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    Clinical Trial Results:
    Does allopurinol reduce right ventricular mass in lung disease associated pulmonary hypertension?

    Summary
    EudraCT number
    		 2014-002305-38
    Trial protocol
    		 GB  
    Global end of trial date
    16 Jun 2017

    Results information
    Results version number
    		 v2(current)
    This version publication date
    02 Nov 2018
    First version publication date
    09 Jun 2018
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Noticed mistake in the results of the primary outcome

    Trial information

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    Trial identification
    Sponsor protocol code
    2013CV11
    Additional study identifiers
    ISRCTN number
    		 ISRCTN11081180
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sponsor Reference : 2013CV11
    Sponsors
    Sponsor organisation name
    University of Dundee - NHS Tayside
    Sponsor organisation address
    George Pirie Way, Dundee, United Kingdom,
    Public contact
    Stephen McSwiggan, University of Dundee, Tayside Clinical Trials Unit, 0044 1382383233, s.j.mcswiggan@dundee.ac.uk
    Scientific contact
    Stephen McSwiggan, University of Dundee, Tayside Clinical Trials Unit, 0044 1382383233, s.j.mcswiggan@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
    22 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective will be to see if Allopurinol can improve right ventricular hypertrophy in patients with pulmonary hypertension associated with COPD or interstitial lung disease(ILD). This will be done by measuring the size of the right side of the heart muscle with an MRI scan before and after one years of treatment with allopurinol or placebo.
    Protection of trial subjects
    All adverse events (AEs) and serious adverse events (SAEs) will be recorded from the time a participant consents to join the study until the last study visit. Participants with unresolved AEs at the last study visit will be followed up until resolution or 30 days after last patient, last visit (LPLV), whichever is sooner. SUSARS will be followed until resolution.
    Background therapy
    		 All the patients currently prescribed medication for their lung disease will continue as normal.
    Evidence for comparator
    		 A possible new way to treat lung disease related pulmonary hypertension (PH) is Allopurinol (Xanthine Oxidase Inhibitor) which decreases both uric acid and oxidative stress. The case for allopurinol is based on several different factors. Firstly, in primary pulmonary hypertension serum uric acid independently predicts mortality. Furthermore, when vasodilator therapy is given, the change in urate correlates very well (r= 0·68 p<0·0011) with the change in total pulmonary resistance. This accords well with experimental evidence that uric acid decreases NO production in cultured pulmonary artery endothelial cells. Secondly, both hypoxia and tobacco smoke are known from many studies to up-regulate xanthine oxidase and therefore to increase its production of both uric acid and oxidative stress. Thirdly, and most importantly, there are five experimental studies all showing that allopurinol inhibits hypoxia induced pulmonary vasoconstriction, pulmonary hypertension, endothelial dysfunction and vascular remodelling. Fourthly, there is one human study where allopurinol improved endothelial function in hypoxic patients.However, this study looked at the brachial artery. Indeed, there is a wealth of data that allopurinol improves systemic endothelial function in many other diseases characterised by oxidative stress. Although this is supportive to some extent, the pulmonary vasculature is clearly very different from the systemic vasculature. Fifthly, allopurinol profoundly reduces oxidative stress (OS) and OS is known to directly promote RV hypertrophy as well as cause pulmonary vascular abnormalities. There is a sixth, albeit, fairly speculative further reason for studying allopurinol in lung disease. Allopurinol blocks an oxidase enzyme which “wastes” molecular oxygen by converting it into oxygen free radicals. Therefore in theory blocking this oxidase should boost tissue oxygen.
    Actual start date of recruitment
    01 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    9
    From 65 to 84 years
    63
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of 191 patients screened, 72 were randomised, and 66 completed per protocol.

    Pre-assignment
    Screening details
    		 Aged 18 years or over, previously diagnosed with COPD or ILD, screening echocardiography based diagnosis of PH, stable lung disease medication for at least two weeks prior to consent, no contraindications to MRI, no allergy or intolerance to allopurinol, LVEF > 45% on echocardiography, CKD class 3B or greater, severe hepatic disease

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Double blind medication (allopurinol or placebo) will be prepared, packaged and labelled by Tayside Pharmaceuticals. Randomisation was carried out by Tayside Pharmaceuticals using block randomisation in twelve groups of six (with three active/three placebo in each block). They used a validated randomisation program and securely backed up both the randomisation seed and the randomisation allocation. A copy of the allocation was supplied to the Clinical Trials Pharmacy at Ninewells Hospital.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Received placebo tablets
    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
    100mg once daily for 2 weeks, then 300mg once daily for 4 weeks and then 300mg twice daily for 10.5 weeks

    Arm title
    		 Allopurinol
    Arm description
    		 Received allopurinol tablets
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Allopurinol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg once daily for 2 weeks, 300mg once daily for 4 weeks and then 300mg twice daily for 10.5 weeks

    Number of subjects in period 1
    		Placebo Allopurinol
    Started
    36
    36
    Completed
    32
    31
    Not completed
    4
    5
         Adverse event, serious fatal
    1
    -
         Physician decision
    1
    -
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 72 72
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 9 9
        From 65-84 years
    		 63 63
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71 ( 6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 28
        Male
    		 44 44
    Long-term oxygen use
    Units: Subjects
        Yes
    		 5 5
        No
    		 67 67
    Chronic lung disease
    Units: Subjects
        COPD
    		 67 67
        ILD
    		 5 5
    BMI
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 29 ( 5 ) -
    Smoking history
    Units: Pack-years
        arithmetic mean (standard deviation)
    		 48.6 ( 27.8 ) -
    FEV1
    Units: % predicted
        arithmetic mean (standard deviation)
    		 60 ( 21 ) -
    Pulmonary acceleration time
    Units: ms
        arithmetic mean (standard deviation)
    		 96.0 ( 10.9 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Received placebo tablets

    Reporting group title
    Allopurinol
    Reporting group description
    		 Received allopurinol tablets

    Primary: Change in right ventricular mass (RVM)

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    End point title
    		 Change in right ventricular mass (RVM)
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: gram(s)
        arithmetic mean (standard error)
    0.97 ( 1.20 )
    1.85 ( 1.56 )
    Statistical analysis title
    		 Intention-to-treat analysis
    Comparison groups
    Allopurinol v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 t-test, 2-sided
    Confidence interval

    Primary: Change in right ventricular mass index (RVMI)

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    End point title
    		 Change in right ventricular mass index (RVMI)
    End point description
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: gram(s)/square meter
        arithmetic mean (standard error)
    0.50 ( 0.60 )
    0.70 ( 0.75 )
    Statistical analysis title
    		 Intention-to-treat analysis
    Comparison groups
    Placebo v Allopurinol
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Change in left ventricular mass (LVM)

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    End point title
    		 Change in left ventricular mass (LVM)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: gram(s)
        arithmetic mean (standard error)
    -1.9 ( 2.8 )
    0.8 ( 3.2 )
    No statistical analyses for this end point

    Secondary: Change in left ventricular mass index (LVMI)

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    End point title
    		 Change in left ventricular mass index (LVMI)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: gram(s)/square meter
        arithmetic mean (standard error)
    -1.1 ( 1.2 )
    0.1 ( 1.5 )
    No statistical analyses for this end point

    Secondary: Change in SGRQ total score

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    End point title
    		 Change in SGRQ total score
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    -1.3 ( 2.0 )
    -0.9 ( 1.7 )
    No statistical analyses for this end point

    Secondary: BDI-TDI score

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    End point title
    		 BDI-TDI score
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    -0.1 ( 0.9 )
    -0.7 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Change in six minute walk distance (6MWD)

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    End point title
    		 Change in six minute walk distance (6MWD)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: meter
        arithmetic mean (standard error)
    -10.0 ( 12.5 )
    8.8 ( 10.0 )
    No statistical analyses for this end point

    Secondary: Change in NT-ProBNP

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    End point title
    		 Change in NT-ProBNP
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: picogram(s)
        arithmetic mean (standard error)
    289.4 ( 213.3 )
    -87.6 ( 127.2 )
    No statistical analyses for this end point

    Secondary: Change in right ventricular end-systolic volume (RVESV)

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    End point title
    		 Change in right ventricular end-systolic volume (RVESV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    3.8 ( 2.8 )
    4.8 ( 2.5 )
    No statistical analyses for this end point

    Secondary: Change in right ventricular end-diastolic volume (RVEDV)

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    End point title
    		 Change in right ventricular end-diastolic volume (RVEDV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    5.6 ( 4.2 )
    8.8 ( 4.2 )
    No statistical analyses for this end point

    Secondary: Change in right ventricular stroke volume (RVSV)

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    End point title
    		 Change in right ventricular stroke volume (RVSV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    1.6 ( 2.7 )
    3.0 ( 3.1 )
    No statistical analyses for this end point

    Secondary: Change in right ventricular ejection fraction (RVEF)

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    End point title
    		 Change in right ventricular ejection fraction (RVEF)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: percent
        arithmetic mean (standard error)
    1.7 ( 1.7 )
    1.3 ( 2.4 )
    No statistical analyses for this end point

    Secondary: Change in left ventricular end-systolic volume (LVESV)

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    End point title
    		 Change in left ventricular end-systolic volume (LVESV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    2.9 ( 2.6 )
    1.3 ( 2.4 )
    No statistical analyses for this end point

    Secondary: Change in left ventricular end-diastolic volume (LVEDV)

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    End point title
    		 Change in left ventricular end-diastolic volume (LVEDV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    3.8 ( 4.1 )
    7.2 ( 4.4 )
    No statistical analyses for this end point

    Secondary: Change in left ventricular stroke volume (LVSV)

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    End point title
    		 Change in left ventricular stroke volume (LVSV)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: millilitre(s)
        arithmetic mean (standard error)
    0.4 ( 2.6 )
    5.8 ( 3.3 )
    No statistical analyses for this end point

    Secondary: Change in left ventricular ejection fraction (LVEF)

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    End point title
    		 Change in left ventricular ejection fraction (LVEF)
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: percent
        arithmetic mean (standard error)
    0.0 ( 1.3 )
    3.0 ( 2.0 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for physical functioning

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    End point title
    		 Change in SF-36 score for physical functioning
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    2.9 ( 2.4 )
    -1.1 ( 3.1 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for physical role limitations

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    End point title
    		 Change in SF-36 score for physical role limitations
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    8.2 ( 6.4 )
    1.7 ( 5.7 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for emotional role limitations

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    End point title
    		 Change in SF-36 score for emotional role limitations
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    1.5 ( 8.5 )
    -5.8 ( 6.5 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for energy/fatigue

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    End point title
    		 Change in SF-36 score for energy/fatigue
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    4.5 ( 3.8 )
    -0.8 ( 2.6 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for emotional well-being

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    End point title
    		 Change in SF-36 score for emotional well-being
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    0.3 ( 3.1 )
    4.6 ( 2.8 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for social functioning

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    End point title
    		 Change in SF-36 score for social functioning
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    -1.6 ( 4.0 )
    -2.4 ( 3.6 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for pain

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    End point title
    		 Change in SF-36 score for pain
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    1.1 ( 4.7 )
    -4.1 ( 3.5 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for general health

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    End point title
    		 Change in SF-36 score for general health
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    0.0 ( 3.3 )
    0.1 ( 2.7 )
    No statistical analyses for this end point

    Secondary: Change in SF-36 score for health change

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    End point title
    		 Change in SF-36 score for health change
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Placebo Allopurinol
    Number of subjects analysed
    35
    36
    Units: unit(s)
        arithmetic mean (standard error)
    7.0 ( 5.3 )
    5.6 ( 4.0 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events were recorded from the time the participants consented to join the study until the last study visit. Participants with unresolved AEs at the last study visit were followed up until resolution or 30 days after last patient, last visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Randomised & analysed subjects
    Reporting group description
    		 -

    Serious adverse events
    		 Randomised & analysed subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 71 (25.35%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Transitional cell cancer of renal pelvis and ureter metastatic
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
    Additional description: Drug-induced syncope
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulum
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal obstruction
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomised & analysed subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 71 (88.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    6
    Intermittent claudication
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Malaise
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Peripheral swelling
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Testicular swelling
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Epistaxis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    4
    Oropharyngeal pain
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    5
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood cholesterol increased
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    5
    Blood glucose increased
         subjects affected / exposed
    8 / 71 (11.27%)
         occurrences all number
    8
    Blood urea increased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Mean cell volume increased
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Laceration
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Overdose
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Procedural vomiting
    Additional description: Intermittent vomiting due to post-nasal drip
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Rib fracture
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Skin injury
    Additional description: Injury to left leg - cut to left shin
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    5
    Drug withdrawal convulsions
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Dysgeusia
    Additional description: Metallic taste
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    4 / 71 (5.63%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Visual acuity reduced
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Retinal detachment
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    7
    Dyspepsia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Rectal haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hepatic steatosis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    2
    Hyperhidrosis
    Additional description: Increased sweating
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Urinary retention
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Back pain
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Groin pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Muscle spasms
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    6 / 71 (8.45%)
         occurrences all number
    6
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Eye infection
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    2
    Furuncle
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    3 / 71 (4.23%)
         occurrences all number
    3
    Hordeolum
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Laryngitis
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nail infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Oral candidiasis
         subjects affected / exposed
    2 / 71 (2.82%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    7
    Viral infection
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 71 (7.04%)
         occurrences all number
    5
    Type 2 diabetes mellitus
         subjects affected / exposed
    1 / 71 (1.41%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2015
    Amendment to seek approval for patients suffering from interstitial lung disease to be eligible for recruitment in the study.
    05 Oct 2015
    Amendment to seek approval to - Change exclusion criteria from 'already had gout' to ' - Change the timing of six minute walk test from doing two at randomisation visit to doing one as a practice test at screening visit and a second one at randomisation. - Remove the measurement of diffusion capacity of lung for carbon monoxide - Add an additional patient identification centre using SPCRN - Allow study visits 3, 4, 6 and 8 to be done at the location of participant's convenience such as their home
    21 Apr 2016
    Amendment to seek approval for adding NHS Grampian as another centre for recruitment for the study.
    21 Dec 2016
    Amendment to seek approval to: - Change the follow-up period from 12 months to a minimum of 9 months - Change software for the analysis of MRI images to Circle Cardiovascular Imaging (Calgary, Canada)

    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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