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    Clinical Trial Results:
    A Long-Term Extension Study of Lesinurad in Combination with Allopurinol for Subjects Completing an Efficacy and Safety Study of Lesinurad and Allopurinol.

    Summary
    EudraCT number
    2012-004389-16
    Trial protocol
    DE   ES   BE  
    Global end of trial date
    17 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Dec 2017
    First version publication date
    29 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RDEA594-306
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Ardea Biosciences, Inc
    Sponsor organisation address
    9390 Towne Centre Dr., San Diego, United States,
    Public contact
    Nihar Bhakta, MD, Ardea Biosciences, Inc., +1 858-652-6671, nbhakta@ardeabio.com
    Scientific contact
    Nihar Bhakta, MD, Ardea Biosciences, Inc, +1 858-652-6671, nbhakta@ardeabio.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
    17 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the long-term efficacy and safety of lesinurad in combination with allopurinol.
    Protection of trial subjects
    This study was conducted in accordance with the protocol, International Conference on Harmonisation (ICH) E6 Good Clinical Practice (GCP), the Declaration of Helsinki (2008), and all other applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Feb 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 States: 512
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Ukraine: 58
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    South Africa: 66
    Country: Number of subjects enrolled
    Australia: 12
    Country: Number of subjects enrolled
    New Zealand: 16
    Worldwide total number of subjects
    716
    EEA total number of subjects
    39
    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)
    640
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects who had been randomized to lesinurad 200 mg or 400 mg plus allopurinol in Study RDEA594-301 or Study RDEA594-302 continued to receive the same dose of lesinurad plus allopurinol in this extension study (LESU 200 mg CONT + ALLO group or LESU 400 mg CONT + ALLO group).

    Pre-assignment
    Screening details
    718 subjects (59.2%) enrolled in this optional extension Study RDEA594-306. Although 717 subjects were randomized to a lesinurad dose group or were to continue on their same dose of lesinurad, only 716 subjects received at least 1 dose of lesinurad in the extension study.

    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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    lesinurad 200 mg + allopurinol
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    lesinurad
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg

    Arm title
    lesinurad 400 mg + allopurinol
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    lesinurad
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg

    Number of subjects in period 1
    lesinurad 200 mg + allopurinol lesinurad 400 mg + allopurinol
    Started
    362
    354
    Completed
    216
    216
    Not completed
    146
    138
         Adverse event, serious fatal
    7
    5
         Consent withdrawn by subject
    46
    52
         Prohibited or contraindicated medication
    5
    2
         Adverse event, non-fatal
    34
    41
         Gout flare
    -
    2
         Lost to follow-up
    26
    18
         Sponsor terminated study
    6
    5
         Protocol deviation
    22
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    lesinurad 200 mg + allopurinol
    Reporting group description
    -

    Reporting group title
    lesinurad 400 mg + allopurinol
    Reporting group description
    -

    Reporting group values
    lesinurad 200 mg + allopurinol lesinurad 400 mg + allopurinol Total
    Number of subjects
    362 354 716
    Age Categorical
    Units: Subjects
        < 65 years
    325 315 640
        >=65 years
    37 39 76
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    51.0 ( 11.04 ) 51.7 ( 10.55 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    13 12 25
        Male
    349 342 691
    Region of Enrollment
    Includes subjects who were randomized and received at least one dose of study medication in the extension study.
    Units: Subjects
        United States
    252 260 512
        Canada
    9 3 12
        Ukraine
    33 25 58
        Poland
    6 13 19
        Germany
    7 5 12
        Spain
    2 2 4
        Belgium
    3 1 4
        Switzerland
    1 0 1
        South Africa
    33 33 66
        Australia
    6 6 12
        New Zealand
    10 6 16

    End points

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    End points reporting groups
    Reporting group title
    lesinurad 200 mg + allopurinol
    Reporting group description
    -

    Reporting group title
    lesinurad 400 mg + allopurinol
    Reporting group description
    -

    Primary: Proportion of subjects with an sUA level that is < 6.0 mg/dL

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    End point title
    Proportion of subjects with an sUA level that is < 6.0 mg/dL [1]
    End point description
    Proportion of Subjects in Study 306 With sUA < 6.0 mg/dL from the Core Studies 301 and 302 and Extension Study 306, assessed after each subject had completed 12 months in the extension study - Observed Cases
    End point type
    Primary
    End point timeframe
    Up to approximately 2.5 years (at Extension Month 12)
    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: No statistical analysis available as EndPoint groups are a total of Placebo + Allopurinol and Lesinurad + Allopurinol.
    End point values
    lesinurad 200 mg + allopurinol lesinurad 400 mg + allopurinol
    Number of subjects analysed
    276
    213
    Units: Proportion of Subjects
        number (not applicable)
    63.8
    75.8
    No statistical analyses for this end point

    Secondary: Resolution of at least 1 target tophus

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    End point title
    Resolution of at least 1 target tophus
    End point description
    The proportion of subjects with ≥ 1 target tophus at Baseline in Study RDEA594-301 or RDEA594-302 who experience complete resolution of at least 1 target tophus at any time up to Month 12 of the extension - Observed Cases
    End point type
    Secondary
    End point timeframe
    Up to approximatley 2.5 years (at Extension Month 12)
    End point values
    lesinurad 200 mg + allopurinol lesinurad 400 mg + allopurinol
    Number of subjects analysed
    40
    37
    Units: Proportion of Subjects
        number (not applicable)
    45.0
    48.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The maximum time on lesinurad plus allopurinol was 1198 days in this extension study. The median and range of duration of exposure to lesinurad in this extension study, including dosing interruptions, was comparable across the groups.
    Adverse event reporting additional description
    Safety is assessed on the population of randomized subjects who received at least 1 dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    lesinurad 400 mg + allopurinol
    Reporting group description
    Subjects who had been randomized to lesinurad 200 mg or 400 mg plus allopurinol in Study RDEA594-301 or Study RDEA594-302 continued to receive the same dose of lesinurad plus allopurinol in this extension study.

    Reporting group title
    lesinurad 200 mg + allopurinol
    Reporting group description
    Subjects who had been randomized to lesinurad 200 mg or 400 mg plus allopurinol in Study RDEA594-301 or Study RDEA594-302 continued to receive the same dose of lesinurad plus allopurinol in this extension study.

    Serious adverse events
    lesinurad 400 mg + allopurinol lesinurad 200 mg + allopurinol
    Total subjects affected by serious adverse events
         subjects affected / exposed
    45 / 354 (12.71%)
    48 / 362 (13.26%)
         number of deaths (all causes)
    5
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 354 (0.28%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuroendocrine carcinoma
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 354 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral arterial stenosis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Iliac artery stenosis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Cardiac ablation
         subjects affected / exposed
    1 / 354 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device battery replacement
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         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 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (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
    Pulmonary embolism
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 354 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Delusional disorder, unspecified type
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    XIIth nerve injury
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 354 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 354 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 354 (0.85%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    1 / 354 (0.28%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 354 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocarditis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    0 / 354 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery occlusion
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Complicated migraine
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegic migraine
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Migraine
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer haemorrhage
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peptic ulcer
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia, obstructive
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 354 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    3 / 354 (0.85%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 354 (0.28%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    8 / 354 (2.26%)
    3 / 362 (0.83%)
         occurrences causally related to treatment / all
    5 / 8
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    2 / 354 (0.56%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Knee deformity
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 354 (0.00%)
    5 / 362 (1.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 354 (0.56%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 354 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian infection
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection staphylococcal
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         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
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    lesinurad 400 mg + allopurinol lesinurad 200 mg + allopurinol
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    184 / 354 (51.98%)
    185 / 362 (51.10%)
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    56 / 354 (15.82%)
    44 / 362 (12.15%)
         occurrences all number
    77
    57
    Vascular disorders
    Hypertension
         subjects affected / exposed
    36 / 354 (10.17%)
    27 / 362 (7.46%)
         occurrences all number
    49
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 354 (3.11%)
    21 / 362 (5.80%)
         occurrences all number
    12
    21
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    33 / 354 (9.32%)
    31 / 362 (8.56%)
         occurrences all number
    40
    36
    Back pain
         subjects affected / exposed
    25 / 354 (7.06%)
    30 / 362 (8.29%)
         occurrences all number
    29
    40
    Pain in extremity
         subjects affected / exposed
    20 / 354 (5.65%)
    19 / 362 (5.25%)
         occurrences all number
    25
    23
    Musculoskeletal pain
         subjects affected / exposed
    16 / 354 (4.52%)
    9 / 362 (2.49%)
         occurrences all number
    18
    12
    Osteoarthritis
         subjects affected / exposed
    11 / 354 (3.11%)
    13 / 362 (3.59%)
         occurrences all number
    13
    16
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    45 / 354 (12.71%)
    44 / 362 (12.15%)
         occurrences all number
    65
    58
    Nasopharyngitis
         subjects affected / exposed
    33 / 354 (9.32%)
    38 / 362 (10.50%)
         occurrences all number
    46
    50
    Bronchitis
         subjects affected / exposed
    23 / 354 (6.50%)
    16 / 362 (4.42%)
         occurrences all number
    24
    18
    Sinusitis
         subjects affected / exposed
    16 / 354 (4.52%)
    23 / 362 (6.35%)
         occurrences all number
    23
    30

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Jun 2013
    The primary purpose of this amendment was to expand guidance on subject hydration and to expand the management algorithm if a subject experiences an elevated serum creatinine or kidney stone.
    02 Jan 2014
    The primary purpose of this amendment was to modify the combination therapy extension study, RDEA594-306, in all countries where the study is ongoing to ensure patient safety. The changes were intended to better reflect the association of acute renal failure with lesinurad, especially in the monotherapy setting, and to emphasize the requirement for subjects to concomitantly take lesinurad with a xanthine oxidase inhibitor (allopurinol).
    07 Oct 2015
    The primary purpose of this amendment was to require all active subjects who are receiving lesinurad 400 mg in combination with allopurinol to have the dose of lesinurad decreased to 200 mg. Lesinurad 200 mg in combination with an XO inhibitor continues to have a favorable benefit-risk profile.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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