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    Clinical Trial Results:
    A Phase 4, Randomized, Double-Blind, Multicenter, Placebo-Controlled Study to Evaluate the Safety and Efficacy of Lesinurad 200 mg in Combination With a Xanthine Oxidase Inhibitor (XOI), Compared With an XOI Alone, in Subjects With Gout and Estimated Creatinine Clearance 30 to <60 mL/min Who Have Not Achieved Target Serum Uric Acid Levels on an XOI Alone

    Summary
    EudraCT number
    		 2017-001191-30
    Trial protocol
    		 CZ   HU   PL  
    Global end of trial date
    25 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Oct 2021
    First version publication date
    22 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RDEA594-401
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03226899
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ironwood Pharmaceuticals, Inc.
    Sponsor organisation address
    100 Summer Street Suite 2300 , Boston MA , United States, 02110
    Public contact
    Ironwood Study Chair, Ironwood Pharmaceuticals, Inc., 001 617-621-7722, Info@ironwoodpharma.com
    Scientific contact
    Ironwood Study Chair, Ironwood Pharmaceuticals, Inc., 001 617-621-7722, Info@ironwoodpharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Feb 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety over 24 months of lesinurad 200 mg once daily (qd) when used in combination with a xanthine oxidase inhibitor (XOI), compared with XOI alone, in subjects with gout and moderate renal impairment (estimated creatinine clearance 30 to <60 mL/min) who have not reached target serum uric acid (sUA) levels on an XOI alone.
    Protection of trial subjects
    Prior to participation in any study-specific procedures, each subject must sign and date an EC-approved written ICF in a language the subject can understand. The language in the written information about the study should be as non-technical as practical, and should be understandable to the subject. Before informed consent is obtained, the Investigator should provide the subject ample time and opportunity to inquire about the study and to decide whether or not to participate. All questions about the study should be answered to the satisfaction of the subject. The written ICF should be signed and personally dated by the subject and by the person who conducted the informed consent discussion, with any additional signatures obtained as required by applicable local regulations and EC requirements. Each subject will be informed that participation is voluntary and that he/she can withdraw from the study at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Jul 2017
    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 States: 147
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Czechia: 21
    Country: Number of subjects enrolled
    Hungary: 29
    Worldwide total number of subjects
    242
    EEA total number of subjects
    95
    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)
    83
    From 65 to 84 years
    159
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study included an approximate 1-month Screening Period.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer
    Blinding implementation details
    Treatment group assignments were blinded to minimize bias in study assessments and monitoring.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo + XOI
    Arm description
    		 Placebo oral tablet once daily (QD) plus a stable, medically appropriate dose of an xanthine oxidase inhibitor (XOI)
    Arm type
    		 Placebo

    Investigational medicinal product name
    matching placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All doses of investigational product (IP) were taken daily, in the morning with food and 1 cup (8 oz; 240 mL) of water. Subjects were instructed to drink 2 liters (68 oz) of liquid a day.

    Investigational medicinal product name
    XOI
    Investigational medicinal product code
    Other name
    allopurinol, febuxostat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All doses of investigational product (IP) were taken daily, in the morning with food and 1 cup (8 oz; 240 mL) of water. Subjects were instructed to drink 2 liters (68 oz) of liquid a day.

    Investigational medicinal product name
    colchicine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gout flare prophylaxis: commercially available colchicine was provided through the Month 6 study visit. Actual colchicine dose (0.5 or 0.6 mg qd) and frequency were adjusted based on the local label, subject medical history, and clinical judgement.

    Investigational medicinal product name
    corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gout flare prophylaxis: Subjects unable to take colchicine are permitted to take a short course of low-dose oral corticosteroids up to the Month 3 study visit

    Arm title
    		 Lesinurad + XOI
    Arm description
    		 Lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lesinurad
    Investigational medicinal product code
    Other name
    RDEA594
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All doses of IP were taken daily, in the morning with food and 1 cup (8 oz; 240 mL) of water. Subjects were instructed to drink 2 liters (68 oz) of liquid a day.

    Investigational medicinal product name
    XOI
    Investigational medicinal product code
    Other name
    allopurinol, febuxostat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All doses of investigational product (IP) were taken daily, in the morning with food and 1 cup (8 oz; 240 mL) of water. Subjects were instructed to drink 2 liters (68 oz) of liquid a day.

    Investigational medicinal product name
    colchicine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gout flare prophylaxis: commercially available colchicine was provided through the Month 6 study visit. Actual colchicine dose (0.5 or 0.6 mg qd) and frequency were adjusted based on the local label, subject medical history, and clinical judgement.

    Investigational medicinal product name
    corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Gout flare prophylaxis: Subjects unable to take colchicine are permitted to take a short course of low-dose oral corticosteroids up to the Month 3 study visit

    Number of subjects in period 1
    		Placebo + XOI Lesinurad + XOI
    Started
    118
    124
    Completed
    0
    0
    Not completed
    118
    124
         Did not complete study /24 months of treatment
    118
    124

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo + XOI
    Reporting group description
    		 Placebo oral tablet once daily (QD) plus a stable, medically appropriate dose of an xanthine oxidase inhibitor (XOI)

    Reporting group title
    Lesinurad + XOI
    Reporting group description
    		 Lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI

    Reporting group values
    		 Placebo + XOI Lesinurad + XOI Total
    Number of subjects
    		 118 124 242
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 67.3 ± 8.00 66.4 ± 10.10 -
    Gender categorical
    Units: Subjects
        Female
    		 22 28 50
        Male
    		 96 96 192
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 26 20 46
        Not Hispanic or Latino
    		 92 104 196
    Race
    Units: Subjects
        Asian
    		 1 2 3
        Native Hawaiian or Other Pacific Islander
    		 2 1 3
        Black or African American
    		 14 24 38
        White
    		 99 95 194
        Unknown or Not Reported
    		 2 2 4

    End points

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    End points reporting groups
    Reporting group title
    Placebo + XOI
    Reporting group description
    		 Placebo oral tablet once daily (QD) plus a stable, medically appropriate dose of an xanthine oxidase inhibitor (XOI)

    Reporting group title
    Lesinurad + XOI
    Reporting group description
    		 Lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI

    Primary: Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6

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    End point title
    		 Percentage of Participants Who Achieve Serum Urate (sUA) < 6.0 mg/dL at Month 6 [1]
    End point description
    Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least 1 dose of study drug. N=Participants with a value at Month 6.
    End point type
    Primary
    End point timeframe
    Month 6
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics are presented per protocol. Statistical analyses not performed as the study was prematurely terminated.
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    80
    80
    Units: percentage of participants
        number (not applicable)
    33.8
    58.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time

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    End point title
    		 Percentage of Participants Who Achieve sUA < 6.0 mg/dL Over Time
    End point description
    Modified Intent-to-Treat (mITT) Population: all randomized participants who received at least 1 dose of study drug. n=participants with a value at baseline and given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116
    123 [2]
    Units: percentage of participants
    number (not applicable)
        Baseline; n=116, 123
    10.3
    10.6
        Month 1; n=111, 119
    35.1
    58.8
        Month 3; n=99, 101
    36.4
    52.5
        Month 6; n=80, 80
    33.8
    58.8
        Month 9; n=50, 42
    34.0
    42.9
        Month 12; n=28, 23
    42.9
    56.5
        Month 15; n=11, 8
    45.5
    62.5
        Month 18; n=1, 0
    0.0
    99999
    Notes
    [2] - 99999=not applicable; no participants in this arm at this time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment

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    End point title
    		 Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
    End point description
    Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. n=participants with a value at baseline and given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116 [3]
    123 [4]
    Units: µmol/L
    arithmetic mean (standard deviation)
        Change at Month 1; n=111, 119
    -57.0 ± 96.2
    -120.3 ± 105.3
        Change at Month 3; n=99, 101
    -59.8 ± 98.6
    -106.8 ± 116.2
        Change at Month 6; n=80, 80
    -54.6 ± 103.1
    -125.8 ± 140.0
        Change at Month 9; n=50, 42
    -70.6 ± 128.4
    -95.9 ± 106.5
        Change at Month 12; n=28, 23
    -78.7 ± 122.4
    -69.6 ± 110.4
        Change at Month 15; n=11, 8
    -92.6 ± 91.4
    -116.6 ± 76.3
        Change at Month 18; n=1, 0
    0.00 ± 999999
    99999 ± 99999
        Last On-Treatment; n=111, 119
    -57.0 ± 104.7
    -125.5 ± 121.4
        Last Off-Treatment; n=6, 11
    -70.7 ± 105.4
    -156.6 ± 149.2
    Notes
    [3] - 99999=not applicable; 1 participant in this arm at this time point.
    [4] - 999999=not applicable; 0 participants in this arm at this time point.
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment

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    End point title
    		 Percent Change From Baseline in sUA Over Time, Including the Last Value On and Off Treatment
    End point description
    Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. n=participants with a value at baseline and given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116 [5]
    123 [6]
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Month 1; n=111, 119
    -11.3 ± 18.8
    -24.0 ± 19.3
        Change at Month 3; n=99, 101
    -11.1 ± 18.8
    -21.2 ± 21.7
        Change at Month 6; n=80, 80
    -10.0 ± 21.7
    -23.9 ± 24.4
        Change at Month 9; n=50, 42
    -12.6 ± 27.3
    -18.6 ± 20.2
        Change at Month 12; n=28, 23
    -15.2 ± 22.8
    -14.7 ± 26.7
        Change at Month 15; n=11, 8
    -18.9 ± 17.5
    -26.1 ± 16.3
        Change at Month 18; n=1, 0
    0.00 ± 99999
    999999 ± 999999
        Last On-Treatment; n=111, 119
    -10.6 ± 22.1
    -24.8 ± 22.8
        Last Off-Treatment; n=6, 11
    -16.1 ± 25.8
    -27.3 ± 22.6
    Notes
    [5] - 99999=not applicable; 1 participant in this arm at this time point.
    [6] - 999999=not applicable; 0 participants in this arm at this time point.
    No statistical analyses for this end point

    Secondary: Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24

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    End point title
    		 Change From Baseline in Estimated Creatinine Clearance (eCrCl) at Month 24
    End point description
    The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 months
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: mL/min
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [7] - Due to early study termination, no participant reached Month 24; these data are not available.
    [8] - Due to early study termination, no participant reached Month 24; these data are not available.
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in eCrCl at Month 24

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    End point title
    		 Percent Change From Baseline in eCrCl at Month 24
    End point description
    The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 months
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: percent change
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [9] - Due to early study termination, no participant reached Month 24; these data are not available.
    [10] - Due to early study termination, no participant reached Month 24; these data are not available.
    No statistical analyses for this end point

    Secondary: Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment

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    End point title
    		 Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
    End point description
    The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight. Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. n=Participants with a value at baseline and given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116 [11]
    123 [12]
    Units: mL/min
    arithmetic mean (standard deviation)
        Change at Month 1; n=111, 119
    0.13 ± 9.67
    -1.29 ± 6.45
        Change at Month 3; n=99, 101
    -0.69 ± 7.41
    -1.53 ± 8.65
        Change at Month 6; n=80, 80
    -1.84 ± 7.58
    -1.80 ± 7.02
        Change at Month 9; n=50, 42
    -0.78 ± 6.85
    -2.10 ± 7.97
        Change at Month 12; n=28, 23
    -2.14 ± 7.03
    -4.30 ± 6.34
        Change at Month 15; n=11, 8
    0.36 ± 6.07
    -6.00 ± 8.49
        Change at Month 18; n=1, 0
    -19.0 ± 99999
    999999 ± 999999
        Last On-Treatment; n=111, 119
    -1.03 ± 6.97
    -1.91 ± 8.19
        Last Off-Treatment; n=6, 11
    2.33 ± 5.61
    -2.45 ± 5.41
    Notes
    [11] - 99999=not applicable; 1 participant in the arm at this time point.
    [12] - 999999=not applicable; 0 participants in the arm at this time point.
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment

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    End point title
    		 Percent Change From Baseline in eCrCl Over the Study Period, Including the Last Value On and Off Treatment
    End point description
    The eCrCl was calculated by the Cockcroft-Gault formula using ideal body weight. Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo. n=Participants with a value at baseline and given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Months 1, 3, 6, 9, 12, 15, 18
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116 [13]
    123 [14]
    Units: percent change
    arithmetic mean (standard deviation)
        Change at Month 1; n=111, 119
    1.16 ± 19.90
    -2.07 ± 15.30
        Change at Month 3; n=99, 101
    -0.18 ± 17.70
    -2.14 ± 20.12
        Change at Month 6; n=80, 80
    -2.49 ± 17.96
    -3.01 ± 15.32
        Change at Month 9; n=50, 42
    -0.26 ± 18.67
    -3.42 ± 17.05
        Change at Month 12; n=28, 23
    -3.38 ± 15.71
    -8.1 ± 12.9
        Change at Month 15; n=11, 8
    3.67 ± 18.6
    -11.0 ± 16.5
        Change at Month 18; n=1, 0
    -31.7 ± 99999
    999999 ± 999999
        Last On-Treatment; n=111, 119
    -1.13 ± 16.86
    -3.04 ± 18.21
        Last Off-Treatment; n=6, 11
    4.14 ± 13.67
    -5.35 ± 13.52
    Notes
    [13] - 99999=not applicable; 1 participant in the arm at this time point.
    [14] - 999999=not applicable; 0 participants in the arm at this time point.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period

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    End point title
    		 Percentage of Participants With Serum Creatinine (sCr) Elevations (≥1.5 × Baseline) Over the Study Period
    End point description
    Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo.
    End point type
    Secondary
    End point timeframe
    up to 18 months
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116
    123
    Units: percentage of participants
        number (not applicable)
    5.2
    7.3
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period

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    End point title
    		 Percentage of Participants Meeting Criteria (eg, Based on sCr or eCrCl Criteria) for Treatment Discontinuations Over the Study Period
    End point description
    Kidney function was monitored throughout the study by measuring sCr and calculating eCrCl by Cockcroft-Gault formula using ideal body weight. Treatment discontinuations were required if a participant experienced an absolute sCr ≥4.0 mg/dL or an eCrCl <20 mL/min (based on central laboratory results). Safety Population: all randomized participants who received at least 1 dose of lesinurad or placebo.
    End point type
    Secondary
    End point timeframe
    up to 18 months
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    116
    123
    Units: percentage of participants
        number (not applicable)
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants Renal-Related and Kidney Stone Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Renal-related and kidney stone events were based on Medical Dictionary for Regulatory Activities (MedDRA) "Renal and Urinary Disorders" system organ classification. AEs that started on or after the first dose of study drug in this study, or those AEs with onset prior to the first dose of study drug but worsened after the first dose of study drug, were considered treatment emergent.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through each participant's study duration, up to approximately 18 months.
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    118
    124
    Units: percentage of participants
    number (not applicable)
        Treatment-Emergent SAEs
    0.0
    0.8
        Treatment-Emergent AEs
    4.2
    5.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Contributing Factors to Renal SAEs as Adjudicated by the Renal Event Adjudication Committee (REAC)

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    End point title
    		 Percentage of Participants With Contributing Factors to Renal SAEs as Adjudicated by the Renal Event Adjudication Committee (REAC)
    End point description
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through each participant's study duration, up to approximately 18 months.
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    0 [15]
    0 [16]
    Units: percentage of participants
        number (not applicable)
    Notes
    [15] - This was not analyzed; no events were adjudicated since the study was terminated early.
    [16] - This was not analyzed; no events were adjudicated since the study was terminated early.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs)

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    End point title
    		 Percentage of Participants With Cardiac Event Adjudication Committee (CEAC)-Adjudicated Major Adverse Cardiovascular Events (MACEs)
    End point description
    MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through each participant's study duration, up to approximately 18 months.
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    0 [17]
    0 [18]
    Units: percentage of participants
        number (not applicable)
    Notes
    [17] - This was not analyzed; no events were adjudicated since the study was terminated early.
    [18] - This was not analyzed; no events were adjudicated since the study was terminated early.
    No statistical analyses for this end point

    Secondary: Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+)

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    End point title
    		 Incidence of CEAC-Adjudicated MACEs or Hospitalization for Unstable Angina (MACE+)
    End point description
    MACEs are defined as Cardiovascular Death, Nonfatal Myocardial Infarction, and Nonfatal Stroke.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug through each participant's study duration, up to approximately 18 months.
    End point values
    		 Placebo + XOI Lesinurad + XOI
    Number of subjects analysed
    0 [19]
    0 [20]
    Units: events/year
        number (not applicable)
    Notes
    [19] - This was not analyzed; no events were adjudicated since the study was terminated early.
    [20] - This was not analyzed; no events were adjudicated since the study was terminated early.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug through each participant's study duration, up to approximately 18 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo + XOI
    Reporting group description
    		 Placebo oral tablet once daily (QD) plus a stable, medically appropriate dose of an xanthine oxidase inhibitor (XOI)

    Reporting group title
    Lesinurad + XOI
    Reporting group description
    		 Lesinurad 200 mg oral tablet QD plus a stable, medically appropriate dose of an XOI

    Serious adverse events
    		 Placebo + XOI Lesinurad + XOI
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 118 (5.93%)
    13 / 124 (10.48%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer recurrent
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         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
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 118 (0.00%)
    2 / 124 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stent occlusion
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Emphysema
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 118 (0.85%)
    0 / 124 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 118 (0.00%)
    1 / 124 (0.81%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo + XOI Lesinurad + XOI
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 118 (7.63%)
    18 / 124 (14.52%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 118 (3.39%)
    3 / 124 (2.42%)
         occurrences all number
    4
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 118 (0.85%)
    3 / 124 (2.42%)
         occurrences all number
    1
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 118 (0.00%)
    4 / 124 (3.23%)
         occurrences all number
    0
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 118 (3.39%)
    5 / 124 (4.03%)
         occurrences all number
    5
    5
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    0 / 118 (0.00%)
    3 / 124 (2.42%)
         occurrences all number
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Mar 2017
    The primary purpose of this amendment was to address regulatory feedback and to add a Month 1 study visit. Per the original protocol, the first on-treatment visit was scheduled for Month 3. In addition, minor revisions to improve clarity or provide additional detail were made to language describing study entry criteria; pregnancy and fertility testing; sourcing, dispensing, and dosing of study medications; premature discontinuation from the study; analysis populations; definition of adverse events (AEs); AEs of special interest; gout flare assessments; and current cumulative lesinurad exposure data.
    21 Jun 2017
    The primary purpose of this amendment was to address a request from the United States Food and Drug Administration (FDA) to omit “Investigator decision” and “Sponsor’s decision” from the list of possible reasons for early discontinuation from the study. The FDA also requested revisions to the charter of the Renal Events Adjudication Committee (REAC); protocol language related to the responsibilities of the REAC was amended to reflect those revisions. In addition, minor changes were made to improve clarity and consistency with respect to the following: treatment “discontinuation” and study “withdrawal”; subjects who prematurely discontinue investigational product (IP); referencing study visits to the Baseline Visit rather than to Day 1; destruction of unused XOI and colchicine; recording of overdoses; dispensing of XOI at the Month 24 Visit; vital status assessment at the End of Study Visit.

    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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