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    Clinical Trial Results:
    Impact of Eplerenone on Asymptomatic Left Ventricular Diastolic Dysfunction in Diabetic Patients

    Summary
    EudraCT number
    		 2011-006123-37
    Trial protocol
    		 IE  
    Global end of trial date
    23 Nov 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Dec 2016
    First version publication date
    08 Dec 2016
    Other versions
    Summary report(s)
    		 Study Synopsis

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    SI-C-019
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Solvotrin Innovations Ltd
    Sponsor organisation address
    Hoffmann Park, Inchera, Little Island, Cork, Ireland, T45 YX04
    Public contact
    Clinical Trials Project Manager, Solvotrin Innovations Ltd, +353 21 4205339, fionaryan@solvotrin.com
    Scientific contact
    Clinical Trials Project Manager, Solvotrin Innovations Ltd, +353 21 4205339, fionaryan@solvotrin.com
    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
    23 Nov 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Nov 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the change in Left Atrial Volume Index (LAVI), measured by magnetic resonance imaging (MRI) in the treated group vs. the untreated group
    Protection of trial subjects
    This study was carried out in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Before initiating the study, all relevant documentation including the study protocol and patient information and informed consent form were reviewed and approved by the relevant competent authority and the St Vincent's University Hospital Ethics Committee. Each participant was provided with an information and consent form in clear, simple language and was given ample time to inquire about details of the study and to decide whether of not to participate in the study. Participants anonymity was maintained at all times throughout the study.
    Background therapy
    		 Usual medical care
    Evidence for comparator
    		 The comparator group was usual medical care. There was no placebo.
    Actual start date of recruitment
    03 Sep 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ireland: 52
    Worldwide total number of subjects
    52
    EEA total number of subjects
    52
    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)
    36
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Trial participants were recruited from the Blood Pressure Unit of St Michael's Hospital, Dun Laoghaire, Co Dublin. Male and female patients >18 years of age were eligible to participate once eligibility criteria were met.

    Pre-assignment
    Screening details
    		 The STOP-HF database was screened to identify patients that met the inclusion criteria (age, diabetes, diastolic dysfunction). Potentially eligible patients were invited to a 'Screening visit' at which eligibility was further assessed/confirmed.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Unblinded study

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (eplerenone)
    Arm description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eplerenone
    Investigational medicinal product code
    Other name
    Inspra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eplerenone 25mg once daily orally for one month. Dose increased to 50mg once daily orally for the remainder of the study (11 months) providing the increase in creatinine from baseline is no greater than 25% and the potassium level within one week of commencing eplerenone is <5.5 mmol/L.

    Arm title
    		 Control
    Arm description
    		 Usual medical care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Intervention (eplerenone) Control
    Started
    28
    24
    Completed
    28
    24
    Period 2
    Period 2 title
    12 months
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention (eplerenone)
    Arm description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eplerenone
    Investigational medicinal product code
    Other name
    Inspra
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eplerenone 25mg once daily orally for one month. Dose increased to 50mg once daily orally for the remainder of the study (11 months) providing the increase in creatinine from baseline is no greater than 25% and the potassium level within one week of commencing eplerenone is <5.5 mmol/L.

    Arm title
    		 Control
    Arm description
    		 Usual medical care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Intervention (eplerenone) Control
    Started
    28
    24
    Completed
    24
    24
    Not completed
    4
    0
         Consent withdrawn by subject
    3
    -
         Adverse event, non-fatal
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention (eplerenone)
    Reporting group description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care

    Reporting group values
    		 Intervention (eplerenone) Control Total
    Number of subjects
    		 28 24 52
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 9 16
        From 65-84 years
    		 21 15 36
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 72 (65 to 76) 67 (63 to 72) -
    Gender categorical
    Units: Subjects
        Female
    		 6 8 14
        Male
    		 22 16 38
    Diabetes
    The demographics and comorbidity profile of the population are typical of patients with asymptomatic left ventricular diastolic dysfunction (ALVDD). In this diabetic population, subject had diabetes for over 10 years. At baseline, the majority of the study population had hypertension (over 85%) and over two thirds had dyslipidaemia. There was no statistical significance of the variables (clinical assessment, medical history, lifestyle factors, and medication) between the intervention and control groups.
    Units: Subjects
        Diabetes
    		 28 24 52
        No diabetes
    		 0 0 0
    Hypertension
    Units: Subjects
        Hypertension
    		 25 21 46
        No hypertension
    		 3 3 6
    Dyslipidemia
    Units: Subjects
        Dyslipidemia
    		 19 16 35
        No dyslipidemia
    		 9 8 17
    Atrial fibrillation
    Units: Subjects
        Atrial fibrillation
    		 0 0 0
        No atrial fibrillation
    		 28 24 52
    Ischemic heart disease
    Units: Subjects
        Ischemic heart disease
    		 9 2 11
        No ischemic heart disease
    		 19 22 41
    Percutaneous coronary intervention
    Units: Subjects
        Percutaneous coronary intervention
    		 1 0 1
        No Percutaneous coronary intervention
    		 27 24 51
    Coronary artery bypass graft
    Units: Subjects
        Coronary artery bypass graft
    		 5 0 5
        No coronary artery bypass graft
    		 23 24 47
    Stroke
    Units: Subjects
        Stroke
    		 1 0 1
        No stroke
    		 27 24 51
    Smoking history
    Units: Subjects
        Current smoker
    		 1 1 2
        Former smoker
    		 15 13 28
        Never smoked
    		 11 9 20
        Not reported
    		 1 1 2
    Alcohol habit
    Units: Subjects
        Drinks alcohol
    		 22 17 39
        Does not drink alcohol
    		 6 7 13
    Medication history. Angiotensin converting enzyme (ACE) inhibitor
    Units: Subjects
        ACE inhibitor
    		 15 16 31
        No ACE inhibitor
    		 13 8 21
    Medication history: Angiotensin receptor blocker (ARB)
    Units: Subjects
        ARB
    		 10 4 14
        No ARB
    		 18 20 38
    Medication history: Diuretic
    Units: Subjects
        Diuretic
    		 13 12 25
        No diuretic
    		 15 12 27
    Medication history: Beta-blocker
    Units: Subjects
        Beta-blocker
    		 18 14 32
        No beta-blocker
    		 10 10 20
    Medication history: Alpha-blocker
    Units: Subjects
        Alpha-blocker
    		 10 9 19
        No alpha-blocker
    		 18 15 33
    Medication history: Calcium channel blocker (CCB)
    Units: Subjects
        CCB
    		 15 8 23
        No CCB
    		 13 16 29
    Medication history: Statin
    Units: Subjects
        Statin
    		 21 15 36
        No statin
    		 7 9 16
    Medication history: Antiplatelet
    Units: Subjects
        Antiplatelet
    		 21 22 43
        No antiplatelet
    		 7 2 9
    Medication history: Biguanide
    Units: Subjects
        Biguanide
    		 20 18 38
        No biguanide
    		 8 6 14
    Medication history: Sulphonylurea
    Units: Subjects
        Sulphonylurea
    		 7 4 11
        No sulphonylurea
    		 21 20 41
    Medication history: Thiazolidinedione
    Units: Subjects
        Thiazolidinedione
    		 2 1 3
        No thiazolidinedione
    		 26 23 49
    Medication history: Gliptin
    Units: Subjects
        Gliptin
    		 5 5 10
        No gliptin
    		 23 19 42
    Medication history: GLP-1 agonist
    Units: Subjects
        GLP-1 agonist
    		 1 0 1
        No GLP-1 agonist
    		 27 24 51
    Medication history: Insulin
    Units: Subjects
        Insulin
    		 5 4 9
        No insulin
    		 23 20 43
    Body Mass Index (BMI)
    Units: kg/m2
        median (inter-quartile range (Q1-Q3))
    		 30.2 (27.02 to 32.92) 30 (27.9 to 33.12) -
    Height
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 175 (163.25 to 180.23) 171.5 (161.88 to 179) -
    Weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 89.6 (81.43 to 99.28) 86.3 (83 to 98.33) -
    Waist
    Units: cm
        median (inter-quartile range (Q1-Q3))
    		 106.75 (99.5 to 114.75) 107.5 (103.75 to 112) -
    Heart rate
    Units: Beats per minute
        median (inter-quartile range (Q1-Q3))
    		 62.5 (57.5 to 72) 63 (57.5 to 67.5) -
    Systolic Blood Pressure (SBP)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 136 (123.5 to 144) 134 (122.25 to 146.25) -
    Diastolic Blood Pressure (DBP)
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    		 75 (69.25 to 85.75) 74.5 (66.75 to 82) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention (eplerenone)
    Reporting group description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care
    Reporting group title
    Intervention (eplerenone)
    Reporting group description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care

    Primary: Change of left atrial volume index (LAVI) (measured by MRI)

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    End point title
    		 Change of left atrial volume index (LAVI) (measured by MRI)
    End point description
    The primary endpoint of this study was the change in LAVI measured by cardiac MRI between the study groups. Accordingly, the efficacy evaluations for primary and secondary endpoints were carried out on subjects with paired baseline and 12 month analyses. The endpoint analysis, therefore, excludes the four subjects who were withdrawn from the study. Treatment with eplerenone for 12 months did not result in a significant impact on LAVI measured by MRI.
    End point type
    Primary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: ml/m2
        median (inter-quartile range (Q1-Q3))
    0.32 (-3.47 to 3.01)
    0.77 (-3.13 to 4.97)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Control v Intervention (eplerenone)
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7817
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: b-type natriuretic peptide (BNP) (Change)

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    End point title
    		 b-type natriuretic peptide (BNP) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    0 (-10.85 to 20.58)
    -1.45 (-28.95 to 15.65)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5416
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Carboxy-terminal propeptide of procollagen type I (PICP) (Change)

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    End point title
    		 Carboxy-terminal propeptide of procollagen type I (PICP) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    -44.04 (-191.72 to 64.74)
    -7.69 (-63.46 to 51.23)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.3219
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Matrix metalloproteinase-1 (MMP-1) (Change)

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    End point title
    		 Matrix metalloproteinase-1 (MMP-1) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    7752.02 (1710.01 to 15248.07)
    7801.07 (2474.48 to 22017.26)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9422
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Matrix metalloproteinase-9 (MMP-9) (Change)

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    End point title
    		 Matrix metalloproteinase-9 (MMP-9) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: ng/mL
        median (inter-quartile range (Q1-Q3))
    20556.64 (3509.67 to 48564.5)
    39190.54 (-15653.1 to 75745.61)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.7539
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Left ventricular mass index (LVMI) (Change)

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    End point title
    		 Left ventricular mass index (LVMI) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: g/m2
        median (inter-quartile range (Q1-Q3))
    0.95 (-8.51 to 11.17)
    -2.71 (-20.45 to 3.45)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0806
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Left ventricular ejection fraction (LVEF) (Change)

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    End point title
    		 Left ventricular ejection fraction (LVEF) (Change)
    End point description
    For the doppler-echocardiographic markers of diastolic function, there were no between-group changes in the study groups. Eplerenone did not manifest significant changes in measurements of diastolic function.
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    0.5 (-5.25 to 4.75)
    -2 (-5 to 2)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4262
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Left atrial volume index (LAVI) (measured by Doppler Echo) (Change)

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    End point title
    		 Left atrial volume index (LAVI) (measured by Doppler Echo) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: mL/m2
        median (inter-quartile range (Q1-Q3))
    0.3 (-1 to 5.8)
    1.3 (-4 to 2.8)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.6918
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: E/E' average (ratio) (Change)

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    End point title
    		 E/E' average (ratio) (Change)
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: Ratio
        median (inter-quartile range (Q1-Q3))
    -0.15 (-1.92 to 0.48)
    1.15 (-1.08 to 2.05)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.2446
    Method
    		 t-test, 2-sided
    Confidence interval

    Post-hoc: Systolic blood pressure (SBP) (Change)

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    End point title
    		 Systolic blood pressure (SBP) (Change)
    End point description
    Eplerenone is a blood pressure lowering agent. As an exploratory endpoint, a post-hoc analysis of the effects of eplerenone on blood pressure was carried out. Eplerenone did not have any significant effect on blood pressure in this study cohort.
    End point type
    Post-hoc
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    -0.5 (-8.5 to 5)
    -3.5 (-8 to 1.25)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.5388
    Method
    		 t-test, 2-sided
    Confidence interval

    Post-hoc: Diastolic blood pressure (DBP) (Change)

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    End point title
    		 Diastolic blood pressure (DBP) (Change)
    End point description
    End point type
    Post-hoc
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    -1 (-4.25 to 2.25)
    -1.5 (-5.25 to 2)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.9025
    Method
    		 t-test, 2-sided
    Confidence interval

    Post-hoc: Pulse pressure (Change)

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    End point title
    		 Pulse pressure (Change)
    End point description
    There is a progressive increase in pulse pressure in the control group, which is significant. The pulse pressure in the intervention group is maintained with eplerenone. High pulse pressure is a strong predictor for evolving heart dysfunction, especially for older adults. Pulse pressure beyond 60 is considered as a risk factor of cardiovascular disease. Thus, while the blood pressure parameters did not improve with eplerenone, the pulse pressure is maintained, which suggests a potential effect of eplerenone.
    End point type
    Post-hoc
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: mmHg
        median (inter-quartile range (Q1-Q3))
    0 (-3 to 4.25)
    -1.5 (-5.5 to 1)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Post-hoc
    Analysis type
    		 equivalence
    P-value
    		 = 0.0402
    Method
    		 t-test, 2-sided
    Confidence interval

    Post-hoc: Heart rate (Change)

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    End point title
    		 Heart rate (Change)
    End point description
    End point type
    Post-hoc
    End point timeframe
    Baseline to 12 months
    End point values
    		 Intervention (eplerenone) Control
    Number of subjects analysed
    24
    24
    Units: beats per minute
        median (inter-quartile range (Q1-Q3))
    -2 (-4.5 to 1)
    0.5 (-4.5 to 3)
    Statistical analysis title
    		 Comparison of change between groups
    Comparison groups
    Intervention (eplerenone) v Control
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.4201
    Method
    		 t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From signing of the informed consent form through 30 days after the last dose of investigational product.
    Adverse event reporting additional description
    Information was collected at each visit based on information provided spontaneously by the subject and/or through questioning. If any changes to medication suggested a new illness or worsening of a pre-existing condition, the subject was questioned further. Abnormal laboratory/test results if deemed medically significant, were considered AEs
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Intervention (eplerenone)
    Reporting group description
    		 Usual medical therapy and additional treatment with eplerenone. Eplerenone was administered at an initial dose of 25 mg once daily and increased to 50 mg once daily after one month (providing the increase in creatinine from baseline was no greater than 25% and the potassium level within one week of commencing eplerenone was <5.5 mmol/L)

    Reporting group title
    Control
    Reporting group description
    		 Usual medical care

    Serious adverse events
    		 Intervention (eplerenone) Control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 28 (17.86%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
    Additional description: Postural hypotension
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Angioedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Intervention (eplerenone) Control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 28 (78.57%)
    13 / 24 (54.17%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    7 / 28 (25.00%)
    1 / 24 (4.17%)
         occurrences all number
    7
    1
    General body pains
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Angioedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Sleep apnoea syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    Blood iron decreased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Prostatic specific antigen increased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dizziness postural
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dyspnoea
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Dyspnoea exertional
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Nervous system disorders
    Tension headache
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1
    Hypochromic anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Diuresis excessive
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Dysuria
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Renal impairment
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Diabetic neuropathy
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Joint swelling
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Muscular weakness
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 24 (8.33%)
         occurrences all number
    2
    2
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 24 (8.33%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 28 (14.29%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    Paronychia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    Wound infection
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 24 (0.00%)
         occurrences all number
    2
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 24 (4.17%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2014
    Inclusion Criteria No 2 amended: Diastolic dysfunction on Doppler-echocardiogram as evidenced by either LAVI >32ml/m2 and/or e' <10 cm/s. Previously, only patients with diastolic dysfunction as evidenced by LAVI >32ml/m2 were eligible for inclusion.

    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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