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    Clinical Trial Results:
    IMPRESS-AF: IMproved exercise tolerance in patients with PReserved Ejection fraction by Spironolactone on myocardial fibrosiS in Atrial Fibrillation

    Summary
    EudraCT number
    		 2014-003702-33
    Trial protocol
    		 GB  
    Global end of trial date
    27 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Mar 2021
    First version publication date
    05 Mar 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_14-150
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    University of Birmingham, Birmingham, United Kingdom,
    Public contact
    Eduard Shantsila, University of Birmingham, +44 01215075086, eduard.shantsila1@nhs.net
    Scientific contact
    Eduard Shantsila, University of Birmingham, +44 01215075086, eduard.shantsila1@nhs.net
    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
    27 Sep 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The IMPRESS-AF trial addressed whether two years of treatment with spironolactone as compared to placebo improves exercise tolerance, quality of life and diastolic function in patients with permanent AF and preserved left ventricular ejection fraction (LVEF).
    Protection of trial subjects
    *The trial will be managed by the Primary Care Clinical Trials Unit (PCCRTU), an NIHR accredited CTU that is experienced in the management of clinical trials. The unit has developed the infrastructure, processes and systems to eliminate potential risks and burdens wherever possible and manage where this is not the case. * Spironolactone is a widely used drug and has a large evidence base for the effective treatment in heart failure. Side effects and safety data are therefore well established. * Cardiopulmonary exercise test and 6minute walk test: there is a small risk of complications, such as myocardial infarction,left ventricular rupture, ventricular fibrillation or ventricular tachycardia The study involves low risk patients. Any participant presenting with factors associated with higher risk of complications (eg, symptomatic coronary disease, recent acute coronary events, severe valvular disease, impaired left ventricular systolic function) will be excluded from the study. Protocol specific training will be given to the personnel who will be performing the tests and taking the bloods. The tests will be done on a hospital site and facilities and staff for emergency help will be available at all times. * Blood tests may cause minimal discomfort and bruising at the site of the needle going through the skin. All blood sampling will be done by experienced clinical research fellow.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2015
    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: 250
    Worldwide total number of subjects
    250
    EEA total number of subjects
    250
    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)
    41
    From 65 to 84 years
    199
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients ≥ 50 years old, no spironolactone treatment with permanent AF according to ESC criteria as a cardiac arrhythmia with surface ECG ‘absolutely’ irregular RR intervals, no distinct P waves on surface ECG, atrial cycle length usually variable and <300 bpm, duration of the AF >12 months & no plans for pharmacological/electrical cardioversion

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 spironolactone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    spironolactone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Arm title
    		 placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    a single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Number of subjects in period 1
    		spironolactone placebo
    Started
    125
    125
    Completed
    125
    125
    Period 2
    Period 2 title
    12 month time point
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 spironolactone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    spironolactone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Arm title
    		 placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    a single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Number of subjects in period 2
    		spironolactone placebo
    Started
    125
    125
    Completed
    111
    117
    Not completed
    14
    8
         Consent withdrawn by subject
    11
    7
         death
    3
    1
    Period 3
    Period 3 title
    24 month time point
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 spironolactone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    spironolactone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Arm title
    		 placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    a single 25 milligram tablet taken orally once per day (typically to be taken during the morning, but can be taken regularly at other time of day if preferable) for a 24 month period

    Number of subjects in period 3
    		spironolactone placebo
    Started
    111
    117
    Completed
    101
    106
    Not completed
    10
    11
         Consent withdrawn by subject
    8
    9
         death
    2
    2

    Baseline characteristics

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

    Reporting group title
    placebo
    Reporting group description
    		 -

    Reporting group values
    		 spironolactone placebo Total
    Number of subjects
    		 125 125 250
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.4 ± 7.1 72.3 ± 7.9 -
    Gender categorical
    Units: Subjects
        Female
    		 28 31 59
        Male
    		 97 94 191
    Peak VO2
    The dichotomised peak VO2 score (ml O2/kg/min) was used as the stratification variable
    Units: Subjects
        ≤ 16 mL
    		 77 78 155
        > 16 mL
    		 48 47 95
        Not recorded
    		 0 0 0
    Current medication
    1 patients data missing (reporting group 2)
    Units: Subjects
        Yes
    		 123 124 247
        No
    		 2 0 2
        Not recorded
    		 0 1 1
    Smoking status
    Units: Subjects
        Current smoker
    		 6 8 14
        Ex-smoker
    		 66 68 134
        Non-smoker
    		 53 49 102
        Not recorded
    		 0 0 0
    Ethnicity
    Units: Subjects
        White
    		 118 118 236
        Mixed
    		 1 0 1
        Black
    		 3 3 6
        Asian
    		 3 2 5
        Other ethnic group
    		 0 2 2
        Not recorded
    		 0 0 0
    Peak VO2
    Units: ml O2/kg/min
        arithmetic mean (standard deviation)
    		 14.5 ± 4.6 14.6 ± 5.1 -
    BMI
    2 patients data missing (reporting group 2)
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 30.4 ± 5.2 30.5 ± 5.6 -
    Alcohol use
    Units: Units per week
        arithmetic mean (standard deviation)
    		 7.2 ± 9.9 8.8 ± 10.8 -
    6 minute walk test
    Units: meters
        arithmetic mean (standard deviation)
    		 256.7 ± 83.4 270.4 ± 89.5 -
    Resting heart rate
    Units: bpm
        arithmetic mean (standard deviation)
    		 87.3 ± 19.4 86.7 ± 18.7 -
    Peak heart rate during CPET
    Units: bpm
        arithmetic mean (standard deviation)
    		 128.4 ± 26.1 129.9 ± 25.4 -
    BNP
    One patient data not recorded (Reporting group 2)
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 163.5 ± 125.4 183.3 ± 168.5 -
    Systolic blood pressure
    One patient data not recorded (Reporting group 2)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 129.2 ± 15.5 130.1 ± 15.0 -
    Diastolic blood pressure
    One patient data not recorded (Reporting group 2)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 75.7 ± 10.9 75.6 ± 13.9 -
    Waist circumference
    Two patients data not recorded (Reporting group 2)
    Units: cm
        arithmetic mean (standard deviation)
    		 99.5 ± 12.5 100.3 ± 14.4 -
    Hip circumference
    Two patients data not recorded (Hip circumference) reporting group 2
    Units: cm
        arithmetic mean (standard deviation)
    		 107.4 ± 10.0 108.0 ± 13.2 -
    Left ventricular ejection fraction
    Units: percent
        arithmetic mean (standard deviation)
    		 60.4 ± 5.4 60.5 ± 5.7 -
    Mitral valve measurement
    Units: E/E’ ratio
        arithmetic mean (standard deviation)
    		 10.7 ± 4.4 10.6 ± 4.2 -
    EQ-5D-5L
    9 patient's data not recorded (4 reporting group 1, 5 reporting group 2)
    Units: Score
        arithmetic mean (standard deviation)
    		 0.81 ± 0.19 0.83 ± 0.16 -
    ML WHF
    To score MLWHF (Minnesota Living with Heart Failure) questionnaire, it was allowed that at most 20% of 21 responses missing which was equivalent to 4 data items. If there were less than or equal to 4 data items missing then we used mean substitution to impute the missing responses and then scored the questionnaire by summating the responses to all 21 questions; otherwise, the persons score was left missing. 12 patients data was not recorded (8 reporting arm 1, 4 reporting arm 2)
    Units: Score
        arithmetic mean (standard deviation)
    		 22.9 ± 20.4 21.9 ± 22.9 -

    End points

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

    Reporting group title
    placebo
    Reporting group description
    		 -
    Reporting group title
    spironolactone
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -
    Reporting group title
    spironolactone
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Primary: peak VO2 on cardiopulmonary exercise testing (Primary analysis adjusted for stratification variable)

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    End point title
    		 peak VO2 on cardiopulmonary exercise testing (Primary analysis adjusted for stratification variable)
    End point description
    The primary analysis followed intention to treat principles including participants regardless of their compliance with the medication. Participants with missing data for the final assessment were excluded except for those who died before the 24 month follow-up assessment. For these participants, their peak VO2 scores at 24 months were imputed as zero values regardless of cause. Whilst the value of 0 was not actually measured, it allowed inclusion of the patient in the study and it should be a suitable reflection of the health state of the patient. The imputation rules were defined prior to any data analysis and reported in the Statistical Analysis Plan. A value of 0 was assigned to peak VO2 score for those who died before the 24 month follow-up assessment
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    103
    106
    Units: ml O2/kg/min
        arithmetic mean (standard deviation)
    14.03 ± 5.38
    14.45 ± 5.14
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    placebo v spironolactone
    Number of subjects included in analysis
    209
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Exercise tolerance measured by 6-minute walking test (a simple test of exercise performance) at 2 years- Primary analysis (adjusted for stratification variable)

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    End point title
    		 Exercise tolerance measured by 6-minute walking test (a simple test of exercise performance) at 2 years- Primary analysis (adjusted for stratification variable)
    End point description
    Analyses of secondary outcomes were performed on the intention to treat basis as for the primary outcome. For the 6 minute walking test, the analysis substituted a zero value for those participants who had died before the 24 month follow-up assessment regardless of causes. Placebo group is the reference group.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    105
    107
    Units: meter
        arithmetic mean (standard deviation)
    312.90 ± 108.12
    330.43 ± 112.16
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: left ventricular diastolic function (E/E’ ratio on echocardiography) assessed at 2 years (Primary analysis (adjusted for stratification variable)

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    End point title
    		 left ventricular diastolic function (E/E’ ratio on echocardiography) assessed at 2 years (Primary analysis (adjusted for stratification variable)
    End point description
    if patients who died before the 24 month follow-up assessment, no imputation was done for these missing values and so analysis for those was done on all available data only, i.e. complete case analysis.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    101
    106
    Units: E/E’ ratio
        arithmetic mean (standard deviation)
    9.00 ± 3.05
    9.72 ± 3.57
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Brain natriuretic peptide level (BNP) at 2 years Primary analysis (adjusted for stratification variable)

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    End point title
    		 Brain natriuretic peptide level (BNP) at 2 years Primary analysis (adjusted for stratification variable)
    End point description
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    101
    105
    Units: pg/mL
        arithmetic mean (standard deviation)
    179.43 ± 170.55
    185.61 ± 109.65
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    206
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Quality of life (EQ-5D-5L questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)

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    End point title
    		 Quality of life (EQ-5D-5L questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)
    End point description
    Analyses of secondary outcomes were performed on the intention to treat basis as for the primary outcome. EQ-5D-5L score, the lowest value across the whole participants was assigned to those who died before the 12 month follow-up assessment (Placebo group is the reference group)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    106
    111
    Units: EuroQol score
        arithmetic mean (standard deviation)
    0.83 ± 0.21
    0.84 ± 0.18
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.67
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Quality of life (EQ-5D-5L questionnaire) over the 24 month duration Primary analysis (adjusted for stratification variable)

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    End point title
    		 Quality of life (EQ-5D-5L questionnaire) over the 24 month duration Primary analysis (adjusted for stratification variable)
    End point description
    Analyses of secondary outcomes were performed on the intention to treat basis as for the primary outcome. EQ-5D-5L score, the lowest value across the whole participants was assigned to those who died before the 24 month follow-up assessment (Placebo group is the reference group)
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    98
    104
    Units: EuroQol score
        arithmetic mean (standard deviation)
    0.82 ± 0.24
    0.84 ± 0.20
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.77
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Quality of life (MLWHF questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)

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    End point title
    		 Quality of life (MLWHF questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)
    End point description
    Analyses of secondary outcomes were performed on the intention to treat basis as for the primary outcome. Minnesota Living with Heart Failure questionnaire, the highest value across the whole participants was assigned to those who died before the 12 month follow-up assessment. Minnesota Living with Heart Failure questionnaire; score ranges from 0 to 105 with a higher score reflecting poorer quality of life
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    101
    110
    Units: MLWHF score
        arithmetic mean (standard deviation)
    18.44 ± 20.89
    16.90 ± 17.76
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    211
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.51
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: Quality of life (MLWHF questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)

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    End point title
    		 Quality of life (MLWHF questionnaire) over the two year duration Primary analysis (adjusted for stratification variable)
    End point description
    Analyses of secondary outcomes were performed on the intention to treat basis as for the primary outcome. Minnesota Living with Heart Failure questionnaire, the highest value across the whole participants was assigned to those who died before the 24 month follow-up assessment. Minnesota Living with Heart Failure questionnaire; score ranges from 0 to 105 with a higher score reflecting poorer quality of life
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    96
    104
    Units: MLWHF score
        arithmetic mean (standard deviation)
    17.39 ± 22.72
    15.34 ± 20.35
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Regression, Linear
    Confidence interval

    Secondary: spontaneous return to sinus rhythm (ECG) at 2 years- Primary analysis (adjusted for stratification variable)

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    End point title
    		 spontaneous return to sinus rhythm (ECG) at 2 years- Primary analysis (adjusted for stratification variable)
    End point description
    Analysis undertaken on complete cases only. “Yes” means spontaneous return to sinus rhythm (ECG) after 2 years of treatment (Placebo group is the reference group)
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    101
    106
    Units: number
        Yes
    8
    4
        No
    93
    102
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    spironolactone v placebo
    Number of subjects included in analysis
    207
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.21
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: rates of all-cause hospitalisations during 2 year follow-up Participants with at least one event- Primary analysis (adjusted for stratification variable)

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    End point title
    		 rates of all-cause hospitalisations during 2 year follow-up Participants with at least one event- Primary analysis (adjusted for stratification variable)
    End point description
    End point type
    Secondary
    End point timeframe
    during 24 month follow up
    End point values
    		 spironolactone placebo
    Number of subjects analysed
    118
    123
    Units: number
    18
    28
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The SAE reporting period was from the date of consent (screening) until 7 days after the last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    spironolactone
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 spironolactone placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 125 (18.40%)
    32 / 125 (25.60%)
         number of deaths (all causes)
    5
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 125 (0.00%)
    3 / 125 (2.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Penile cancer
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer metastatic
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    lung cancer
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pulmonary emboli
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    sacrohysteropexy
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    total hip replacement
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Total knee replacement
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden death
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Immune system disorders
    Facial swelling
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    shortness of breath
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    fracture neck of femur
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 125 (0.80%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    symptomatic bradycardia
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    dilated right ventricle
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    complications of Bypass surgery
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina episode
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope Asystole Pacemaker insertion
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 125 (0.80%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Stroke
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    transient ischaemic attack
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    intra cranial bleed
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Iron deficiency anaemia
    Additional description: Chest infection with symptomatic iron deficiency anaemia.
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    unilateral loss of vision
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gut emboli
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    upper GI bleeding
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    duodenal bleeding ulcer
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary clot
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    cellulitis sepsis
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Diarrhoea
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    diarrhoea and vomiting
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    infected left leg ulcers
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 125 (2.40%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest infection
         subjects affected / exposed
    2 / 125 (1.60%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    septic arthritis
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septicaemia
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    infective endocarditis
         subjects affected / exposed
    0 / 125 (0.00%)
    2 / 125 (1.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    clostridium difficile bacterial sepsis
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 spironolactone placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 125 (69.60%)
    65 / 125 (52.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignancy
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Constitutional Symptoms
         subjects affected / exposed
    15 / 125 (12.00%)
    22 / 125 (17.60%)
         occurrences all number
    20
    30
    Haemorrhage/Bleeding
         subjects affected / exposed
    2 / 125 (1.60%)
    3 / 125 (2.40%)
         occurrences all number
    2
    3
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 125 (1.60%)
    0 / 125 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    17 / 125 (13.60%)
    5 / 125 (4.00%)
         occurrences all number
    40
    9
    Breast swelling
         subjects affected / exposed
    11 / 125 (8.80%)
    4 / 125 (3.20%)
         occurrences all number
    26
    10
    Sexual/Reproductive Function
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 125 (0.80%)
         occurrences all number
    1
    1
    Cardiac disorders
    Cardiac Arrhythmia/ Cardiac General
         subjects affected / exposed
    21 / 125 (16.80%)
    33 / 125 (26.40%)
         occurrences all number
    34
    65
    Nervous system disorders
    Neurology
         subjects affected / exposed
    7 / 125 (5.60%)
    5 / 125 (4.00%)
         occurrences all number
    9
    6
    Eye disorders
    Ocular/Visual
         subjects affected / exposed
    2 / 125 (1.60%)
    3 / 125 (2.40%)
         occurrences all number
    2
    3
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    13 / 125 (10.40%)
    19 / 125 (15.20%)
         occurrences all number
    18
    24
    Skin and subcutaneous tissue disorders
    Dermatology/Skin
         subjects affected / exposed
    6 / 125 (4.80%)
    5 / 125 (4.00%)
         occurrences all number
    9
    7
    Renal and urinary disorders
    Estimated glomerular filtration < 30 mL/min/1.73m2
         subjects affected / exposed
    8 / 125 (6.40%)
    2 / 125 (1.60%)
         occurrences all number
    8
    2
    Renal
         subjects affected / exposed
    0 / 125 (0.00%)
    1 / 125 (0.80%)
         occurrences all number
    0
    1
    Genitourinary
         subjects affected / exposed
    3 / 125 (2.40%)
    1 / 125 (0.80%)
         occurrences all number
    4
    1
    Endocrine disorders
    Endocrine
         subjects affected / exposed
    1 / 125 (0.80%)
    1 / 125 (0.80%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal/Soft Tissue
         subjects affected / exposed
    16 / 125 (12.80%)
    23 / 125 (18.40%)
         occurrences all number
    20
    26
    Infections and infestations
    Infection
         subjects affected / exposed
    12 / 125 (9.60%)
    10 / 125 (8.00%)
         occurrences all number
    13
    11
    Metabolism and nutrition disorders
    Hyperkalaemia (≥5.1 mmol/L)
         subjects affected / exposed
    46 / 125 (36.80%)
    17 / 125 (13.60%)
         occurrences all number
    72
    30
    Hyperkalaemia (≥6.0 mmol/L)
         subjects affected / exposed
    3 / 125 (2.40%)
    0 / 125 (0.00%)
         occurrences all number
    3
    0
    Serum creatinine ever >220 μmol/L
         subjects affected / exposed
    1 / 125 (0.80%)
    0 / 125 (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
    10 Mar 2015
    Change in blood tests Change in drug manufacturer. Removal of GP checklist. Addition of rebooking tests. Clarification of randomisation and blinding.
    01 May 2015
    Inclusion in the trial is no longer conditional on the patient having normal BNP levels (<100pg/mL). Clarification of personnel designated as CI and PI. Trial Management Group to meet regularly rather than weekly (section 14.3). Amendment of section 6.3 (Blinding) to clarify that individual sealed code break envelopes will be used, rather than a master list. Change of trial statistician due to retirement of original person. Pharmacy to audit drug storage facility annually, rather than six monthly, in line with internal NHS policy (section 7.1.4). Non-responders to invitation from Primary Care to be sent a reminder letter (Section 4.1 and 8.1). Minor corrections to grammar and spelling.
    12 Oct 2015
    A mechanistic sub-analysis of impact of biomarkers of fibrosis and haemostasis in the study population (Appendix 1) To include a timeline for visit windows. The Ability to understand questionnaires being removed as an inclusion criteria and added as an exclusion criteria.(section 4.1)
    10 Mar 2016
    IMP dispensing schedule amended to reflect that Drug will be dispensed at different clinic visits for a small number of patients. GP invitation letter amended to reflect that The University of Birmingham will keep the information provided on reply slips on a secure database until they are no longer needed, and they will then be destroyed. Telephone pre-screening added to the protocol. Participants that have expressed an interest will be prescreened by telephone and asked the medical questions outlined in section 3.1. Minor corrections to grammar and spelling.
    05 Jan 2017
    Threshold for withdrawal due to hyperkalaemia increased to K+>6.0 mmol/L, up from >5.5 mmol/L. Reduced follow-up focussed on trial outcomes permitted for patients that have withdrawn from trial treatment only. Increased flexibility for dispensing of trial medication to ensure continuous supply. Changes to reflect merger of trials units at University of Birmingham. Clarifications to required trial assessments, time window frame permitted for follow up visits at month 6, 12 and 18 changed and to monitoring of concomitant medications. Minor corrections and clarifications.
    13 Apr 2017
    Section 6.3: Additional spare bottles of trial medication will be ordered as required as part of the scheduled order has been added. Section 7.2: to ensure consistency of wording throughout the protocol nonlife threatening side effects such as gynaecomastia has been changed to “significant” gynaecomastia. IMP re-up-titration clarification added: “the patient is likely to maintain potassium levels ≤5.0 mmol/L after returning to a full dose” Section 8.4: Participant incentive detailed in the protocol in line with approved PIS v5 dated 30th March 2015. Section 8.5: Definitions of Patient discontinuation in the trial have been added. Section 8.6: The process of informing patients of their treatment allocation after data analysis has been completed stipulated. Section 9: Reference Safety Information (RSI) is specified as undesirable effects of Summary of Medicinal Product Characteristics (SmPC) for spironolactone 25mg (updated 13/04/2016). Assessment of all Adverse Events changed from CI & PI to PI & medically qualified delegate. PI signature page added. Data manager name added.

    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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