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    Clinical Trial Results:
    The effect of spironolactone on calcineurin inhibitor induced nephrotoxicity

    Summary
    EudraCT number
    		 2011-002243-98
    Trial protocol
    		 DK  
    Global end of trial date
    08 Apr 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Apr 2022
    First version publication date
    25 Apr 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    29702
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01602861
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Odense University Hospital
    Sponsor organisation address
    J.B. Winsløws Vej 4, Odense C, Denmark, 5000
    Public contact
    Forskerenheden, Department of nephrology, OUH, Odense, DK, +45 30299610, line.mortensen@rsyd.dk
    Scientific contact
    Forskerenheden, Department of nephrology, OUH, Odense, DK, 30299610 30299610, line.mortensen@rsyd.dk
    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
    30 Aug 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Apr 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Apr 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether renal function in kidney transplant patients can be preserved by the addition of spironolactone to standard treatment
    Protection of trial subjects
    Regular scheduled visits Frequent measurements of plasma potassium after dosage adjustments
    Background therapy
    		 Standard of care Immunosuppression including a calcineurininhibitor
    Evidence for comparator
    		 Calcineurin inhibitors (CNI) are one of the cornerstones of the immunosuppressive therapy after solid organ transplantation. The introduction of CNI has caused a significant decrease in acute rejections. However, CNI also have severe side effects including renal interstitial fibrosis and tubular atrophy, a term also referred to as CNI nephrotoxicity. In the transplanted kidney this contributes to impaired kidney function and eventually reduced graft survival. The mineralocorticoid aldosterone may be involved in the development of renal fibrosis. Recent observations suggest that aldosterone plays a central role in the pathogenesis of CNI nephrotoxicity and that the mineralocorticoid-receptor-blocker spironolactone could be a useful agent to prevent it.
    Actual start date of recruitment
    25 Feb 2013
    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
    Denmark: 180
    Worldwide total number of subjects
    180
    EEA total number of subjects
    180
    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)
    148
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Inclusion was performed from February 2013 to April 2021. Patients were included from outpatient clinics at the four participating sites.

    Pre-assignment
    Screening details
    		 Renal transplant patients were identified through the outpatient clinics in the respective sites. Assessed for eligibility (n=959) Excluded (n=771), hereof Not meeting inclusion criteria (n= 422), Declined participation (n=270), Eligible, but not approached (n=79) Included (n=188), hereof Declined after inclusion (n=8) Randomized (n=180)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Spironolactone
    Arm description
    		 Spironolactone 25-50 mg OD
    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
    25-50 mg once daily

    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
    1 tablet daily, increased to 2 tablets daily after 3 months if well tolerated

    Number of subjects in period 1
    		Spironolactone Placebo
    Started
    90
    90
    Completed
    65
    74
    Not completed
    25
    16
         Consent withdrawn by subject
    2
    -
         Adverse event, non-fatal
    22
    16
         Death
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Spironolactone 25-50 mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Spironolactone Placebo Total
    Number of subjects
    		 90 90 180
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 72 76 148
        From 65-84 years
    		 18 14 32
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54 ( 11 ) 53 ( 12 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 35 63
        Male
    		 62 55 117
    Chrome-EDTA clearance
    Renal function
    Units: mL/min
        arithmetic mean (standard deviation)
    		 58 ( 23 ) 52 ( 18 ) -
    Systolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 135 ( 13 ) 133 ( 12 ) -
    Diastolic blood pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 80 ( 7 ) 79 ( 7 ) -
    Plasma potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.2 ( 0.4 ) 4.2 ( 0.5 ) -
    Plasma aldosterone
    Units: pg/mL
        geometric mean (inter-quartile range (Q1-Q3))
    		 84.4 (55.9 to 118.8) 78.4 (59.9 to 103.4) -
    Age of transplanted kidney
    Units: Years
        median (inter-quartile range (Q1-Q3))
    		 4.4 (1.1 to 10.0) 2.0 (0.7 to 6.6) -

    End points

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    End points reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Spironolactone 25-50 mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Chrome-EDTA clearance

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    End point title
    		 Chrome-EDTA clearance
    End point description
    Change from baseline in renal function measured as chrome-EDTA clearance (mL/min) compared to placebo group
    End point type
    Primary
    End point timeframe
    Baseline to 3 years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    63
    72
    Units: mL/min
        arithmetic mean (confidence interval 95%)
    -7.07 (-9.60 to -4.53)
    0.12 (-2.27 to 2.52)
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Linear mixed effects regressions model using maximum likelihood estimation. The model included fixed effects for time and interaction between the randomization group and time and a random intercept for patient.
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -7.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.63
         upper limit
    		 -3.75

    Secondary: Proteinuria

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    End point title
    		 Proteinuria
    End point description
    Change in 24-hour proteinuria from baseline to 3 years in spironolactone group compared to placebo
    End point type
    Secondary
    End point timeframe
    Baseline to 3 years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    57
    66
    Units: g/day
        arithmetic mean (confidence interval 95%)
    0.07 (-0.87 to 0.22)
    0.03 (-0.07 to 0.13)
    Statistical analysis title
    		 Statistical analysis 2
    Statistical analysis description
    Linear mixed effects regressions models using maximum likelihood estimation. The model included fixed effects for time and interaction between the randomization group and time and a random intercept for patient.
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.15
         upper limit
    		 0.22

    Secondary: Fibrosis Banff CT score

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    End point title
    		 Fibrosis Banff CT score
    End point description
    Renal biopsies performed in a subgroup of participants at baseline and after two years (n=48)
    End point type
    Secondary
    End point timeframe
    Baseline to two years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    23
    25
    Units: Number of patients
        CT0
    7
    8
        CT1
    12
    12
        CT2
    2
    4
        CT3
    2
    1
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxons matched-pair signed rank test
    Confidence interval

    Secondary: Fibrosis Banff CI score

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    End point title
    		 Fibrosis Banff CI score
    End point description
    Renal biopsies performed in a subgroup of participants at baseline and after two years (n=48)
    End point type
    Secondary
    End point timeframe
    Baseline to two years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    23
    25
    Units: Number of patients
        CI0
    4
    3
        CI1
    13
    14
        CI2
    5
    7
        CI3
    1
    1
    Statistical analysis title
    		 Statistical analysis 3
    Statistical analysis description
    Banff scores were tested for changes over two years using Wilcoxons matched-pair signed rank test
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxons matched-pair signed rank test
    Confidence interval

    Secondary: Fibrosis Banff AH score

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    End point title
    		 Fibrosis Banff AH score
    End point description
    Renal biopsies at baseline and 2 years in a subgroup (n=48)
    End point type
    Secondary
    End point timeframe
    Baseline to two years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    23
    25
    Units: Number of patients
        AH0
    5
    4
        AH1
    7
    8
        AH2
    4
    9
        AH3
    7
    4
    Statistical analysis title
    		 Statistical analysis 3
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Wilcoxons matched-pair signed rank test
    Confidence interval

    Secondary: Fibrosis pointcounting

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    End point title
    		 Fibrosis pointcounting
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to two years
    End point values
    		 Spironolactone Placebo
    Number of subjects analysed
    23
    25
    Units: Percentage fibrosis
        arithmetic mean (confidence interval 95%)
    -0.52 (-5.22 to 4.18)
    -3.08 (-8.44 to 2.28)
    Statistical analysis title
    		 Statistical analysis 4
    Comparison groups
    Placebo v Spironolactone
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.55
         upper limit
    		 4.44
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.47

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded during the full 3-year intervention
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 None
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Spironolactone 25-50 mg OD

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Spironolactone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 90 (53.33%)
    46 / 90 (51.11%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ cervix uteri
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ishemic ulcer
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suspected deep vein thrombosis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosed AV-fistula
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aneurism on brachial artery
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (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
    Quinckes edema
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    4 / 90 (4.44%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 90 (4.44%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Planned operations
         subjects affected / exposed
    16 / 90 (17.78%)
    19 / 90 (21.11%)
         occurrences causally related to treatment / all
    0 / 28
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Electric shock
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 90 (0.00%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knife wound
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bleeding after kidney biopsy
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Digoxin intoxication
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azathioprine
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Edema
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    2 / 90 (2.22%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired vision
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Hemolysis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anemia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Intraocular bleeding
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 90 (4.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal bleeding
         subjects affected / exposed
    4 / 90 (4.44%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 90 (3.33%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ruptured spleen
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gall bladder polyp
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystolithiasis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rejection in kidney graft
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Creatinine increase
         subjects affected / exposed
    6 / 90 (6.67%)
    9 / 90 (10.00%)
         occurrences causally related to treatment / all
    4 / 7
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hypocalcemia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone tumor
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    3 / 90 (3.33%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    7 / 90 (7.78%)
    7 / 90 (7.78%)
         occurrences causally related to treatment / all
    0 / 23
    0 / 25
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 90 (6.67%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unknown focus
         subjects affected / exposed
    7 / 90 (7.78%)
    8 / 90 (8.89%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst infection
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 90 (3.33%)
    4 / 90 (4.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegaloviræmia
         subjects affected / exposed
    1 / 90 (1.11%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 90 (2.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 90 (0.00%)
    3 / 90 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spondylodiscitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epiglottitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epididymitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 90 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condylomata acuminata
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 90 (1.11%)
         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: 0.05%
    Non-serious adverse events
    		 Spironolactone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    85 / 90 (94.44%)
    88 / 90 (97.78%)
    Injury, poisoning and procedural complications
    Accidents
         subjects affected / exposed
    15 / 90 (16.67%)
    13 / 90 (14.44%)
         occurrences all number
    19
    14
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    6 / 90 (6.67%)
    4 / 90 (4.44%)
         occurrences all number
    6
    6
    Chest pain
         subjects affected / exposed
    1 / 90 (1.11%)
    8 / 90 (8.89%)
         occurrences all number
    1
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 90 (12.22%)
    13 / 90 (14.44%)
         occurrences all number
    14
    13
    General disorders and administration site conditions
    Malaise
    Additional description: Unspecified malaise
         subjects affected / exposed
    34 / 90 (37.78%)
    25 / 90 (27.78%)
         occurrences all number
    51
    40
    Dizziness
         subjects affected / exposed
    23 / 90 (25.56%)
    18 / 90 (20.00%)
         occurrences all number
    29
    21
    Edema
         subjects affected / exposed
    10 / 90 (11.11%)
    8 / 90 (8.89%)
         occurrences all number
    11
    8
    Hypertension
         subjects affected / exposed
    9 / 90 (10.00%)
    13 / 90 (14.44%)
         occurrences all number
    10
    15
    Hypotension
         subjects affected / exposed
    18 / 90 (20.00%)
    13 / 90 (14.44%)
         occurrences all number
    25
    13
    Acidosis
         subjects affected / exposed
    7 / 90 (7.78%)
    3 / 90 (3.33%)
         occurrences all number
    7
    3
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    17 / 90 (18.89%)
    20 / 90 (22.22%)
         occurrences all number
    20
    23
    Abdominal pain
         subjects affected / exposed
    8 / 90 (8.89%)
    8 / 90 (8.89%)
         occurrences all number
    12
    8
    Weight increased
         subjects affected / exposed
    5 / 90 (5.56%)
    7 / 90 (7.78%)
         occurrences all number
    5
    10
    Dyspepsia
         subjects affected / exposed
    7 / 90 (7.78%)
    4 / 90 (4.44%)
         occurrences all number
    8
    6
    Nausea
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 90 (6.67%)
         occurrences all number
    4
    6
    Vomiting
         subjects affected / exposed
    6 / 90 (6.67%)
    4 / 90 (4.44%)
         occurrences all number
    10
    4
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    11 / 90 (12.22%)
    12 / 90 (13.33%)
         occurrences all number
    12
    14
    Cough
         subjects affected / exposed
    4 / 90 (4.44%)
    11 / 90 (12.22%)
         occurrences all number
    4
    11
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    10 / 90 (11.11%)
    6 / 90 (6.67%)
         occurrences all number
    10
    8
    Pruritus
         subjects affected / exposed
    5 / 90 (5.56%)
    6 / 90 (6.67%)
         occurrences all number
    5
    6
    Renal and urinary disorders
    Rise in plasma creatinine
         subjects affected / exposed
    33 / 90 (36.67%)
    21 / 90 (23.33%)
         occurrences all number
    56
    27
    Endocrine disorders
    Gynecomasty
         subjects affected / exposed
    19 / 90 (21.11%)
    12 / 90 (13.33%)
         occurrences all number
    24
    16
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    28 / 90 (31.11%)
    27 / 90 (30.00%)
         occurrences all number
    38
    45
    Gout
         subjects affected / exposed
    3 / 90 (3.33%)
    8 / 90 (8.89%)
         occurrences all number
    8
    9
    Back pain
         subjects affected / exposed
    7 / 90 (7.78%)
    11 / 90 (12.22%)
         occurrences all number
    7
    12
    Infections and infestations
    Infection
    Additional description: All bacterial, viral and funghal infections occurring throughout the study
         subjects affected / exposed
    64 / 90 (71.11%)
    60 / 90 (66.67%)
         occurrences all number
    178
    191
    Metabolism and nutrition disorders
    Hyperkalemia
         subjects affected / exposed
    16 / 90 (17.78%)
    8 / 90 (8.89%)
         occurrences all number
    25
    8

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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