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    Clinical Trial Results:
    The Effect of Spironolactone on Pain in Older People with Osteoarthris

    Summary
    EudraCT number
    		 2013-002638-19
    Trial protocol
    		 GB  
    Global end of trial date
    28 Jan 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Jul 2016
    First version publication date
    23 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2012GR03
    Additional study identifiers
    ISRCTN number
    		 ISRCTN02046668
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Dundee / NHS Tayside
    Sponsor organisation address
    TASC, Ninewells Hospital, Dundee, United Kingdom, DD1 9SY
    Public contact
    Dr Miles Witham, University of Dundee, 44 01382 383086, m.witham@dundee.ac.uk
    Scientific contact
    Dr Miles Witham, University of Dundee, 44 01382 383086, m.witham@dundee.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This pilot study’s purpose it to provide preliminary evidence on which to base sample size calculations for a possible future trial which will answer the question: “Is spironolactone more effective than placebo in reducing knee pain in older people with symptomatic osteoarthritis (OA) of the knee, when given in addition to usual analgesia?”
    Protection of trial subjects
    Participants were recruited via a range of opt-in strategies to protect confidentiality and prevent unwanted contact. Informed consent was sought after ample time for participants to ask questions prior to engaging in trial procedures. Participants were enrolled only if they met inclusion and exclusion criteria designed to minimize risk from the IMP - in particular screening checks on renal function, sodium and potassium were conducted, and concomitant use of medications likely to exacerbate side effects of spironolactone (ie ACEi, ARB, NSAID) were exclusion criteria Frequent checks on blood pressure, renal function and electrolytes were conducted during the trial, and adverse events were sought at each study visit. A DMC was convened to review safety data during the trial.
    Background therapy
    		 Usual analgesic therapy was allowed during the trial as per normal clinical practice. Participants using NSAID medications were excluded from the trial due to the increased risk of interaction with spironolactone.
    Evidence for comparator
    		 Placebo was selected as comparator as the aim of the trial was to test the efficacy of spironolactone as add-on therapy to usual analgesics, rather than as a replacement for usual analgesia. Aldosterone is known to have pro-inflammatory effects, including stimulation of cytokine production, which might contribute to the low-level chronic inflammation seen in osteoarthritis. Spironolactone, as a blocker of aldosterone, might therefore be able to reverse this process. Data from a previous trial of spironolactone in older, functionally impaired people suggested an improvement in quality of life and a reduction in pain in the subgroup of participants with osteoarthritis (Am J Med 2013;126:590-7). This previous result provided the evidence that initiated this trial.
    Actual start date of recruitment
    01 Nov 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: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    86
    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)
    0
    From 65 to 84 years
    77
    85 years and over
    9

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruited from primary care via Scottish Primary care research network; via advertising; via SHARE register

    Pre-assignment
    Screening details
    		 Telephone prescreen, then screening visit to check eligibility criteria. Renal function and potassium checked at screening visit

    Period 1
    Period 1 title
    Randomised treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Matching IMP and placebo (overencapsulated IMP) prepared by an independent provider (Tayside Pharmaceuticals), dispensed in identical bottles with no external indication of allocation group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Spironolactone
    Arm description
    		 Oral spironolactone 25mg once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Spironolactone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25mg once daily for 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo taken once a day for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule taken orally once per day for 12 weeks

    Number of subjects in period 1
    		Spironolactone Placebo
    Started
    43
    43
    Completed
    43
    43

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Oral spironolactone 25mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken once a day for 12 weeks

    Reporting group values
    		 Spironolactone Placebo Total
    Number of subjects
    		 43 43 86
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 77.4 ( 4.8 ) 76.1 ( 5.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 26 27 53
        Male
    		 17 16 33
    Subject analysis sets

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised participants (Intention to treat)

    Subject analysis sets values
    		 ITT analysis set
    Number of subjects
    86
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    76.7 ( 5 )
    Gender categorical
    Units: Subjects
        Female
    53
        Male
    33

    End points

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    End points reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Oral spironolactone 25mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken once a day for 12 weeks

    Subject analysis set title
    ITT analysis set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All randomised participants (Intention to treat)

    Primary: WOMAC pain subscale

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    End point title
    		 WOMAC pain subscale
    End point description
    Unadjusted
    End point type
    Primary
    End point timeframe
    Change between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: Units
        arithmetic mean (confidence interval 95%)
    -1 (-1.6 to -0.4)
    -1.7 (-2.3 to -1.2)
    -0.01 (-0.9 to 0.88)
    Statistical analysis title
    		 Primary outcome analysis
    Statistical analysis description
    Between-group mixed-model regression, adjusting for baseline values and for site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.19
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.27
         upper limit
    		 1.33

    Secondary: WOMAC stiffness subscale

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    End point title
    		 WOMAC stiffness subscale
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: Units
        arithmetic mean (confidence interval 95%)
    -1 (-1.6 to -0.3)
    -1.7 (-2.3 to -1.2)
    -0.2 (-1.18 to 0.78)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusting for baseline values and site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.58
    Method
    		 Mixed models analysis
    Parameter type
    		 Median difference (final values)
    Point estimate
    0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.64
         upper limit
    		 1.13

    Secondary: WOMAC physical function subscale

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    End point title
    		 WOMAC physical function subscale
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: Units
        arithmetic mean (confidence interval 95%)
    -1 (-1.5 to -0.5)
    -1.1 (-1.7 to -0.5)
    -0.3 (-1.19 to 0.6)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values and site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.98
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.74
         upper limit
    		 0.76

    Secondary: EuroQol EQ5D

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    End point title
    		 EuroQol EQ5D
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: Units
        arithmetic mean (confidence interval 95%)
    0.02 (-0.05 to 0.09)
    0.03 (-0.03 to 0.1)
    0.07 (-0.02 to 0.16)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values, site and use of neuropathic drugs
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.12

    Secondary: EuroQol EQ5D visual analog scale

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    End point title
    		 EuroQol EQ5D visual analog scale
    End point description
    End point type
    Secondary
    End point timeframe
    Change from baseline to 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: Units
        arithmetic mean (confidence interval 95%)
    0.5 (-4.1 to 5)
    0.14 (-5.23 to 5.51)
    -2.19 (-9.11 to 4.73)
    Statistical analysis title
    		 Secondary analysis
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values, site and use of neuropathic drugs
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.78
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 5.19

    Secondary: Urine CTX II

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    End point title
    		 Urine CTX II
    End point description
    End point type
    Secondary
    End point timeframe
    Change between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: ug/L
        arithmetic mean (confidence interval 95%)
    0.1 (-0.8 to 0.9)
    -0.03 (-0.81 to 0.75)
    0.24 (-0.93 to 1.41)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values and site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.83
         upper limit
    		 1.24

    Secondary: Serum matrix metalloproteinase 3

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    End point title
    		 Serum matrix metalloproteinase 3
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: ng/ml
        arithmetic mean (confidence interval 95%)
    1 (-2 to 5)
    2.86 (-1.34 to 7.07)
    -1.44 (-9 to 6.11)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values and site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.46
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.98
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.32
         upper limit
    		 3.36

    Secondary: Morning cortisol

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    End point title
    		 Morning cortisol
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between baseline and 12 weeks
    End point values
    		 Spironolactone Placebo ITT analysis set
    Number of subjects analysed
    43
    43
    86
    Units: ng/ml
        arithmetic mean (confidence interval 95%)
    13 (-1 to 27)
    8.85 (-2.56 to 20.26)
    8.15 (-9.62 to 25.95)
    Statistical analysis title
    		 Secondary outcome
    Statistical analysis description
    Between-group mixed-model regression, adjusted for baseline values and site
    Comparison groups
    Spironolactone v Placebo
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    6.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.66
         upper limit
    		 22.73

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    screening visit to 12 week (final) visit
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Spironolactone
    Reporting group description
    		 Oral spironolactone 25mg once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo taken once a day for 12 weeks

    Serious adverse events
    		 Spironolactone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 43 (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
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 43 (2.33%)
         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%
    Non-serious adverse events
    		 Spironolactone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 43 (58.14%)
    24 / 43 (55.81%)
    Investigations
    Blood creatine increased
         subjects affected / exposed
    2 / 43 (4.65%)
    1 / 43 (2.33%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 43 (2.33%)
         occurrences all number
    3
    1
    Vomiting
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 43 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 43 (9.30%)
    2 / 43 (4.65%)
         occurrences all number
    5
    2
    Renal and urinary disorders
    Urinary tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    2 / 43 (4.65%)
         occurrences all number
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 43 (9.30%)
    4 / 43 (9.30%)
         occurrences all number
    4
    4
    Back pain
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 43 (4.65%)
         occurrences all number
    1
    2
    Pain in extremity
         subjects affected / exposed
    2 / 43 (4.65%)
    3 / 43 (6.98%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2013
    Clarification of Safety assessment procedures.
    27 Jan 2014
    Addition of an exclusion criterion.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26413749
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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
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