A.3Full title of the trial
    Evaluating different rate control therapies in permanent atrial fibrillation: A prospective, randomised, open-label, blinded endpoint study comparing digoxin and beta-blockers as initial rate control therapy.
    RAte control Therapy Evaluation in permanent Atrial Fibrillation: RATE-AF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    RAte control Therapy Evaluation in permanent Atrial Fibrillation: RATE-AF
    A.3.2Name or abbreviated title of the trial where available
    RATE-AF
    A.4.1Sponsor's protocol code numberRG_14-187
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02391337
    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 SponsorUniversity of Birmingham
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Institue of Health Research
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of Birmingham
    B.5.2Functional name of contact pointDipak Kotecha
    B.5.3 Address:
    B.5.3.1Street AddressInstitute of Cardiovascular Sciences, University of Birmingham, Medical School
    B.5.3.2Town/ cityBirmingham
    B.5.3.3Post codeB15 2TT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44 (0) 7974 115676
    B.5.6E-maild.kotecha@bham.ac.uk
    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 Yes
    D.2.1.1.1Trade name Digoxin
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameDigoxin
    D.3.4Pharmaceutical form Coated tablet
    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 INNDigoxin
    D.3.9.1CAS number 20830-75-5
    D.3.9.3Other descriptive nameCardiac glycoside
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number62.5 to 250
    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 Yes
    D.2.1.1.1Trade name Bisoprolol
    D.2.1.1.2Name of the Marketing Authorisation holderAccord Healthcare Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameBisoprolol
    D.3.4Pharmaceutical form Coated tablet
    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 INNBisoprolol
    D.3.9.1CAS number 66722-44-9
    D.3.9.3Other descriptive namebeta1-selective-adrenoceptor blocking agent
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.25 to 15
    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
    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
    Irregular and often very fast heart rate
    E.1.1.2Therapeutic area Diseases [C] - Cardiovascular Diseases [C14]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    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
    Patient-reported quality of life (QoL), with a predefined focus on physical well-being using the SF-36 (a QoL tool) physical component summary at six months.
    E.2.2Secondary objectives of the trial
    Patient-reported QoL using three separate tools:
    • SF-36 global and domain-specific scores at 6 and 12 months
    • EQ-5D-5L summary index and visual analogue scale at six and twelve months
    • AFEQT overall score at six and twelve months
    Cardiac function:
    • Echocardiography at 12 months
    • Diastolic function at 12 months
    • Functional assessment:
    • Six-minute walking distance at 6 and 12 months
    • Change in European Heart Rhythm Association (EHRA) class at 6 and 12 months
    Biomarkers:
    • Change in B-type natriuretic peptide (BNP) levels at 6 months
    • Change in heart rate using 24-hour ambulatory ECG
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Adult patients aged 60 years or older
    • Permanent AF, characterised (at time of randomisation) as a physician decision for rate-control with no plans for cardioversion, anti-arrhythmic medication, or ablation therapy
    • Symptoms of breathlessness (New York Heart Association Class II or more)
    • Able to provide written informed consent
    E.4Principal exclusion criteria
    • Established clinical indication for beta-blocker therapy, e.g. myocardial infarction in the last 6 months
    • Known contraindications for therapy with beta-blockers or digoxin, e.g. a history of severe bronchospasm that would preclude use of beta-blockers, or known intolerance to these medications
    • Baseline heart rate <60 bpm
    • History of second or third-degree heart block
    • Supraventricular arrhythmias associated with accessory conducting pathways (e.g. Wolff-Parkinson-White syndrome) or a history of ventricular tachycardia or fibrillation
    • Planned pacemaker implantation (including cardiac resynchronisation therapy), pacemaker-dependent rhythm or history of atrioventricular node ablation
    • Decompensated heart failure (evidenced by need for intravenous inotropes, vasodilators or diuretics) within 14 days prior to randomisation
    • A current diagnosis of obstructive hypertrophic cardiomyopathy, myocarditis or constrictive pericarditis
    • Received or on waiting list for heart transplantation
    • Receiving renal replacement therapy
    • Major surgery, including thoracic or cardiac surgery, within 3 months of randomisation
    • Severe, concomitant non-cardiovascular disease (including malignancy) that is expected to reduce life expectancy
    E.5 End points
    E.5.1Primary end point(s)
    Patient-reported quality of life (QoL), with a predefined focus on physical well-being using the SF-36 physical component summary at six months.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Six months
    E.5.2Secondary end point(s)
    Secondary objectives

    • Generic and AF-specific patient-reported QoL using the SF-36 global and domain-specific scores, the AFEQT overall score and the EQ-5D-5L summary index and visual analogue scale at six and twelve months.
    • Echocardiographic left-ventricular ejection fraction (LVEF) and diastolic function (E/e’ and composite of diastolic indices) at twelve months.
    • Functional assessment, including 6-minute walking distance achieved, change in European Heart Rhythm Association (EHRA) class and cognitive function at six and twelve months.
    • Change in B-type natriuretic peptide (BNP) levels as a surrogate for total cardiac strain at six months.
    • Change in heart rate from baseline and group comparison using 24-hour ambulatory ECG.

    Feasibility objectives

    • Successful methods for recruitment
    • Key issues that affect retention of participants, such as convenience, compliance and cross-over (target of 85% study completion rate).
    • Drug discontinuation rate and adverse reactions leading to drug discontinuation.
    • Therapy-induced requirement for additional treatment (e.g. pacemaker implantation).
    • Population-specific standard deviations and proportions to enable sample size calculation for a future trial.
    • Assessment of cardiovascular outcomes including a composite of adverse clinical events (mortality, thromboembolic events, myocardial infarction and cardiovascular interventions).

    Exploratory objectives

    • Correlation of baseline measures, including QoL questionnaires and unblinded baseline investigations such as QoL, BNP, LVEF, E/e’, EHRA, intracellular methods and heart rate.
    • Impact of therapy on intracellular sodium and calcium concentration and cardiotonic steroid levels as biomarkers of cellular response at six and twelve months.
    • Impact of combination therapy on outcomes, including comparison of bisoprolol/non-dihydropyridine calcium channel blocker (CCB) vs. bisoprolol/digoxin vs. digoxin/CCB vs. single therapies.
    • Change in cognitive function at twelve months
    • Qualitative research of patient-reported QoL using focus groups to explore patient acceptability, optimal delivery methods and responsiveness.
    • Assessment of the validity and reproducibility of echocardiographic measures in patients with AF.
    • Correlation of serum digoxin concentration with change in QoL and intracellular methods.
    • Cost-consequence economic analysis from an NHS perspective.
    E.5.2.1Timepoint(s) of evaluation of this end point
    approximately 2-3 months, 6 and 12 months
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Pilot - determining feasibility for a future clinical trial (recruitment, retention, sample size)
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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
    Prospective randomised open-label, blinded endpoint (PROBE) trial
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    The end of the trial will be 30 days after last data capture i.e. 30 days after the date of the last visit of the last patient undergoing the protocol-based therapy. This will allow sufficient time for the completion of protocol procedures, data collection and input.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 145
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state160
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 160
    F.4.2.2In the whole clinical trial 160
    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 will be on trial medication for 12 months and will be followed-up, during this period according to the protocol. At the end of the 12 months, the participants may continue on medication as per clinical practice but it will not be considered part of the trial intervention. The follow-up phase of the trial will cease when the 12 month follow-up has been completed for the last participant recruited.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation West Midlands NIHR Clinical Research Network
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-07-18
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-03-07
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