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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2015-005043-13
    Trial protocol
    		 GB  
    Global end of trial date
    26 Feb 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Apr 2021
    First version publication date
    14 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_14-187
    Additional study identifiers
    ISRCTN number
    		 ISRCTN95259705
    US NCT number
    		 NCT02391337
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Aston Webb Building , Birmingham, United Kingdom, B15 2TT
    Public contact
    Dipak Kotecha, University of Birmingham, +44 (0) 7974 115676, d.kotecha@bham.ac.uk
    Scientific contact
    Dipak Kotecha, University of Birmingham, +44 (0) 7974 115676, d.kotecha@bham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Feb 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Dec 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main 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.
    Protection of trial subjects
    All sites were provided with the Rate-AF protocol that provided specific instruction relating to inclusion/exclusion criteria and trial patient safety. There was clear instruction relating to trial intervention safety and considerations detailed within the protocol. Rate-AF had a Data Monitoring Committee to monitor patient safety throughout the trial.
    Background therapy
    		 Atrial fibrillation is a common heart rhythm disturbance, causing discomfort for patients, a high risk of stroke, frequent hospital admissions and a two-fold increase in death. The number of patients with this condition are expected to double in the next 20 years. Medications to control heart-rate are used in the majority of patients, although the choice of agent is often guided by local preference rather than evidence from controlled trials. Despite the fact that patients with atrial fibrillation have high rates of other cardiac conditions such as heart failure, clinicians have insufficient evidence to personalise the use of different therapies. This feasibility study allowed us to develop a range of methods that could characterise patients according to the pumping and relaxing function of the heart, the burden of symptoms and to identify new blood markers. In this way, the investigators hoped to improve clinical practice guidelines, allowing doctors to prescribe appropriate treatments for the right patients. The research focused around a randomised trial of two medication strategies, providing much-needed data on the comparison of digoxin and beta-blockers (two commonly-used drugs in patients with atrial fibrillation). It also allowed us to identify the best way to record patient-reported quality of life and develop robust techniques to determine heart function using non-invasive imaging, facilitating the conduct of a large-scale clinical trial. The key objectives of the research programme were to define the optimal medications for patients with atrial fibrillation and identify the most valid, reproducible and cost-effective methods to examine patients. The ultimate aim of the project was to improve clinical outcomes in atrial fibrillation, benefiting patients, the National Health Service and the global community.
    Evidence for comparator
    		 A prospective, randomised, open-label, blinded-endpoint (PROBE) study design. Recruited patients will receive either: Digoxin- The maintenance dose of oral digoxin will be either 62.5μg or 125μg according to the pre-defined treatment schedule and up titrated, as required, to 250μg daily. A single loading dose of four tablets (250 or 500μg according to target maintenance dose) will be prescribed in digoxin-naïve participants, where necessary OR Beta-blocker- Oral bisoprolol will be commenced at either 1.25mg, 2.5mg or 5mg according to the treatment schedule and uptitrated, as required, to 15mg daily. Patients will be followed-up for the duration of treatment.
    Actual start date of recruitment
    20 Dec 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 161
    Worldwide total number of subjects
    161
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    15
    From 65 to 84 years
    117
    85 years and over
    29

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 First patient was randomised on the 20th December 2016 and the last patient was randomised on the 01st October 2018. A total of 161 patients were randomised into the Rate-AF Trial across one centre. Patients were equally recruited with 80 patients in the Bisoprolol arm and 81 in the Digoxin arm.

    Pre-assignment
    Screening details
    		 A total of 390 were screened for the trial, of these screened 161 were randomised.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [1]
    Blinding implementation details
    A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Digoxin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Digoxin Tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial maintenance doses will initially be 62.5 or 125 μg orally (at the clinician’s discretion, taking into account age and renal function), with planned up-titration to 125/250 μg. The maximum trial dose will be 250 μg daily. A single loading dose of four tablets (250 or 500 μg according to target maintenance dose) will be prescribed in digoxin-naïve participants. The clinician is permitted to omit the loading dose or prescribe a second, where necessary. Unblinded serum digoxin concentrations will be assessed at visits 2 and 3, with results reported back to the relevant clinician(s). This process will assist in monitoring compliance, adjusting dosage in cases of low serum levels and avoiding toxicity.

    Arm title
    		 Bisoprolol
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial starting doses will be 1.25 or 2.5 or 5 mg (at the clinician’s discretion), with planned up-titration to 10 mg in increments of 1.25 or 2.5 mg. The maximum trial dose will be 15 mg daily. No loading dose is required.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding implementation details: A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.
    Number of subjects in period 1
    		Digoxin Bisoprolol
    Started
    81
    80
    Completed
    81
    80
    Period 2
    Period 2 title
    6 months follw-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [2]
    Blinding implementation details
    A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Digoxin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Digoxin Tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial maintenance doses will initially be 62.5 or 125 μg orally (at the clinician’s discretion, taking into account age and renal function), with planned up-titration to 125/250 μg. The maximum trial dose will be 250 μg daily. A single loading dose of four tablets (250 or 500 μg according to target maintenance dose) will be prescribed in digoxin-naïve participants. The clinician is permitted to omit the loading dose or prescribe a second, where necessary. Unblinded serum digoxin concentrations will be assessed at visits 2 and 3, with results reported back to the relevant clinician(s). This process will assist in monitoring compliance, adjusting dosage in cases of low serum levels and avoiding toxicity.

    Arm title
    		 Bisoprolol
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial starting doses will be 1.25 or 2.5 or 5 mg (at the clinician’s discretion), with planned up-titration to 10 mg in increments of 1.25 or 2.5 mg. The maximum trial dose will be 15 mg daily. No loading dose is required.

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding implementation details: A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.
    Number of subjects in period 2
    		Digoxin Bisoprolol
    Started
    81
    80
    Completed
    76
    74
    Not completed
    5
    6
         Adverse event, serious fatal
    4
    5
         Consent withdrawn by subject
    1
    1
    Period 3
    Period 3 title
    12 month follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [3]
    Blinding implementation details
    A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Digoxin
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Digoxin Tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial maintenance doses will initially be 62.5 or 125 μg orally (at the clinician’s discretion, taking into account age and renal function), with planned up-titration to 125/250 μg. The maximum trial dose will be 250 μg daily. A single loading dose of four tablets (250 or 500 μg according to target maintenance dose) will be prescribed in digoxin-naïve participants. The clinician is permitted to omit the loading dose or prescribe a second, where necessary. Unblinded serum digoxin concentrations will be assessed at visits 2 and 3, with results reported back to the relevant clinician(s). This process will assist in monitoring compliance, adjusting dosage in cases of low serum levels and avoiding toxicity.

    Arm title
    		 Bisoprolol
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bisoprolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Trial starting doses will be 1.25 or 2.5 or 5 mg (at the clinician’s discretion), with planned up-titration to 10 mg in increments of 1.25 or 2.5 mg. The maximum trial dose will be 15 mg daily. No loading dose is required.

    Notes
    [3] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding implementation details: A prospective, randomised, open-label, blinded endpoint trial comparing digoxin and beta-blockers as initial rate control therapy with investigator blinded endpoint. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.
    Number of subjects in period 3
    		Digoxin Bisoprolol
    Started
    76
    74
    Completed
    73
    72
    Not completed
    3
    2
         Adverse event, serious fatal
    -
    2
         Consent withdrawn by subject
    1
    -
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Digoxin
    Reporting group description
    		 -

    Reporting group title
    Bisoprolol
    Reporting group description
    		 -

    Reporting group values
    		 Digoxin Bisoprolol Total
    Number of subjects
    		 81 80 161
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 11 4 15
        From 65-84 years
    		 59 58 117
        85 years and over
    		 11 18 29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 74.4 ( 8.4 ) 76.8 ( 8.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 36 38 74
        Male
    		 45 42 87
    On anticoagulant before randomisation
    Units: Subjects
        No
    		 9 17 26
        Yes
    		 72 63 135
    EHRA class
    *Minimisation variables Note: EHRA Class was categorised into (Class 1, 2a) and (Class 2b, 3, 4) for the minimisation algorithm
    Units: Subjects
        Cat 1
    		 0 0 0
        Cat 2a
    		 3 3 6
        Cat 2b
    		 35 40 75
        Cat 3
    		 38 27 65
        Cat 4
    		 5 10 15
    NYHA class
    Units: Subjects
        Class I
    		 0 0 0
        Class II
    		 47 53 100
        Class III
    		 32 24 56
        Class IV
    		 2 3 5
    Previous diagnosis of heart failure?
    Units: Subjects
        No
    		 46 56 102
        Yes
    		 35 24 59
    Any signs of heart failure at baseline
    Units: Subjects
        No
    		 32 45 77
        Yes
    		 49 35 84
    Type I diabetes
    Units: Subjects
        No
    		 81 80 161
        Yes
    		 0 0 0
    Type II diabetes
    Units: Subjects
        No
    		 65 58 123
        Yes
    		 16 22 38
    Unplanned admission for AF or HF in last 12 months
    Units: Subjects
        No
    		 65 65 130
        Yes
    		 16 15 31
    Any previous cardioversions
    Units: Subjects
        No
    		 74 71 145
        Yes
    		 7 9 16
    Previously undergone AF ablation
    Units: Subjects
        No
    		 79 79 158
        Yes
    		 2 1 3
    Previous history of anti-arrhythmic drugs
    Units: Subjects
        No
    		 75 72 147
        Yes
    		 6 8 14
    Self-declared ethnicity
    Units: Subjects
        White - English / Welsh / Scottish / Northern Iris
    		 72 66 138
        White - Irish
    		 4 8 12
        Asian / Asian British – Indian
    		 3 2 5
        Asian / Asian British – Pakistani
    		 0 3 3
        Black / African / Caribbean / Black British – Afri
    		 0 1 1
        Black / African / Caribbean / Black British – Cari
    		 2 0 2
    Creatinine
    Units: (micromol/L)
        arithmetic mean (standard deviation)
    		 87.9 ( 25.1 ) 91.4 ( 23.1 ) -
    Baseline NTproBNP
    Units: (pg/mL)
        arithmetic mean (standard deviation)
    		 1473.3 ( 2134 ) 1339.2 ( 1107.5 ) -
    Radial artery heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 87.8 ( 12 ) 86.9 ( 10.3 ) -
    Apex beat heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 98.3 ( 15.1 ) 99 ( 16.8 ) -
    12-Lead ECG Heart Rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 100.3 ( 16.8 ) 99.2 ( 19.2 ) -
    Systolic BP
    Units: mmHg
        arithmetic mean (standard deviation)
    		 134.5 ( 14.9 ) 137.1 ( 17.5 ) -
    Estimated ejection fraction
    Units: Percentage
        arithmetic mean (standard deviation)
    		 56.2 ( 8.8 ) 57.6 ( 10.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Digoxin
    Reporting group description
    		 -

    Reporting group title
    Bisoprolol
    Reporting group description
    		 -
    Reporting group title
    Digoxin
    Reporting group description
    		 -

    Reporting group title
    Bisoprolol
    Reporting group description
    		 -
    Reporting group title
    Digoxin
    Reporting group description
    		 -

    Reporting group title
    Bisoprolol
    Reporting group description
    		 -

    Primary: Primary outcome- SF36v2 PCS

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    End point title
    		 Primary outcome- SF36v2 PCS [1]
    End point description
    The primary outcome is the SF-36v2 physical component summary (PCS) score at 6 months.
    End point type
    Primary
    End point timeframe
    6 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The CI instructed that we do not provide the analyses and just to enter the minimum fields only. Full analysis result has already been published in the paper, Jama.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    76
    74
    Units: Score
        arithmetic mean (standard deviation)
    28.9 ( 11.6 )
    27.2 ( 10.2 )
    31.9 ( 11.7 )
    29.7 ( 11.4 )
    No statistical analyses for this end point

    Secondary: SF36v2 Physical Component Summary (PCS)

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    End point title
    		 SF36v2 Physical Component Summary (PCS)
    End point description
    End point type
    Secondary
    End point timeframe
    6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    72
    72
    Units: score
        arithmetic mean (standard deviation)
    28.9 ( 11.6 )
    27.2 ( 10.2 )
    32.5 ( 13 )
    29.4 ( 12.4 )
    No statistical analyses for this end point

    Secondary: SF-36v2 Mental Component Summary (MCS)

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    End point title
    		 SF-36v2 Mental Component Summary (MCS)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    76
    74
    72
    72
    Units: Score
        arithmetic mean (standard deviation)
    50.4 ( 10.2 )
    49.5 ( 10 )
    51.1 ( 10.6 )
    50 ( 10.4 )
    53.6 ( 8.9 )
    51.3 ( 10.1 )
    No statistical analyses for this end point

    Secondary: SF-36v2 Physical Function Domain Score (PF)

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    End point title
    		 SF-36v2 Physical Function Domain Score (PF)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    26.8 ( 12.6 )
    25.9 ( 12.2 )
    29.2 ( 13.7 )
    27.7 ( 13.6 )
    31.5 ( 14.1 )
    27.5 ( 13 )
    No statistical analyses for this end point

    Secondary: SF-36 Role Limitation Due to Physical Domain score (RP)

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    End point title
    		 SF-36 Role Limitation Due to Physical Domain score (RP)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    31.8 ( 12.6 )
    29.6 ( 12.1 )
    34.2 ( 12 )
    31.3 ( 12.8 )
    37 ( 12.6 )
    32 ( 12.4 )
    No statistical analyses for this end point

    Secondary: SF-36 Role Limitation Due to Emotional Problems Domain score (RE)

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    End point title
    		 SF-36 Role Limitation Due to Emotional Problems Domain score (RE)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 .
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    40.2 ( 14.3 )
    39.8 ( 15 )
    42 ( 13.3 )
    38.7 ( 14.9 )
    45.2 ( 12.9 )
    40.7 ( 15.5 )
    No statistical analyses for this end point

    Secondary: SF-36v2 Social Functioning Domain Score (SF)

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    End point title
    		 SF-36v2 Social Functioning Domain Score (SF)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    42.8 ( 12.3 )
    41.3 ( 12 )
    46.1 ( 11.5 )
    43.5 ( 12.5 )
    45.6 ( 12.3 )
    43.3 ( 11.6 )
    No statistical analyses for this end point

    Secondary: SF-36v2 Mental Health Domain (MH)

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    End point title
    		 SF-36v2 Mental Health Domain (MH)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    48 ( 11.6 )
    48.2 ( 9.5 )
    48.2 ( 10.7 )
    49.4 ( 11.2 )
    51.3 ( 9.3 )
    51.8 ( 9.5 )
    No statistical analyses for this end point

    Secondary: SF-36v2 Energy/Vitality Domain Score (EV)

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    End point title
    		 SF-36v2 Energy/Vitality Domain Score (EV)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    43.4 ( 9.6 )
    40.3 ( 10 )
    44.9 ( 10.4 )
    43 ( 10 )
    47.1 ( 9.9 )
    42 ( 10 )
    No statistical analyses for this end point

    Secondary: SF-36v2- Pain Score (Pain)

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    End point title
    		 SF-36v2- Pain Score (Pain)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    80
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    39.1 ( 12.2 )
    37.5 ( 10.9 )
    42 ( 12.1 )
    41 ( 11.6 )
    40.5 ( 12.7 )
    41.9 ( 12.5 )
    No statistical analyses for this end point

    Secondary: SF-36v2- General Health Perception Domain Score (GHP)

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    End point title
    		 SF-36v2- General Health Perception Domain Score (GHP)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    72
    72
    Units: Score
        arithmetic mean (standard deviation)
    40.5 ( 9.4 )
    39 ( 9.4 )
    41.6 ( 9.6 )
    40 ( 9.8 )
    42.8 ( 9.9 )
    39.6 ( 10 )
    No statistical analyses for this end point

    Secondary: EQ-5D-5L summary index score

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    End point title
    		 EQ-5D-5L summary index score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    0.67 ( 0.19 )
    0.63 ( 0.22 )
    0.66 ( 0.27 )
    0.65 ( 0.23 )
    0.66 ( 0.27 )
    0.62 ( 0.29 )
    No statistical analyses for this end point

    Secondary: EQ-5D-5L visual analogue scale (VAS) score

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    End point title
    		 EQ-5D-5L visual analogue scale (VAS) score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    64 ( 16.6 )
    61.6 ( 20.3 )
    71.8 ( 16.3 )
    68.5 ( 17.1 )
    72.2 ( 17 )
    66.2 ( 17.9 )
    No statistical analyses for this end point

    Secondary: AFEQT overall score

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    End point title
    		 AFEQT overall score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    62.2 ( 16.7 )
    57.2 ( 17.6 )
    72.1 ( 17.9 )
    65.6 ( 16.8 )
    75.6 ( 17.1 )
    68.1 ( 16.1 )
    No statistical analyses for this end point

    Secondary: Echocardiographic LVEF

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    End point title
    		 Echocardiographic LVEF
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    56.2 ( 8.8 )
    57.6 ( 10.5 )
    59.7 ( 8.7 )
    59.8 ( 7.3 )
    No statistical analyses for this end point

    Secondary: Diastolic Function E/e

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    End point title
    		 Diastolic Function E/e
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    73
    72
    Units: Score
        arithmetic mean (standard deviation)
    10.7 ( 4.5 )
    10.2 ( 4.7 )
    10.8 ( 5.1 )
    10.8 ( 5.5 )
    No statistical analyses for this end point

    Secondary: Composite of diastolic indices

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    End point title
    		 Composite of diastolic indices
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    73
    72
    Units: Percentages
        No
    68
    72
    65
    65
        Yes
    13
    8
    8
    7
    No statistical analyses for this end point

    Secondary: Radial Heart Rate (bpm)

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    End point title
    		 Radial Heart Rate (bpm)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: bpm
        arithmetic mean (standard deviation)
    87.8 ( 12 )
    86.9 ( 10.3 )
    76.2 ( 9.7 )
    73.9 ( 10.8 )
    76 ( 9 )
    73.8 ( 10 )
    No statistical analyses for this end point

    Secondary: Apical Heart rate

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    End point title
    		 Apical Heart rate
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: bpm
        arithmetic mean (standard deviation)
    98.3 ( 15.1 )
    99 ( 16.8 )
    78.4 ( 10.5 )
    76.2 ( 11.1 )
    78.3 ( 9.2 )
    76.2 ( 10.6 )
    No statistical analyses for this end point

    Secondary: 12-lead ECG Heart rate (bpm)

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    End point title
    		 12-lead ECG Heart rate (bpm)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: bpm
        arithmetic mean (standard deviation)
    100.3 ( 16.8 )
    99.2 ( 19.2 )
    76.9 ( 12.1 )
    74.8 ( 11.6 )
    75.4 ( 9.9 )
    74.3 ( 11.2 )
    No statistical analyses for this end point

    Secondary: 24-hour ambulatory average Heart rate (bpm)

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    End point title
    		 24-hour ambulatory average Heart rate (bpm)
    End point description
    This measurement was just done once. Change in heart rate using 24-hour ambulatory ECG.
    End point type
    Secondary
    End point timeframe
    24-hour time period
    End point values
    		 Digoxin Bisoprolol
    Number of subjects analysed
    76
    78
    Units: bpm
        arithmetic mean (standard deviation)
    78.9 ( 11.3 )
    73.7 ( 10.9 )
    No statistical analyses for this end point

    Secondary: Distance covered (in metres) from the six-minute walk test

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    End point title
    		 Distance covered (in metres) from the six-minute walk test
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    79
    74
    73
    71
    69
    Units: Metres
        median (inter-quartile range (Q1-Q3))
    321 (120 to 419)
    330 (90 to 450)
    335.5 (180 to 422)
    348 (180 to 431)
    366 (233 to 435)
    329 (120 to 429)
    No statistical analyses for this end point

    Secondary: NTproBNP

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    End point title
    		 NTproBNP
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline, 6 and 12 months.
    End point values
    		 Digoxin Bisoprolol Digoxin Bisoprolol Digoxin Bisoprolol
    Number of subjects analysed
    81
    80
    76
    74
    73
    72
    Units: ng/L
        median (inter-quartile range (Q1-Q3))
    1091 (710 to 1522)
    1040.5 (752.5 to 1480)
    1057.5 (625.5 to 1531)
    1209 (837 to 1531)
    960 (626 to 1531)
    1249.5 (847 to 1890)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Targeted AEs reported on the CRF were reportable to the RATE-AF Trial Office up to 30 days post last IMP administration. Any SUSAR related to the IMP was expected to be reported irrespective of how long after IMP administration the reaction has occurred.
    Adverse event reporting additional description
    Adverse events (AEs) were recorded in the medical records and CRFs. Most AE/ARs that occurred in the trial, whether they are serious or not, were 'expected' treatment-related toxicities due to the drugs used in this trial.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Digoxin
    Reporting group description
    		 -

    Reporting group title
    Bisoprolol
    Reporting group description
    		 -

    Serious adverse events
    		 Digoxin Bisoprolol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 81 (16.05%)
    21 / 80 (26.25%)
         number of deaths (all causes)
    4
    7
         number of deaths resulting from adverse events
    4
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Secondary Malignancy
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 81 (2.47%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Vascular disorders
    Haemorrhage/Bleeding
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Constitutional Symptoms
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Pulmonary/Upper Respiratory
         subjects affected / exposed
    1 / 81 (1.23%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Arrhythmia
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac general
         subjects affected / exposed
    1 / 81 (1.23%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Nervous system disorders
    Pain
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurology
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphatics
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 80 (3.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hepatobiliary disorders
    Hepatobiliary/Pancreas
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatology/Skin
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal/Genitourinary
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal/Soft Tissue
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 81 (0.00%)
    4 / 80 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Digoxin Bisoprolol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 81 (24.69%)
    51 / 80 (63.75%)
    Cardiac disorders
    Symptomatic bradycardia
         subjects affected / exposed
    0 / 81 (0.00%)
    5 / 80 (6.25%)
         occurrences all number
    0
    5
    Symptomatic hypotension
         subjects affected / exposed
    0 / 81 (0.00%)
    6 / 80 (7.50%)
         occurrences all number
    0
    7
    General disorders and administration site conditions
    Peripheral oedema
         subjects affected / exposed
    1 / 81 (1.23%)
    11 / 80 (13.75%)
         occurrences all number
    1
    12
    Dizziness
         subjects affected / exposed
    4 / 81 (4.94%)
    24 / 80 (30.00%)
         occurrences all number
    4
    28
    Headache
         subjects affected / exposed
    5 / 81 (6.17%)
    9 / 80 (11.25%)
         occurrences all number
    5
    11
    Lethargy
         subjects affected / exposed
    7 / 81 (8.64%)
    30 / 80 (37.50%)
         occurrences all number
    7
    37
    Eye disorders
    Blurred Vision
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 80 (1.25%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Gastrointestinal upset
         subjects affected / exposed
    5 / 81 (6.17%)
    8 / 80 (10.00%)
         occurrences all number
    5
    8
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract symptoms
         subjects affected / exposed
    1 / 81 (1.23%)
    13 / 80 (16.25%)
         occurrences all number
    1
    15
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jul 2017
    Addition of new site.
    29 May 2018
    * Changes made to protocol. * Changes made to Participant Optional Consent Form. New documents submitted: - Optional Sub Study ‘Nerve Activity and Heart Rate’ Patient information leaflet. - Optional Sub Study ‘Physical Activity and Heart Rate Monitoring’ Patient information leaflet.
    21 Nov 2019
    Change of Principle Investigator.
    13 Dec 2019
    Changes made to protocol.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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