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    Clinical Trial Results:
    A Phase 2, Multicentre, Double-Blind, Placebo and Active Control Efficacy and Safety Study to Evaluate Verinurad combined with Allopurinol in Heart Failure with Preserved Ejection Fraction (AMETHYST)

    Summary
    EudraCT number
    		 2019-004862-16
    Trial protocol
    		 DE   BG   PL   SK   AT  
    Global end of trial date
    29 Apr 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2023
    First version publication date
    12 May 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D5496C00005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04327024
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    Södertälje, Södertälje, Sweden, 151 85
    Public contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 (877)240-9479, information.center@astrazeneca.com
    Scientific contact
    Global Clinical Lead, AstraZeneca Clinical Study Information Center, +1 (877)240-9479, information.center@astrazeneca.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
    09 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to assess effect of verinurad + allopurinol compared to placebo on exercise capacity by analyzing the change from baseline at week 32 in peak VO2 measurements.
    Protection of trial subjects
    Before the start of the clinical study, the clinical study protocol (CSP), Informed consent document (ICDs), and other relevant documents were submitted to the Regulatory Authority for review and approval, in accordance with local regulatory procedures. The study was performed in accordance with ethical principles that had their origin in the Declaration of Helsinki and were consistent with International Council for Harmonization Good Clinical Practice (ICH GCP) and the AstraZeneca policy on Bioethics and Human Biological Samples. The subjects were informed of the nature, significance, implications, and risks of the trial before the study. Informed consent was freely given and evidenced in writing.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 May 2020
    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
    Russian Federation: 35
    Country: Number of subjects enrolled
    Slovakia: 23
    Country: Number of subjects enrolled
    Poland: 16
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    United States: 13
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Australia: 6
    Worldwide total number of subjects
    159
    EEA total number of subjects
    77
    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)
    44
    From 65 to 84 years
    112
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 475 subjects were screened between May 19, 2020, and July 16, 2021, at 59 sites in 12 different countries. Of those screened, 159 were randomized into the study and received treatment, 53 in each arm of the study.

    Pre-assignment
    Screening details
    		 Subjects who met all the of inclusion criteria and none of the exclusion criteria were randomized to a study treatment. Study treatment was titrated over 8 weeks. Colchicine prophylaxis was given during the titration period and during the first 4 weeks of treatment at target dose (12 weeks total).

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verinurad + Allopurinol
    Arm description
    		 12 mg verinurad + 300 mg allopurinol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Allopurinol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg, administered once daily in Weeks 0-3; 200mg, administered once daily in Weeks 4-7; 300mg, administered once daily in Weeks 8-32.

    Investigational medicinal product name
    Verinurad
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    3mg, administered once daily in Weeks 0-3; 7.5mg, administered once daily in Weeks 4-7; 12mg, administered once daily in Weeks 8-32.

    Arm title
    		 Allopurinol
    Arm description
    		 300 mg Allopurinol
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matching verinurad, administered once daily

    Investigational medicinal product name
    Allopurinol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg, administered once daily in Weeks 0-3; 200mg, administered once daily in Weeks 4-7; 300mg, administered once daily in Weeks 8-32.

    Arm title
    		 Placebo
    Arm description
    		 0 mg placebo
    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
    Placebo tablet matching allopurinol, administered once daily

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule matching verinurad, administered once daily

    Number of subjects in period 1
    		Verinurad + Allopurinol Allopurinol Placebo
    Started
    53
    53
    53
    Completed
    51
    49
    50
    Not completed
    2
    4
    3
         Adverse event, serious fatal
    1
    2
    1
         Consent withdrawn by subject
    1
    1
    2
         Non-compliance with study drug
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verinurad + Allopurinol
    Reporting group description
    		 12 mg verinurad + 300 mg allopurinol

    Reporting group title
    Allopurinol
    Reporting group description
    		 300 mg Allopurinol

    Reporting group title
    Placebo
    Reporting group description
    		 0 mg placebo

    Reporting group values
    		 Verinurad + Allopurinol Allopurinol Placebo Total
    Number of subjects
    		 53 53 53 159
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 14 8 22 44
        From 65-84 years
    		 38 43 31 112
        85 years and over
    		 1 2 0 3
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 69.6 ± 9.04 70.6 ± 6.98 67.5 ± 9.77 -
    Sex: Female, Male
    Units: Participants
        Female
    		 21 19 16 56
        Male
    		 32 34 37 103
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 46 46 48 140
        Black or African American
    		 0 3 1 4
        Asian
    		 7 3 4 14
        Other
    		 0 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 6 4 13
        Not Hispanic or Latino
    		 50 47 49 146
        Unknown or Not Reported
    		 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Verinurad + Allopurinol
    Reporting group description
    		 12 mg verinurad + 300 mg allopurinol

    Reporting group title
    Allopurinol
    Reporting group description
    		 300 mg Allopurinol

    Reporting group title
    Placebo
    Reporting group description
    		 0 mg placebo

    Primary: Change from baseline at Week 32 in peak V02 consumption in verinurad + allopurinol compared to placebo (ANCOVA model)

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    End point title
    		 Change from baseline at Week 32 in peak V02 consumption in verinurad + allopurinol compared to placebo (ANCOVA model) [1]
    End point description
    Mean change from baseline in peak VO2 at Week 32 between the treatment groups was compared using change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and baseline peak VO2 included as covariate. H0: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) = 0 Ha: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs placebo) ≠ 0 A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level. Resulting p-value was 0.862. Since this was the first test in the hierarchical test sequence and endpoint was not rejected at a two-sided 0.05 level, the testing sequence did not continue.
    End point type
    Primary
    End point timeframe
    From baseline to Week 32
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arm covered in secondary endpoint
    End point values
    		 Verinurad + Allopurinol Placebo
    Number of subjects analysed
    53
    53
    Units: mL/kg/min
        least squares mean (confidence interval 95%)
    0.27 (-0.56 to 1.10)
    0.37 (-0.45 to 1.19)
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Placebo v Verinurad + Allopurinol
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.862
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.28
         upper limit
    		 1.08

    Secondary: Change from baseline at Week 32 in peak V02 consumption in verinurad+ allopurinol compared to allopurinol monotherapy (ANCOVA model)

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    End point title
    		 Change from baseline at Week 32 in peak V02 consumption in verinurad+ allopurinol compared to allopurinol monotherapy (ANCOVA model) [2]
    End point description
    Mean change from baseline in peak VO2 at Week 32 between the treatment groups was compared using change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and baseline peak VO2 included as covariate. H0: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs allopurinol) = 0 Ha: Difference in mean change from baseline in peak VO2 (verinurad + allopurinol vs allopurinol) ≠ 0 A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level.
    End point type
    Secondary
    End point timeframe
    From baseline to Week 32
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arm covered in secondary endpoint
    End point values
    		 Verinurad + Allopurinol Allopurinol
    Number of subjects analysed
    53
    53
    Units: mL/Kg/min
        least squares mean (confidence interval 95%)
    0.27 (-0.56 to 1.10)
    -0.17 (-1.03 to 0.69)
    Statistical analysis title
    		 ANCOVA analysis
    Comparison groups
    Verinurad + Allopurinol v Allopurinol
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.472
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.76
         upper limit
    		 1.64

    Secondary: Change from baseline at Week 32 in KCCQ-TSS in verinurad+ allopurinol compared to placebo (MMRM)

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    End point title
    		 Change from baseline at Week 32 in KCCQ-TSS in verinurad+ allopurinol compared to placebo (MMRM) [3]
    End point description
    Mean change from baseline in KCCQ-TSS at Week 32 between the treatment groups was compared using MMRM analysis, with change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and visit, visit by treatment, and baseline KCCQ-TSS included as covariates. H0: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs placebo) = 0 Ha: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs placebo) ≠ 0 A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level.
    End point type
    Secondary
    End point timeframe
    From baseline to week 32
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arm covered in secondary endpoint
    End point values
    		 Verinurad + Allopurinol Placebo
    Number of subjects analysed
    51
    48
    Units: score
    least squares mean (confidence interval 95%)
        Week 22
    0.50 (-4.08 to 5.08)
    3.55 (-1.29 to 8.39)
        Week 32
    4.31 (0.28 to 8.33)
    1.16 (-3.02 to 5.34)
    Statistical analysis title
    		 Mixed Models with Repeated Measures Analysis
    Comparison groups
    Verinurad + Allopurinol v Placebo
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.287
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.65
         upper limit
    		 8.94

    Secondary: Change from baseline at Week 32 in KCCQ-TSS in verinurad+ allopurinol compared to allopurinol monotherapy (MMRM)

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    End point title
    		 Change from baseline at Week 32 in KCCQ-TSS in verinurad+ allopurinol compared to allopurinol monotherapy (MMRM) [4]
    End point description
    Mean change from baseline in KCCQ-TSS at Week 32 between the treatment groups was compared using MMRM analysis, with change from baseline (i.e., week 32 value - baseline value) as the dependent variable, treatment as the independent variable and visit, visit by treatment, and baseline KCCQ-TSS included as covariates. H0: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs allopurinol) = 0 Ha: Difference in mean change from baseline in KCCQ-TSS (verinurad + allopurinol vs allopurinol) ≠ 0 A hierarchical test sequence was used for the confirmatory analysis of the primary and secondary objectives in order to address the issue of multiple testing and control the Type I error rate at an overall two-sided 0.05 level.
    End point type
    Secondary
    End point timeframe
    From baseline to week 32
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Other arm covered in secondary endpoint
    End point values
    		 Verinurad + Allopurinol Allopurinol
    Number of subjects analysed
    51
    50
    Units: score
    least squares mean (confidence interval 95%)
        Week 22
    0.50 (-4.08 to 5.08)
    2.85 (-1.91 to 7.62)
        Week 32
    4.31 (0.28 to 8.33)
    4.45 (0.34 to 8.57)
    Statistical analysis title
    		 Mixed Model with Repeated Measures analysis
    Comparison groups
    Verinurad + Allopurinol v Allopurinol
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.96
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 5.61

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected with onset date on or after first dose and up to the end of the study. Serious adverse events were collected with onset date on or after the signing of the informed consent form and up to the end of the study (week 36).
    Adverse event reporting additional description
    All adverse events reported are treatment emergent with onset on or after the first dose and up to the end of the study (week 36).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Allopurinol
    Reporting group description
    		 Description (Arm-group)

    Reporting group title
    Verinurad 12 mg + Allopurinol
    Reporting group description
    		 Description (Arm-group)

    Reporting group title
    Placebo
    Reporting group description
    		 0 mg placebo

    Serious adverse events
    		 Allopurinol Verinurad 12 mg + Allopurinol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 53 (18.87%)
    10 / 53 (18.87%)
    9 / 53 (16.98%)
         number of deaths (all causes)
    2
    1
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure acute
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    5 / 53 (9.43%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Sudden cardiac death
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fissure haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal hernia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive pancreatitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal prolapse
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Allopurinol Verinurad 12 mg + Allopurinol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 53 (49.06%)
    24 / 53 (45.28%)
    20 / 53 (37.74%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
         occurrences all number
    1
    4
    0
    Hypertension
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    2
    1
    2
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    3
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    1
    1
    2
    Epistaxis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    Rales
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    2
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 53 (5.66%)
    0 / 53 (0.00%)
         occurrences all number
    0
    3
    0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    5 / 53 (9.43%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    5
    2
    2
    Blood pressure increased
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    1
    3
    2
    Weight increased
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    0 / 53 (0.00%)
         occurrences all number
    2
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    0
    2
    0
    Ventricular extrasystoles
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    0 / 53 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac failure
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 53 (7.55%)
    4 / 53 (7.55%)
         occurrences all number
    1
    7
    5
    Atrial fibrillation
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    2
    0
    3
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 53 (1.89%)
    1 / 53 (1.89%)
         occurrences all number
    2
    1
    1
    Headache
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 53 (7.55%)
    0 / 53 (0.00%)
         occurrences all number
    0
    4
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 53 (5.66%)
    2 / 53 (3.77%)
         occurrences all number
    0
    3
    2
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    1 / 53 (1.89%)
    5 / 53 (9.43%)
    2 / 53 (3.77%)
         occurrences all number
    1
    7
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    1
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    1
    2
    1
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    1
    1
    3
    Haematuria
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 53 (0.00%)
    1 / 53 (1.89%)
         occurrences all number
    2
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    1 / 53 (1.89%)
         occurrences all number
    1
    2
    1
    Back pain
         subjects affected / exposed
    0 / 53 (0.00%)
    0 / 53 (0.00%)
    2 / 53 (3.77%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 53 (1.89%)
    2 / 53 (3.77%)
         occurrences all number
    3
    1
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 53 (3.77%)
    0 / 53 (0.00%)
         occurrences all number
    1
    2
    0
    Gout
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 53 (3.77%)
    2 / 53 (3.77%)
         occurrences all number
    2
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2020
    • Timelines for study endpoints changed from Week 28 to Week 32. • Extended titration period.
    03 Feb 2021
    • Inclusion of additional treatment arm, 24 mg verinurad + allopurinol. • Updated number of patients that will be randomized/enrolled and estimated screen-failure rate.
    20 Sep 2021
    • Reduction of sample size from 435 to 150 patients. • Removed interim analysis. • Removed the 24 mg verinurad + allopurinol treatment arm.

    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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