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    Clinical Trial Results:
    A Randomised Multicentre Open Label Blinded End Point Trial to Compare the Effects of Spironolactone to Chlortalidone on Left Ventricular Mass and Arterial Stiffness in Stage 3 Chronic Kidney Disease

    Summary
    EudraCT number
    		 2013-002636-25
    Trial protocol
    		 GB  
    Global end of trial date
    09 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2020
    First version publication date
    25 Jun 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_13-013NS
    Additional study identifiers
    ISRCTN number
    		 ISRCTN94696478
    US NCT number
    		 -
    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
    Dr Rebekah Wale, Birmingham Clinical Trials Unit , +44 01214158445, r.wale@bham.ac.uk
    Scientific contact
    Prof. Jonathan Townend, University Hospitals Birmingham, +44 01214158445, John.Townend@uhb.nhs.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
    09 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Apr 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does giving Spironolactone to patients with early stage chronic kidney disease reduce arterial stiffness and left ventricular mass to a greater degree than the standard blood pressure lowering drug treatment, Chlortalidone? Updated April 2016 Does giving Spironolactone to patients with early stage chronic kidney disease reduce left ventricular mass to a greater degree than the standard blood pressure lowering drug treatment, Chlortalidone?
    Protection of trial subjects
    All sites were provided with the SPIRO-CKD 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. SPIRO-CKD had two Data Monitoring Committees to monitor patient safety throughout the trial.
    Background therapy
    		 Chronic Kidney Disease (CKD) is a major but poorly recognised and under-treated risk factor for cardiovascular disease. Stages 2 and 3 CKD are defined by a GFR of 30-89 ml/min/1.73m2 were investigated in this study. There is a graded inverse relationship between cardiovascular risk and GFR which is independent of age, sex and other risk factors such as hypertension and diabetes. While the cardiovascular risk of end-stage CKD is extreme, in public health terms the burden resides in early stage disease (CKD stages 1-3), which is more prevalent, affecting almost 1 in 7 of the entire population, including approximately 4% of those aged 40-59, and more than 40% of those aged over 70 years. Thus, CKD is a potentially important risk factor for cardiovascular disease in the general population. The main pathological features of cardiovascular disease in CKD are: a) Myocardial disease characterised by LVH and fibrosis accompanied by systolic and diastolic dysfunction. b) Arterial wall thickening, stiffening and calcification (arteriosclerosis). c) Coronary and peripheral artery atherosclerosis. Previous research suggested that compared with placebo, the use of spironolactone resulted in large reductions in left ventricular mass and arterial stiffness (pulse wave velocity, augmentation index and aortic distensibility). This trial has given rise to considerable optimism that MRB therapy might help to prevent cardiovascular disease in patients with CKD. Chlortalidone (until recently known by its US adopted name, chlorthalidone) is a thiazide-like diuretic and an effective anti-hypertensive drug proven to reduce blood pressure, adverse cardiovascular events and adverse renal outcomes as effectively as calcium channel blockers or ACE inhibitors. Therefore SPIRO-CKD compared the effects of spironolactone versus chlortalidone on LV mass in patients with stage 2 and stage 3.
    Evidence for comparator
    		 A prospective, randomised, open-label, blinded-endpoint (PROBE) study design. All recruited patients will receive either spironolactone (25mg) or Chlortalidone (½ of a 50mg tablet) daily for 40 weeks. Patients were followed-up for the duration of treatment and for 6 weeks after discontinuation of trial medication (wash-out period).
    Actual start date of recruitment
    02 Sep 2013
    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: 154
    Worldwide total number of subjects
    154
    EEA total number of subjects
    154
    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)
    96
    From 65 to 84 years
    56
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial opened for recruitment on the 3rd June 2014 and the first patient was randomised on the 26th June 2014 and the last patient was randomised on the 21st December 2016. A total of 154 patients were randomised into the SPIRO-CKD Trial with 4 centres recruiting patients into the trial with equal numbers in both arms.

    Pre-assignment
    Screening details
    		 A total of 9325 were screened for the trial, of these screened 154 were randomised.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    A Randomised Multicentre Open Label Blinded End Point Trial to Compare the Effects of Spironolactone to Chlortalidone on Left Ventricular Mass in Stage 2 and Stage 3 Chronic Kidney Disease. A prospective, randomised, open-label, blinded-endpoint (PROBE) study design.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Spironolactone
    Arm description
    		 Baseline
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spironolactone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 25mg tablet OD for 40 weeks orally

    Arm title
    		 Chlortalidone
    Arm description
    		 Baseline
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Chlortalidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlortalidone at a dose of ½ a 50 mg tablet od. The duration of treatment will be 40 weeks in total.

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: SPIRO-CKD was an assessor blind trial.
    Number of subjects in period 1
    		Spironolactone Chlortalidone
    Started
    77
    77
    Completed
    77
    77
    Period 2
    Period 2 title
    Week 40
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Investigator [2]

    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
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One 25mg tablet OD for 40 weeks orally

    Arm title
    		 Chlortalidone
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Chlortalidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Chlortalidone at a dose of ½ a 50 mg tablet od. The duration of treatment will be 40 weeks in total.

    Notes
    [2] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: SPIRO-CKD was an assessor blind trial.
    Number of subjects in period 2
    		Spironolactone Chlortalidone
    Started
    77
    77
    Completed
    69
    69
    Not completed
    8
    8
         Consent withdrawn by subject
    4
    3
         Adverse event, non-fatal
    3
    3
         Pregnancy
    -
    1
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Baseline

    Reporting group title
    Chlortalidone
    Reporting group description
    		 Baseline

    Reporting group values
    		 Spironolactone Chlortalidone Total
    Number of subjects
    		 77 77 154
    Age categorical
    Units: Subjects
        Less than 55 years
    		 35 35 70
        55 and over
    		 42 42 84
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.5 ± 13.8 56.3 ± 15.1 -
    Gender categorical
    Units: Subjects
        Female
    		 24 24 48
        Male
    		 53 53 106
    Smoking Status
    Units: Subjects
        Never smoked
    		 37 37 74
        Ex-smoker
    		 35 29 64
        Current smoker
    		 5 11 16
    Systolic Blood Pressure
    Units: Subjects
        <130mmHg
    		 32 32 64
        ≥130mmHg
    		 45 45 90
    Is the cause of Chronic Kidney Disease known?
    Is the cause known?
    Units: Subjects
        Yes
    		 60 59 119
        No
    		 17 18 35
    Patient with previous Myocardial Infarction (MI)
    Units: Subjects
        Yes
    		 1 4 5
        No
    		 76 73 149
    Patients with a history of Hypertension
    Patients with a history of hypertension
    Units: Subjects
        Yes
    		 67 64 131
        No
    		 10 13 23
    Patients with a history of Hypercholesterolemia
    Patients with a history of hypercholesterolemia
    Units: Subjects
        Yes
    		 30 34 64
        No
    		 47 43 90
    Patients previously had a CVA or TIA
    Patients previously had a CVA or TIA
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 76 76 152
    Patients with Asthma
    Patients with Asthma
    Units: Subjects
        Yes
    		 8 11 19
        No
    		 69 66 135
    Patients with COPD
    Patients with COPD
    Units: Subjects
        Yes
    		 1 1 2
        No
    		 76 76 152
    Patients with Liver Disease
    Units: Subjects
        Yes
    		 3 1 4
        No
    		 74 76 150
    Malignancy
    Patients with previous malignancy
    Units: Subjects
        Yes
    		 5 6 11
        No
    		 72 71 143
    ACE Inhibitor Medication
    Units: Subjects
        Yes
    		 40 41 81
        No
    		 35 36 71
        Missing
    		 2 0 2
    ARB Medication
    Units: Subjects
        Yes
    		 33 32 65
        No
    		 42 45 87
        Missing
    		 2 0 2
    CCB Medication
    Units: Subjects
        Yes
    		 33 23 56
        No
    		 42 54 96
        Missing
    		 2 0 2
    Alpha Blocker Medication
    Units: Subjects
        Yes
    		 13 6 19
        No
    		 62 71 133
        Missing
    		 2 0 2
    Beta Blocker Medication
    Units: Subjects
        Yes
    		 13 13 26
        No
    		 62 64 126
        Missing
    		 2 0 2
    Cause of Chronic Kidney Disease
    Units: Subjects
        Primary glomerulonephritis
    		 29 20 49
        Interstitial nephropathies
    		 5 10 15
        Hereditary Nephropathy
    		 15 16 31
        Renal vascular disease
    		 2 4 6
        Hypertensive nephropathy
    		 4 3 7
        Secondary Glomerulonephritis
    		 0 3 3
        Other multisystem disease
    		 2 2 4
        Other
    		 3 1 4
        No cause known
    		 17 18 35
    Height
    Units: Metres
        arithmetic mean (standard deviation)
    		 1.7 ± 0.1 1.7 ± 0.1 -
    Weight
    Units: Kilograms
        arithmetic mean (standard deviation)
    		 85.5 ± 15.7 80.1 ± 13.7 -
    BMI
    Units: BMI
        arithmetic mean (standard deviation)
    		 29.5 ± 5.0 27.6 ± 3.8 -
    Systolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 133.9 ± 13.8 135.3 ± 14.4 -
    Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 80.3 ± 10.3 80.5 ± 9.3 -
    Pulse Rate
    Units: BPM
        arithmetic mean (standard deviation)
    		 71.8 ± 13.6 70.8 ± 12.4 -
    Creatinine
    Units: umol/L
        arithmetic mean (standard deviation)
    		 128.4 ± 40.5 117.2 ± 31.2 -
    eGFR
    Units: (4v-MDRD) (mL/min/1.73)
        arithmetic mean (standard deviation)
    		 52.2 ± 16.1 56.9 ± 15.3 -
    Potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.4 ± 0.4 4.5 ± 0.3 -

    End points

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    End points reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Baseline

    Reporting group title
    Chlortalidone
    Reporting group description
    		 Baseline
    Reporting group title
    Spironolactone
    Reporting group description
    		 -

    Reporting group title
    Chlortalidone
    Reporting group description
    		 -

    Primary: Left Ventricular Mass (LV)

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    End point title
    		 Left Ventricular Mass (LV)
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: gram(s)/gram
        arithmetic mean (standard deviation)
    130.6 ± 27.7
    123.9 ± 33.1
    124 ± 24.3
    122.2 ± 37.3
    Statistical analysis title
    		 Linear Regression Model
    Statistical analysis description
    A linear regression model was fitted with LV mass at week 40 as the outcome variable, and treatment group (with Chlortalidone as the reference category), baseline LV mass and all the minimisation variables (age, systolic blood pressure and gender) included as covariates in the model.
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.13
         upper limit
    		 0.47
    Variability estimate
    Standard error of the mean

    Primary: LV mass indexed to Body Surface Area (g/m2)

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    End point title
    		 LV mass indexed to Body Surface Area (g/m2)
    End point description
    As an additional sensitivity analysis, LV mass data was also analysed accounting for any missing data at week 40 using multiple imputation methods to impute missing data
    End point type
    Primary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: g/m2
        arithmetic mean (standard deviation)
    65.6 ± 11.9
    64.1 ± 13.9
    62.2 ± 11.4
    63.1 ± 14.9
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.185
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.79
         upper limit
    		 0.74
    Variability estimate
    Standard error of the mean

    Secondary: Changes in arterial stiffness

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    End point title
    		 Changes in arterial stiffness
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    69
    75
    65
    68
    Units: m/s
        arithmetic mean (standard deviation)
    7.37 ± 1.78
    7.6 ± 2.17
    7.34 ± 1.90
    7.5 ± 1.97
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.038
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.384
         upper limit
    		 0.459
    Variability estimate
    Standard error of the mean

    Secondary: Systolic Blood Pressure

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    End point title
    		 Systolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    77
    77
    69
    69
    Units: mmHg
        arithmetic mean (standard deviation)
    133.6 ± 10.7
    135.9 ± 14.2
    123.8 ± 15.3
    127.2 ± 14.2
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.284
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.209
         upper limit
    		 2.129
    Variability estimate
    Standard error of the mean

    Secondary: Diastolic Blood Pressure

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    End point title
    		 Diastolic Blood Pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    77
    77
    69
    69
    Units: mmHg
        arithmetic mean (standard deviation)
    81.7 ± 8.1
    81.2 ± 9.6
    75.8 ± 11.1
    77.6 ± 8.2
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.097
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.398
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.239
         upper limit
    		 0.442
    Variability estimate
    Standard error of the mean

    Secondary: Mean 24 hour peripheral systolic blood pressure

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    End point title
    		 Mean 24 hour peripheral systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    69
    70
    62
    64
    Units: mmHg
        arithmetic mean (standard deviation)
    126.5 ± 11.1
    127.6 ± 13.4
    121.8 ± 12.5
    121.4 ± 14
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.279
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.035
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.667
         upper limit
    		 5.738
    Variability estimate
    Standard error of the mean

    Secondary: Mean 24 hour peripheral diastolic blood pressure

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    End point title
    		 Mean 24 hour peripheral diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    69
    70
    62
    64
    Units: mmHg
        arithmetic mean (standard deviation)
    78.8 ± 8.4
    79.5 ± 9.3
    75.4 ± 9
    74.6 ± 7.9
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.257
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.286
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.951
         upper limit
    		 3.523
    Variability estimate
    Standard error of the mean

    Secondary: Mean 24 hour central systolic blood pressure

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    End point title
    		 Mean 24 hour central systolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    67
    68
    58
    64
    Units: mmHg
        arithmetic mean (standard deviation)
    115.6 ± 9
    117.4 ± 12.6
    111.3 ± 10.6
    110.4 ± 11.5
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.263
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.974
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.503
         upper limit
    		 5.452
    Variability estimate
    Standard error of the mean

    Secondary: Mean 24 hour central diastolic blood pressure

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    End point title
    		 Mean 24 hour central diastolic blood pressure
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    67
    68
    58
    64
    Units: mmHg
        arithmetic mean (standard deviation)
    80 ± 8.1
    81 ± 9.7
    76.9 ± 9.2
    75.6 ± 8.6
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.334
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.187
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.237
         upper limit
    		 3.612
    Variability estimate
    Standard error of the mean

    Secondary: Left ventricular-end systolic volume

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    End point title
    		 Left ventricular-end systolic volume
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: mL
        arithmetic mean (standard deviation)
    30.6 ± 11.3
    32 ± 13.1
    30.8 ± 12.1
    30.7 ± 12.6
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.393
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.073
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.408
         upper limit
    		 3.554
    Variability estimate
    Standard error of the mean

    Secondary: Left ventricular end-systolic volume indexed to Body Surface Area

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    End point title
    		 Left ventricular end-systolic volume indexed to Body Surface Area
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: mL/m^
        arithmetic mean (standard deviation)
    15.4 ± 5.5
    16.6 ± 6.3
    15.5 ± 6.1
    15.9 ± 6.0
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.466
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.472
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.807
         upper limit
    		 1.751
    Variability estimate
    Standard error of the mean

    Secondary: Left ventricular end-diastolic volume

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    End point title
    		 Left ventricular end-diastolic volume
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: mL
        arithmetic mean (standard deviation)
    116 ± 26.1
    114.1 ± 27.4
    114.2 ± 26.7
    108.2 ± 26.5
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.149
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.526
         upper limit
    		 9.936
    Variability estimate
    Standard error of the mean

    Secondary: Left ventricular end-diastolic volume indexed to Body Surface Area

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    End point title
    		 Left ventricular end-diastolic volume indexed to Body Surface Area
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    68
    68
    60
    59
    Units: mL/m^
        arithmetic mean (standard deviation)
    58.4 ± 12.3
    59.3 ± 12.7
    57.4 ± 13.4
    56.3 ± 12.3
    Statistical analysis title
    		 Linear Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.205
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.813
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.006
         upper limit
    		 4.632
    Variability estimate
    Standard error of the mean

    Secondary: Incidence of Hyperkalaemia

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    End point title
    		 Incidence of Hyperkalaemia
    End point description
    15 patients were excluded from this analysis (7 in Spironolactone group and 8 in Chlortalidone group) because these patients withdrew, were lost to follow up or died prior to incidence of hyperkalaemia and did not complete the 40 weeks of trial follow up.
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone
    Number of subjects analysed
    70
    69
    Units: Total Hyperkalaemia Events
        0 incidences
    58
    67
        1 incidence
    7
    2
        2 incidences
    2
    0
        3 incidences
    2
    0
        4 incidences
    1
    0
    Statistical analysis title
    		 Poisson Regression Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002
    Method
    		 Poisson Regression Model
    Parameter type
    		 Incidence Rate Ratio
    Point estimate
    10.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.38
         upper limit
    		 43.66
    Variability estimate
    Standard error of the mean

    Secondary: Changes in UACR ratio

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    End point title
    		 Changes in UACR ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    75
    75
    69
    69
    Units: mg/mmol
        median (inter-quartile range (Q1-Q3))
    5.5 (1.2 to 38.6)
    5 (1.5 to 49)
    4.8 (1.8 to 18)
    2.1 (0.6 to 16.6)
    Statistical analysis title
    		 Ratio of Geometric Mean
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    138
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.046
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 2.75
    Variability estimate
    Standard error of the mean

    Secondary: NT proBNP

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    End point title
    		 NT proBNP
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and week 40
    End point values
    		 Spironolactone Chlortalidone Spironolactone Chlortalidone
    Number of subjects analysed
    70
    70
    63
    56
    Units: pg/ml
        median (inter-quartile range (Q1-Q3))
    74 (41 to 161)
    113.5 (39 to 189)
    78 (38 to 171)
    65.5 (31 to 162)
    Statistical analysis title
    		 Ratio of Geometric Means
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.198
    Method
    		 Regression, Linear
    Parameter type
    		 Ratio of geometric means
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.93
         upper limit
    		 1.41
    Variability estimate
    Standard error of the mean

    Secondary: Decline in Renal Function

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    End point title
    		 Decline in Renal Function
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone
    Number of subjects analysed
    69
    70
    Units: Yes/No
        Yes
    2
    8
        No
    67
    62
    Statistical analysis title
    		 Log Binomial Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.069
    Method
    		 Log Binomial
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.246
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.054
         upper limit
    		 1.118
    Variability estimate
    Standard error of the mean

    Secondary: Symptomatic Hypotension

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    End point title
    		 Symptomatic Hypotension
    End point description
    Requiring discontinuation of trial treatment
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone
    Number of subjects analysed
    69
    69
    Units: Yes/No
        Yes
    0
    0
        No
    69
    69
    No statistical analyses for this end point

    Secondary: Incidence of Side Effects

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    End point title
    		 Incidence of Side Effects
    End point description
    Requiring discontinuation of trial treatment
    End point type
    Secondary
    End point timeframe
    Baseline to week 40
    End point values
    		 Spironolactone Chlortalidone
    Number of subjects analysed
    71
    70
    Units: Yes/No
        Yes
    11
    19
        No
    60
    51
    Statistical analysis title
    		 Log Binomial Model
    Comparison groups
    Spironolactone v Chlortalidone
    Number of subjects included in analysis
    141
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.074
    Method
    		 Log Binomial
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.556
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.292
         upper limit
    		 1.058
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were reportable to the SPIRO-CKD Trial Office up to 6 weeks 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 were recorded in the medical records and case report forms. Most adverse events/reactions that occurred in this trial, whether they were 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
    Spironolactone
    Reporting group description
    		 -

    Reporting group title
    Chlortalidone
    Reporting group description
    		 -

    Serious adverse events
    		 Spironolactone Chlortalidone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 77 (6.49%)
    6 / 77 (7.79%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Fall
    Additional description: Subject tripped and fell onto left side and was admitted into AE and thoracic surgery with a rib fracture and small pneumothorax on left side
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Elective surgery, right ankle reconstruction
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Elective surgery
    Additional description: Elective knee replacement
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Chest pain
    Additional description: Chest pain
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
    Additional description: Collapsed with loss of consciousness which has resulted in a fractured left ankle. In the emergency room was found to have a prolonged QTC on ECG, possibly due to hypotension.
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Shortness of breath, muscle cramps, Anaemia, tiredness
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Perforated diverticulum
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    Additional description: Admitted to hospital with a four day history of upper and lower abdominal pain, diarrhoea, nausea and vomiting, Imaging revealed duodenitis.
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Shortness of breath
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Kidney Pain
         subjects affected / exposed
    1 / 77 (1.30%)
    0 / 77 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
    Additional description: Developed a rash on chest.
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Spironolactone Chlortalidone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 77 (77.92%)
    65 / 77 (84.42%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 77 (16.88%)
    22 / 77 (28.57%)
         occurrences all number
    21
    32
    Headache
         subjects affected / exposed
    11 / 77 (14.29%)
    9 / 77 (11.69%)
         occurrences all number
    14
    13
    General disorders and administration site conditions
    Drowsiness
         subjects affected / exposed
    4 / 77 (5.19%)
    5 / 77 (6.49%)
         occurrences all number
    7
    5
    Symptomatic hypotension
         subjects affected / exposed
    7 / 77 (9.09%)
    9 / 77 (11.69%)
         occurrences all number
    12
    12
    Immune system disorders
    Hypersensitivity reactions
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences all number
    3
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    1
    1
    Reproductive system and breast disorders
    Breast tenderness/enlargement
         subjects affected / exposed
    4 / 77 (5.19%)
    0 / 77 (0.00%)
         occurrences all number
    4
    0
    Gynecomastia
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 77 (0.00%)
         occurrences all number
    6
    0
    Sexual dysfunction
         subjects affected / exposed
    1 / 77 (1.30%)
    1 / 77 (1.30%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
         occurrences all number
    1
    4
    Diarrhoea
         subjects affected / exposed
    8 / 77 (10.39%)
    5 / 77 (6.49%)
         occurrences all number
    10
    5
    GI cramping
         subjects affected / exposed
    1 / 77 (1.30%)
    4 / 77 (5.19%)
         occurrences all number
    1
    4
    Gastric irritation
         subjects affected / exposed
    6 / 77 (7.79%)
    5 / 77 (6.49%)
         occurrences all number
    6
    5
    Nausea
         subjects affected / exposed
    7 / 77 (9.09%)
    5 / 77 (6.49%)
         occurrences all number
    7
    5
    Vomiting
         subjects affected / exposed
    3 / 77 (3.90%)
    1 / 77 (1.30%)
         occurrences all number
    3
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    10 / 77 (12.99%)
    3 / 77 (3.90%)
         occurrences all number
    13
    5
    Psychiatric disorders
    Anorexia
         subjects affected / exposed
    2 / 77 (2.60%)
    0 / 77 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Hyperkalaemia
         subjects affected / exposed
    3 / 77 (3.90%)
    0 / 77 (0.00%)
         occurrences all number
    5
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 77 (0.00%)
    1 / 77 (1.30%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    8 / 77 (10.39%)
    6 / 77 (7.79%)
         occurrences all number
    8
    7
    Parasthesia
         subjects affected / exposed
    3 / 77 (3.90%)
    3 / 77 (3.90%)
         occurrences all number
    5
    4
    Restlessness
         subjects affected / exposed
    1 / 77 (1.30%)
    2 / 77 (2.60%)
         occurrences all number
    11
    4
    Weakness
         subjects affected / exposed
    7 / 77 (9.09%)
    5 / 77 (6.49%)
         occurrences all number
    7
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Jan 2015
    * Changes made to the Protocol * Changes made to the Participant Information Leaflets/Consent Forms * Documents to be submitted: Poster Patient information sheets Consent forms Invitation letter (secondary and primary care)
    23 Apr 2015
    Changes made to the Participant Postal Invitation Letter
    11 Aug 2015
    * Changes to the protocol * Changes to the patient information sheet * Changes made to GP letter
    28 Nov 2016
    * Changes to the protocol * Administrative updates to the patient facing documents SPIRO-CKD Diet sheets SPIRO-CKD GP Letter SPIRO-CKD Participant Postal Invitation to Take Part Letter SPIRO-CKD Letter SPIRO-CKD Screening Information Sheet SPIRO-CKD Participant Information Sheet SPIRO-CKD Sub-studies Information Sheet SPIRO-CKD Screening Consent Form  SPIRO-CKD Informed Consent Form  SPIRO-CKD Sub-studies Consent Form  SPIRO-CKD OPD Poster  SPIRO-CKD Patient End of Study Letter  SPIRO-CKD GP End of Study Lette
    19 Jun 2018
    Amendment to the 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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