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    Clinical Trial Results:
    A Phase 2/3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Alport Syndrome

    Summary
    EudraCT number
    		 2016-004395-22
    Trial protocol
    		 DE   GB   ES   FR  
    Global end of trial date
    30 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    402-C-1603
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03019185
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND number: 131763
    Sponsors
    Sponsor organisation name
    Reata Pharmaceuticals, Inc
    Sponsor organisation address
    5320 Legacy Drive, Plano, United States, 75024
    Public contact
    Clinical Operations, Reata Pharmaceuticals, Inc, 001 4694424838,
    Scientific contact
    Clinical Operations, Reata Pharmaceuticals, Inc, 001 4694424838,
    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
    30 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 2: - To assess the change from baseline in estimated glomerular filtration rate (eGFR) in bardoxolone methyl-treated patients after 12 weeks of treatment. - To assess the safety of bardoxolone methyl after 12 weeks of treatment. Phase 3: - To assess the change from baseline in estimated glomerular filtration rate (eGFR) in bardoxolone methyl-treated patients relative to placebo after 48 weeks of treatment. - To assess the safety of bardoxolone methyl relative to placebo after 48 weeks of treatment.
    Protection of trial subjects
    The independent DMC, which operated under written charter, reviewed unblinded safety data throughout study conduct and made recommendations as appropriate. The DMC began data reviews approximately 3 months after the first patient was enrolled and continued quarterly reviews through the last dose of the last patient enrolled. The DMC evaluated available safety, tolerability, and efficacy data from the Study 1603 Phase 2 prior to opening enrollment in Study 1603 Phase 3. Additionally, the DMC reviewed the progress of Study 1603 Phase 3 and the accumulating unblinded data while the trial was ongoing. The DMC made written recommendations to Sponsor representatives following each meeting. The DMC provided advice to the Sponsor as to whether the trial should continue as is, be modified to protect patient safety, or be terminated. Intrapatient dose-modification decisions were made by investigators, not by the DMC.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Mar 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
    Spain: 8
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Japan: 21
    Country: Number of subjects enrolled
    United States: 135
    Country: Number of subjects enrolled
    Australia: 5
    Country: Number of subjects enrolled
    Puerto Rico: 6
    Worldwide total number of subjects
    187
    EEA total number of subjects
    20
    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)
    25
    Adults (18-64 years)
    159
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 CARDINAL Phase 2 and Phase 3 were conducted under the same protocol. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3.

    Pre-assignment
    Screening details
    		 Patients with a diagnosis of Alport syndrome by genetic testing (documented mutation in a gene associated with Alport syndrome) were screened per the Inclusion/Exclusion criteria defined in the protocol at approved clinical research sites.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 2 Bardoxolone Methyl
    Arm description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bardoxolone methyl capsules
    Investigational medicinal product code
    RTA-402
    Other name
    THYL, CDDO-Me, CDDO-Methyl Ester, NSC 713BARDOXOLONE ME200, Chemical Name: Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study

    Arm title
    		 Phase 3 Placebo
    Arm description
    		 Participants who received placebo (with sham titration) in the Cardinal Phase 3 study
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo capsules
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules administered orally once daily

    Arm title
    		 Phase 3 Bardoxolone Methyl
    Arm description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Bardoxolone methyl capsules
    Investigational medicinal product code
    RTA-402
    Other name
    BARDOXOLONE METHYL, CDDO-Me, CDDO-Methyl Ester, NSC 713200, Chemical Name: Oleana-1,9(11)-dien-28-oic acid, 2-cyano-3,12-dioxo-, methyl ester
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study

    Number of subjects in period 1
    		Phase 2 Bardoxolone Methyl Phase 3 Placebo Phase 3 Bardoxolone Methyl
    Started
    30
    80
    77
    Completed
    24
    79
    75
    Not completed
    6
    1
    2
         Consent withdrawn by subject
    1
    -
    -
         ESKD Resulting in Kidney Transplant
    1
    -
    -
         Withdrawal by Subject
    -
    1
    -
         Lost to follow-up
    3
    -
    2
         Inability to continue due to increased serum creat
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 2 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study

    Reporting group title
    Phase 3 Placebo
    Reporting group description
    		 Participants who received placebo (with sham titration) in the Cardinal Phase 3 study

    Reporting group title
    Phase 3 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study

    Reporting group values
    		 Phase 2 Bardoxolone Methyl Phase 3 Placebo Phase 3 Bardoxolone Methyl Total
    Number of subjects
    		 30 80 77 187
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.63 ( 12.557 ) 39.6 ( 16.03 ) 38.8 ( 14.55 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 48 43 109
        Male
    		 12 32 34 78
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 1 12 14 27
        Native Hawaiian or Pacific Islander
    		 0 0 1 1
        Black or African American
    		 3 2 3 8
        White
    		 26 63 55 144
        Other
    		 0 2 4 6
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 10 9 22
        Not Hispanic or Latino
    		 27 70 68 165
    Baseline Estimated Glomerular Filtration Rate (EGFR)
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    		 54.17 ( 24.075 ) 62.63 ( 18.234 ) 62.74 ( 17.719 ) -
    Baseline Urine Albumin to Creatinine Ration (UACR)
    Units: mg/g
        geometric mean (full range (min-max))
    		 147.83 (2.4 to 1600.0) 134.45 (1.2 to 3031.0) 148.09 (2.1 to 3495.0) -
    Subject analysis sets

    Subject analysis set title
    Phase 2 Comparator
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Phase 2 portion of this study was open-label. Patients in the Phase 2 cohort received bardoxolone methyl throughout the study. A formal test of mean change from baseline in eGFR ≠ 0 was conducted at Week 12, 48, and 100. In order to report a statistical analysis related to a specific endpoint it is required to define at least two comparison groups. This analysis set has been created to provide a comparator for the outcome of the Phase 2 portion of the study.

    Subject analysis sets values
    		 Phase 2 Comparator
    Number of subjects
    30
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    46.63 ( 12.557 )
    Gender categorical
    Units: Subjects
        Female
    18
        Male
    12
    Race
    Units: Subjects
        American Indian or Alaska Native
    0
        Asian
    1
        Native Hawaiian or Pacific Islander
    0
        Black or African American
    3
        White
    26
        Other
    0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    3
        Not Hispanic or Latino
    27
    Baseline Estimated Glomerular Filtration Rate (EGFR)
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    54.17 ( 24.075 )
    Baseline Urine Albumin to Creatinine Ration (UACR)
    Units: mg/g
        geometric mean (full range (min-max))
    147.83 (2.4 to 1600.0)

    End points

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    End points reporting groups
    Reporting group title
    Phase 2 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study

    Reporting group title
    Phase 3 Placebo
    Reporting group description
    		 Participants who received placebo (with sham titration) in the Cardinal Phase 3 study

    Reporting group title
    Phase 3 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study

    Subject analysis set title
    Phase 2 Comparator
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The Phase 2 portion of this study was open-label. Patients in the Phase 2 cohort received bardoxolone methyl throughout the study. A formal test of mean change from baseline in eGFR ≠ 0 was conducted at Week 12, 48, and 100. In order to report a statistical analysis related to a specific endpoint it is required to define at least two comparison groups. This analysis set has been created to provide a comparator for the outcome of the Phase 2 portion of the study.

    Primary: Change from baseline in estimated glomerular filtration rate (eGFR) after 12 weeks of treatment (Phase 2)

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    End point title
    		 Change from baseline in estimated glomerular filtration rate (eGFR) after 12 weeks of treatment (Phase 2) [1]
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks after participant receives the first dose in the Phase 2 study
    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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 2 Bardoxolone Methyl Phase 2 Comparator
    Number of subjects analysed
    30 [2]
    30
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at week 12
    13.37 ( 1.4111 )
    0 ( 0 )
    Notes
    [2] - Intent-to-treat population (all enrolled patients)
    Statistical analysis title
    		 Mean change from baseline eGFR at Week 12
    Statistical analysis description
    A formal test of mean change from baseline in eGFR not equal to 0 was conducted at week 12
    Comparison groups
    Phase 2 Bardoxolone Methyl v Phase 2 Comparator
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean change from baseline
    Point estimate
    13.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 10.48
         upper limit
    		 16.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4111
    Notes
    [3] - Available data from analysis visits Week 1 to Week 12 are included. Missing Data were not imputed

    Primary: Change from baseline in eGFR after 48 weeks of treatment (Phase 3)

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    End point title
    		 Change from baseline in eGFR after 48 weeks of treatment (Phase 3) [4]
    End point description
    End point type
    Primary
    End point timeframe
    48 weeks after participant receives the first dose in the Phase 3 study
    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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 2 Bardoxolone Methyl Phase 2 Comparator
    Number of subjects analysed
    30
    30
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at week 48
    7.4 ( 1.9451 )
    0 ( 0 )
    Statistical analysis title
    		 Mean change from baseline in eGFR after 48 weeks
    Comparison groups
    Phase 2 Bardoxolone Methyl v Phase 2 Comparator
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference (Net)
    Point estimate
    9.49
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 5.38
         upper limit
    		 13.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.813
    Notes
    [5] - Available data from analysis visits Week 1 to Week 48 were included. Missing data were not imputed.

    Primary: Change from baseline in eGFR after 100 weeks of treatment (Phase 3)

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    End point title
    		 Change from baseline in eGFR after 100 weeks of treatment (Phase 3) [6]
    End point description
    End point type
    Primary
    End point timeframe
    100 weeks after participant receives the first dose in the Phase 3 study
    Notes
    [6] - 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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 2 Bardoxolone Methyl Phase 2 Comparator
    Number of subjects analysed
    30
    30
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at Week 100
    4.28 ( 1.7484 )
    0 ( 0 )
    Statistical analysis title
    		 Mean change from baseline in eGFR after 100 weeks
    Comparison groups
    Phase 2 Bardoxolone Methyl v Phase 2 Comparator
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005 [7]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean Difference (Net)
    Point estimate
    7.65
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.41
         upper limit
    		 11.89
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.144
    Notes
    [7] - Available data from analysis visits Week 1 to Week 100 (excluding Week 52) were included. Missing data were not imputed.

    Secondary: Change from baseline in eGFR after 48 weeks of treatment (Phase 2)

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    End point title
    		 Change from baseline in eGFR after 48 weeks of treatment (Phase 2) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    48 weeks after participant receives the first dose in the Phase 2 study
    Notes
    [8] - 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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 2 Bardoxolone Methyl Phase 2 Comparator
    Number of subjects analysed
    30 [9]
    30
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at Week 48
    7.4 ( 1.9451 )
    0 ( 0 )
    Notes
    [9] - Intent-to-treat population (all enrolled patients)
    Statistical analysis title
    		 Mean change from baseline in eGFR 48 weeks - Ph2
    Statistical analysis description
    A formal test of mean change from baseline in eGFR ≠ 0 was conducted at Week 48.
    Comparison groups
    Phase 2 Bardoxolone Methyl v Phase 2 Comparator
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0008 [10]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean change from baseline
    Point estimate
    7.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.4
         upper limit
    		 11.39
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.9451
    Notes
    [10] - Available data from analysis visits Week 1 to Week 48 were included. Missing data were not imputed.

    Secondary: Change from baseline in eGFR after 100 weeks of treatment (Phase 2)

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    End point title
    		 Change from baseline in eGFR after 100 weeks of treatment (Phase 2) [11]
    End point description
    End point type
    Secondary
    End point timeframe
    100 weeks after participant receives the first dose in the Phase 2 study
    Notes
    [11] - 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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 2 Bardoxolone Methyl Phase 2 Comparator
    Number of subjects analysed
    30 [12]
    30
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at Week 100
    4.28 ( 1.7484 )
    0 ( 0 )
    Notes
    [12] - Intent-to-treat population (all enrolled patients)
    Statistical analysis title
    		 Mean change from baseline in eGFR 100 weeks - Ph2
    Comparison groups
    Phase 2 Bardoxolone Methyl v Phase 2 Comparator
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.015 [14]
    Method
    		 Mixed models analysis
    Parameter type
    		 LS Mean change from baseline
    Point estimate
    4.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 7.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.7484
    Notes
    [13] - A formal test of mean change from baseline in eGFR ≠ 0 was conducted at Week 100.
    [14] - Available data from analysis visits Week 1 to Week 100 (excluding Week 52) were included. Missing data were not imputed.

    Secondary: Change from baseline at Week 52 following a 4-week drug treatment withdrawal period (Phase 3)

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    End point title
    		 Change from baseline at Week 52 following a 4-week drug treatment withdrawal period (Phase 3) [15]
    End point description
    End point type
    Secondary
    End point timeframe
    52 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the first year)
    Notes
    [15] - 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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 3 Placebo Phase 3 Bardoxolone Methyl
    Number of subjects analysed
    80
    77
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at Week 52
    -6.08 ( 1.243 )
    -0.99 ( 1.253 )
    Statistical analysis title
    		 Mean change from baseline 52 weeks - Ph3
    Comparison groups
    Phase 3 Bardoxolone Methyl v Phase 3 Placebo
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0021 [16]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference (Net)
    Point estimate
    5.09
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 1.37
         upper limit
    		 8.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.656
    Notes
    [16] - Missing eGFR data were imputed using multiple imputation based on the treatment group to which the patient was assigned.

    Secondary: Change from baseline in eGFR at Week 104 following a 4-week drug treatment withdrawal period (Phase 3)

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    End point title
    		 Change from baseline in eGFR at Week 104 following a 4-week drug treatment withdrawal period (Phase 3) [17]
    End point description
    End point type
    Secondary
    End point timeframe
    104 weeks after participant receives the first dose in the Phase 3 study (or 4 weeks after last dose for patients who discontinued early in the second year)
    Notes
    [17] - 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: The protocol for this study covered both a Phase 2 study portion and a Phase 3 portion. Participants enrolled in Phase 2 were not allowed to enroll in Phase 3; therefore, the end results for each section only include the arms that had patients in that phase.
    End point values
    		 Phase 3 Placebo Phase 3 Bardoxolone Methyl
    Number of subjects analysed
    80
    77
    Units: mL/min/1.73 m^2
    least squares mean (standard error)
        Change from baseline at Week 104
    -8.84 ( 1.353 )
    -4.52 ( 1.395 )
    Statistical analysis title
    		 Mean change from baseline 104 weeks - Ph3
    Comparison groups
    Phase 3 Placebo v Phase 3 Bardoxolone Methyl
    Number of subjects included in analysis
    157
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0232 [18]
    Method
    		 ANCOVA
    Parameter type
    		 LS Mean Difference (Net)
    Point estimate
    4.26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 7.94
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.876
    Notes
    [18] - Missing eGFR data were imputed using multiple imputation based on the treatment group to which the patient was assigned.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from study visit Day 1 to study visit Week 104/Follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Phase 2 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 2 Study

    Reporting group title
    Phase 3 Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl capsules at a starting dose of 5 mg and titrated up to a maximal dose of 20 mg (participants with UACR less than or equal to 300 mg/g) or 30 mg (participants with UACR greater than 300 mg/g) daily in the Cardinal Phase 3 Study

    Reporting group title
    Phase 3 Placebo
    Reporting group description
    		 Participants who received placebo (with sham titration) in the Cardinal Phase 3 study

    Serious adverse events
    		 Phase 2 Bardoxolone Methyl Phase 3 Bardoxolone Methyl Phase 3 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 30 (20.00%)
    8 / 77 (10.39%)
    15 / 80 (18.75%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoid tumour
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Carcinoid tumour pulmonary
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (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
    Colon adenoma
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Prostate cancer
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian mass
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Pneumothorax
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Laceration
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Scapula fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status migrainosus
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ileus
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    End stage renal disease
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Empyema
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    0 / 80 (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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Phase 2 Bardoxolone Methyl Phase 3 Bardoxolone Methyl Phase 3 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 30 (96.67%)
    75 / 77 (97.40%)
    76 / 80 (95.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basosquamous carcinoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Colon adenoma
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hypertension
         subjects affected / exposed
    5 / 30 (16.67%)
    7 / 77 (9.09%)
    8 / 80 (10.00%)
         occurrences all number
    5
    7
    8
    Hypotension
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    2
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Chills
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Fatigue
         subjects affected / exposed
    6 / 30 (20.00%)
    14 / 77 (18.18%)
    12 / 80 (15.00%)
         occurrences all number
    6
    14
    12
    Malaise
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 77 (5.19%)
    0 / 80 (0.00%)
         occurrences all number
    3
    4
    0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 30 (3.33%)
    6 / 77 (7.79%)
    2 / 80 (2.50%)
         occurrences all number
    1
    6
    2
    Oedema peripheral
         subjects affected / exposed
    7 / 30 (23.33%)
    12 / 77 (15.58%)
    10 / 80 (12.50%)
         occurrences all number
    7
    12
    10
    Pain
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    1
    0
    2
    Peripheral swelling
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences all number
    0
    2
    2
    Pyrexia
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 77 (3.90%)
    4 / 80 (5.00%)
         occurrences all number
    1
    3
    4
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Seasonal allergy
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Reproductive system and breast disorders
    Bartholin's cyst
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Cervical discharge
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Menorrhagia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    1
    2
    0
    Oligomenorrhoea
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    4 / 80 (5.00%)
         occurrences all number
    1
    2
    4
    Cough
         subjects affected / exposed
    3 / 30 (10.00%)
    8 / 77 (10.39%)
    3 / 80 (3.75%)
         occurrences all number
    3
    8
    3
    Dyspnoea
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Epistaxis
         subjects affected / exposed
    3 / 30 (10.00%)
    7 / 77 (9.09%)
    0 / 80 (0.00%)
         occurrences all number
    3
    7
    0
    Nasal congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Nasal dryness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 30 (10.00%)
    4 / 77 (5.19%)
    6 / 80 (7.50%)
         occurrences all number
    3
    4
    6
    Rhinitis allergic
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Sinus congestion
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract congestion
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Wheezing
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Anxiety
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Attention deficit/hyperactivity disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Confusional state
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Depression
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    2
    1
    1
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 77 (2.60%)
    3 / 80 (3.75%)
         occurrences all number
    3
    2
    3
    Sleep disorder
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 30 (43.33%)
    36 / 77 (46.75%)
    2 / 80 (2.50%)
         occurrences all number
    13
    36
    2
    Albumin urine present
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    6 / 30 (20.00%)
    19 / 77 (24.68%)
    1 / 80 (1.25%)
         occurrences all number
    6
    19
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 30 (6.67%)
    5 / 77 (6.49%)
    9 / 80 (11.25%)
         occurrences all number
    2
    5
    9
    Blood creatinine increased
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 77 (3.90%)
    8 / 80 (10.00%)
         occurrences all number
    1
    3
    8
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Blood potassium increased
         subjects affected / exposed
    0 / 30 (0.00%)
    4 / 77 (5.19%)
    2 / 80 (2.50%)
         occurrences all number
    0
    4
    2
    Brain natriuretic peptide abnormal
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Brain natriuretic peptide increased
         subjects affected / exposed
    3 / 30 (10.00%)
    11 / 77 (14.29%)
    3 / 80 (3.75%)
         occurrences all number
    3
    11
    3
    Eosinophil count increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 77 (5.19%)
    1 / 80 (1.25%)
         occurrences all number
    2
    4
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    1
    2
    0
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 77 (6.49%)
    2 / 80 (2.50%)
         occurrences all number
    0
    5
    2
    Urine albumin/creatinine ratio increased
         subjects affected / exposed
    2 / 30 (6.67%)
    8 / 77 (10.39%)
    7 / 80 (8.75%)
         occurrences all number
    2
    8
    7
    Vitamin D decreased
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    0
    1
    2
    Weight decreased
         subjects affected / exposed
    3 / 30 (10.00%)
    10 / 77 (12.99%)
    1 / 80 (1.25%)
         occurrences all number
    3
    10
    1
    Weight increased
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    6 / 80 (7.50%)
         occurrences all number
    0
    2
    6
    White blood cell count decreased
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Contusion
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 77 (5.19%)
    1 / 80 (1.25%)
         occurrences all number
    1
    4
    1
    Epicondylitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Foot fracture
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Laceration
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Ligament sprain
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    Limb injury
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Tendon injury
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Left ventricular hypertrophy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    3 / 80 (3.75%)
         occurrences all number
    0
    2
    3
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 30 (3.33%)
    3 / 77 (3.90%)
    12 / 80 (15.00%)
         occurrences all number
    1
    3
    12
    Dysgeusia
         subjects affected / exposed
    4 / 30 (13.33%)
    4 / 77 (5.19%)
    1 / 80 (1.25%)
         occurrences all number
    4
    4
    1
    Headache
         subjects affected / exposed
    6 / 30 (20.00%)
    16 / 77 (20.78%)
    16 / 80 (20.00%)
         occurrences all number
    6
    16
    16
    Migraine
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    2
    1
    2
    Migraine without aura
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    1
    0
    2
    Periodic limb movement disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Presyncope
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    2
    0
    2
    Sinus headache
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Syncope
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 77 (5.19%)
    0 / 80 (0.00%)
         occurrences all number
    2
    4
    0
    Iron deficiency anaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    2
    1
    2
    Eustachian tube dysfunction
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Tinnitus
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    0
    1
    2
    Vertigo
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences all number
    1
    2
    2
    Eye disorders
    Blepharospasm
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    3 / 80 (3.75%)
         occurrences all number
    0
    0
    3
    Dry eye
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    0
    1
    2
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Abdominal distension
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    1
    2
    0
    Abdominal pain
         subjects affected / exposed
    2 / 30 (6.67%)
    8 / 77 (10.39%)
    13 / 80 (16.25%)
         occurrences all number
    2
    8
    13
    Abdominal pain upper
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    4 / 80 (5.00%)
         occurrences all number
    1
    1
    4
    Aphthous ulcer
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Constipation
         subjects affected / exposed
    4 / 30 (13.33%)
    7 / 77 (9.09%)
    4 / 80 (5.00%)
         occurrences all number
    4
    7
    4
    Dental caries
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    2 / 80 (2.50%)
         occurrences all number
    0
    3
    2
    Diarrhoea
         subjects affected / exposed
    4 / 30 (13.33%)
    12 / 77 (15.58%)
    6 / 80 (7.50%)
         occurrences all number
    4
    12
    6
    Dry mouth
         subjects affected / exposed
    3 / 30 (10.00%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    3
    3
    1
    Dyspepsia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    3
    1
    1
    Flatulence
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    1
    1
    2
    Food poisoning
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Functional gastrointestinal disorder
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 30 (0.00%)
    5 / 77 (6.49%)
    3 / 80 (3.75%)
         occurrences all number
    0
    5
    3
    Lip dry
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    6 / 30 (20.00%)
    13 / 77 (16.88%)
    11 / 80 (13.75%)
         occurrences all number
    6
    13
    11
    Oral mucosal exfoliation
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Paraesthesia oral
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Tongue discolouration
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Vomiting
         subjects affected / exposed
    3 / 30 (10.00%)
    7 / 77 (9.09%)
    3 / 80 (3.75%)
         occurrences all number
    3
    7
    3
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Hepatic steatosis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 30 (20.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    6
    2
    0
    Dry skin
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Eczema
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Rash macular
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Rash pruritic
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Albuminuria
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Chronic kidney disease
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences all number
    1
    2
    2
    Dysuria
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences all number
    0
    2
    2
    Haematuria
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Nephrolithiasis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Proteinuria
         subjects affected / exposed
    5 / 30 (16.67%)
    7 / 77 (9.09%)
    6 / 80 (7.50%)
         occurrences all number
    5
    7
    6
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    2
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 77 (1.30%)
    6 / 80 (7.50%)
         occurrences all number
    2
    1
    6
    Arthritis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Back pain
         subjects affected / exposed
    7 / 30 (23.33%)
    9 / 77 (11.69%)
    13 / 80 (16.25%)
         occurrences all number
    7
    9
    13
    Bursitis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Coccydynia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Costochondritis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Flank pain
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 77 (2.60%)
    3 / 80 (3.75%)
         occurrences all number
    2
    2
    3
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Muscle spasms
         subjects affected / exposed
    22 / 30 (73.33%)
    38 / 77 (49.35%)
    27 / 80 (33.75%)
         occurrences all number
    22
    38
    27
    Muscle twitching
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    2 / 80 (2.50%)
         occurrences all number
    0
    1
    2
    Muscular weakness
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    Myalgia
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 77 (5.19%)
    3 / 80 (3.75%)
         occurrences all number
    2
    4
    3
    Neck pain
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Osteoarthritis
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Pain in extremity
         subjects affected / exposed
    2 / 30 (6.67%)
    7 / 77 (9.09%)
    2 / 80 (2.50%)
         occurrences all number
    2
    7
    2
    Plantar fasciitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Spondylitis
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Tendonitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    1
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 77 (3.90%)
    2 / 80 (2.50%)
         occurrences all number
    4
    3
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    1
    1
    1
    Cystitis
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    Ear infection
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    1
    2
    1
    Fungal infection
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    0 / 80 (0.00%)
         occurrences all number
    1
    1
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    3 / 80 (3.75%)
         occurrences all number
    1
    2
    3
    Herpes zoster
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    1 / 80 (1.25%)
         occurrences all number
    2
    0
    1
    Influenza
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 77 (7.79%)
    7 / 80 (8.75%)
         occurrences all number
    3
    6
    7
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    3 / 30 (10.00%)
    18 / 77 (23.38%)
    24 / 80 (30.00%)
         occurrences all number
    3
    18
    24
    Oral herpes
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Otitis externa
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    2 / 80 (2.50%)
         occurrences all number
    0
    0
    2
    Peritonitis
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 30 (3.33%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    1
    1
    3
    Pneumonia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    2
    2
    1
    Rhinitis
         subjects affected / exposed
    0 / 30 (0.00%)
    1 / 77 (1.30%)
    3 / 80 (3.75%)
         occurrences all number
    0
    1
    3
    Sinusitis
         subjects affected / exposed
    2 / 30 (6.67%)
    6 / 77 (7.79%)
    7 / 80 (8.75%)
         occurrences all number
    2
    6
    7
    Skin candida
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Tooth abscess
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 30 (20.00%)
    12 / 77 (15.58%)
    8 / 80 (10.00%)
         occurrences all number
    6
    12
    8
    Urinary tract infection
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 77 (3.90%)
    5 / 80 (6.25%)
         occurrences all number
    2
    3
    5
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    0
    2
    1
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Acidosis
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    2 / 80 (2.50%)
         occurrences all number
    0
    2
    2
    Decreased appetite
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    0
    3
    1
    Dehydration
         subjects affected / exposed
    0 / 30 (0.00%)
    3 / 77 (3.90%)
    0 / 80 (0.00%)
         occurrences all number
    0
    3
    0
    Dyslipidaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 77 (2.60%)
    0 / 80 (0.00%)
         occurrences all number
    0
    2
    0
    Gout
         subjects affected / exposed
    3 / 30 (10.00%)
    2 / 77 (2.60%)
    6 / 80 (7.50%)
         occurrences all number
    3
    2
    6
    Hyperkalaemia
         subjects affected / exposed
    9 / 30 (30.00%)
    11 / 77 (14.29%)
    5 / 80 (6.25%)
         occurrences all number
    9
    11
    5
    Hyperlipidaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    1
    2
    1
    Hyperphosphataemia
         subjects affected / exposed
    2 / 30 (6.67%)
    2 / 77 (2.60%)
    1 / 80 (1.25%)
         occurrences all number
    2
    2
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 77 (0.00%)
    4 / 80 (5.00%)
         occurrences all number
    0
    0
    4
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    2
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 30 (3.33%)
    0 / 77 (0.00%)
    0 / 80 (0.00%)
         occurrences all number
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 77 (3.90%)
    0 / 80 (0.00%)
         occurrences all number
    4
    3
    0
    Metabolic acidosis
         subjects affected / exposed
    4 / 30 (13.33%)
    3 / 77 (3.90%)
    1 / 80 (1.25%)
         occurrences all number
    4
    3
    1
    Vitamin D deficiency
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 77 (1.30%)
    1 / 80 (1.25%)
         occurrences all number
    4
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 May 2018
    Version 2.0
    15 Nov 2018
    Version 3.0
    23 May 2019
    Version 4.0

    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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