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    Clinical Trial Results:
    A Phase 3 Trial of the Efficacy and Safety of Bardoxolone Methyl in Patients with Autosomal Dominant Polycystic Kidney Disease

    Summary
    EudraCT number
    		 2018-004651-20
    Trial protocol
    		 GB   DE   FR   CZ   BE   ES   IT   HU   DK   PL  
    Global end of trial date
    08 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 May 2024
    First version publication date
    12 May 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    402-C-1808
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03918447
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Reata, a wholly owned subsidiary of Biogen
    Sponsor organisation address
    225 Binney Street, Cambridge, United States, 02142
    Public contact
    Study Medical Director, Reata, a wholly owned subsidiary of Biogen, clinicaltrials@biogen.com
    Scientific contact
    Study Medical Director, Reata, a wholly owned subsidiary of Biogen, clinicaltrials@biogen.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
    08 Aug 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to assess the off-treatment change from baseline in estimated glomerular filtration rate (eGFR) at Week 108 and to assess safety and tolerability of bardoxolone methyl.
    Protection of trial subjects
    Written informed consent was obtained from each participant or participant’s legally authorised representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Participants or the participant’s legally authorised representative were given adequate time to review the information in the informed consent/assent and were allowed to ask, and have answered, questions concerning all portions of the conduct of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 May 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 429
    Country: Number of subjects enrolled
    Japan: 64
    Country: Number of subjects enrolled
    Australia: 34
    Country: Number of subjects enrolled
    Spain: 31
    Country: Number of subjects enrolled
    Belgium: 30
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    France: 25
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Czechia: 7
    Worldwide total number of subjects
    667
    EEA total number of subjects
    128
    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)
    631
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at the investigative sites in the United States, Australia, Belgium, Czech Republic, France, Germany, Italy, Japan, Spain, and United Kingdom beginning on 29 May 2019. The study completion date was 8 August 2023.

    Pre-assignment
    Screening details
    		 A total of 667 participants were enrolled and randomized 1:1 to receive either bardoxolone methyl or placebo during the treatment period (up to Week 100) and continued to be assessed in the off-treatment period for 12 weeks (up to Week 112).

    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
    		 Bardoxolone Methyl
    Arm description
    		 During the treatment period, the participants received bardoxolone methyl capsules, once daily (QD) at a starting dose of 5 milligrams (mg), followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility urine albumin to creatinine ratio (UACR) was >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bardoxolone methyl
    Investigational medicinal product code
    Other name
    RTA 402
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Arm title
    		 Placebo
    Arm description
    		 During the treatment period, participants received bardoxolone methyl matching-placebo capsules, orally, QD up to Week 100, with sham titration to maintain the blinding. Participants did not receive a bardoxolone methyl matching placebo capsule during the off-treatment period between Weeks 100 and 112.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as specified in the treatment arm.

    Number of subjects in period 1
    		Bardoxolone Methyl Placebo
    Started
    334
    333
    Completed
    106
    112
    Not completed
    228
    221
         Adverse event, serious fatal
    1
    -
         Consent withdrawn by subject
    19
    17
         Study Terminated By Sponsor
    195
    197
         Lost to follow-up
    13
    6
         Reason not Specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Bardoxolone Methyl
    Reporting group description
    		 During the treatment period, the participants received bardoxolone methyl capsules, once daily (QD) at a starting dose of 5 milligrams (mg), followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility urine albumin to creatinine ratio (UACR) was >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112.

    Reporting group title
    Placebo
    Reporting group description
    		 During the treatment period, participants received bardoxolone methyl matching-placebo capsules, orally, QD up to Week 100, with sham titration to maintain the blinding. Participants did not receive a bardoxolone methyl matching placebo capsule during the off-treatment period between Weeks 100 and 112.

    Reporting group values
    		 Bardoxolone Methyl Placebo Total
    Number of subjects
    		 334 333
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.6 ( 9.46 ) 48.3 ( 9.58 ) -
    Gender categorical
    Units: Participants
        Male
    		 146 160 306
        Female
    		 188 173 361
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 34 45 79
        Black or African American
    		 23 18 41
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        White
    		 269 261 530
        Other
    		 6 8 14
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 29 35 64
        Non-Hispanic/Latino
    		 305 298 603

    End points

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    End points reporting groups
    Reporting group title
    Bardoxolone Methyl
    Reporting group description
    		 During the treatment period, the participants received bardoxolone methyl capsules, once daily (QD) at a starting dose of 5 milligrams (mg), followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility urine albumin to creatinine ratio (UACR) was >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112.

    Reporting group title
    Placebo
    Reporting group description
    		 During the treatment period, participants received bardoxolone methyl matching-placebo capsules, orally, QD up to Week 100, with sham titration to maintain the blinding. Participants did not receive a bardoxolone methyl matching placebo capsule during the off-treatment period between Weeks 100 and 112.

    Subject analysis set title
    Bardoxolone methyl
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    During the treatment period, the participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility UACR was >300 mg/g, the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112. Safety population included all enrolled participants who had received at least 1 dose of study drug. Participants who received 1 dose of bardoxolone methyl were classified in the bardoxolone methyl group.

    Primary: Off-treatment Period: Change From Baseline in eGFR at Week 108

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    End point title
    		 Off-treatment Period: Change From Baseline in eGFR at Week 108
    End point description
    Estimated Glomerular filtration rate (eGFR) is a measure of kidney function assessed through blood/serum. eGFR was measured in millilitres per minute per 1.73 meters square (mL/min/1.73 m^2). Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. A negative change from baseline in eGFR indicates worsened kidney function. Intent-to-Treat (ITT) included all enrolled participants categorised by their randomised treatment group (whether or not they received study drug). ’Subjects analyzed’ indicates the number of participants with data available for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Week 108
    End point values
    		 Bardoxolone Methyl Placebo
    Number of subjects analysed
    70
    79
    Units: mL/min/1.73 m^2
        least squares mean (standard error)
    -4.59 ( 0.817 )
    -5.56 ( 0.769 )
    Statistical analysis title
    		 Bardoxolone Methyl vs. Placebo
    Statistical analysis description
    ANCOVA model with baseline eGFR as a covariate, and treatment group as fixed effects.
    Comparison groups
    Bardoxolone Methyl v Placebo
    Number of subjects included in analysis
    149
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3886
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Means Difference
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.25
         upper limit
    		 3.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.122

    Primary: Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious TEAEs

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious TEAEs [1] [2]
    End point description
    AE:any untoward medical occurrence in a participant regardless of its causal relationship to study drug.AE can be any unfavorable & unintended sign,symptom/disease temporally associated with use of study drug,whether considered to be study-drug related/not.This includes clinically significant abnormal laboratory test result,any newly occurring events/previous conditions that have increased in severity/frequency since administration of study drug. SAE:any AE that at any dose results in death,life-threatening,requires hospitalization/prolongation of existing hospitalisation,substantial disruption of ability to conduct normal life functions,congenital anomaly or is an important medical event.AEs & SAEs that occurred within 30 days after last dose were considered TE. Safety population:Participants who received 1 dose of bardoxolone methyl were classified in bardoxolone methyl group; who received at least 1 dose of placebo & no dose of bardoxolone methyl were classified in placebo group.
    End point type
    Primary
    End point timeframe
    From first dose of the study drug up to end of follow-up (up to Week 112)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: As prespecified in the protocol, only descriptive statistics were planned for this endpoint.
    [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: Data has been reported in the safety analysis set- "Bardoxolone Methyl" arm for the subjects who received bardoxolone methyl.
    End point values
    		 Placebo Bardoxolone methyl
    Number of subjects analysed
    331
    335
    Units: participants
        TEAEs
    296
    314
        Serious TEAEs
    26
    38
    No statistical analyses for this end point

    Secondary: Treatment Period: Change From Baseline in eGFR at Week 100

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    End point title
    		 Treatment Period: Change From Baseline in eGFR at Week 100
    End point description
    eGFR is a measure of kidney function assessed through blood/serum. eGFR was measured in mL/min/1.73 m^2. Higher eGFRs represent better/improved kidney function. Lower eGFRs represent poorer/decreased kidney function. A negative change from baseline in eGFR indicates worsened kidney function. ITT included all enrolled participants categorised by their randomised treatment group (whether or not they received study drug). ’Subjects analyzed’ indicates the number of participants with an eGFR assessment at Week 100.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 100
    End point values
    		 Bardoxolone Methyl Placebo
    Number of subjects analysed
    168
    167
    Units: mL/min/1.73 m^2
        least squares mean (standard error)
    1.31 ( 0.550 )
    -6.64 ( 0.549 )
    Statistical analysis title
    		 Bardoxolone Methyl vs. Placebo
    Statistical analysis description
    Mixed model repeated measure (MMRM) model used baseline eGFR as a covariate, and the following fixed factors: treatment group, time (Week 1 to 100, excluding Week 52), and the interaction between treatment and time. Within-participant errors are modeled using an unstructured covariance matrix.
    Comparison groups
    Bardoxolone Methyl v Placebo
    Number of subjects included in analysis
    335
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models repeated measures analysis
    Parameter type
    		 Least square means difference
    Point estimate
    7.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.41
         upper limit
    		 9.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.777

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of the study drug up to end of follow-up (up to Week 112)
    Adverse event reporting additional description
    Safety population included all enrolled participants who had received at least 1 dose of study drug. Participants who received 1 dose of bardoxolone methyl were classified in the bardoxolone methyl group. Participants who received at least 1 dose of placebo and no dose of bardoxolone methyl were classified in the placebo group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 During the treatment period, participants received bardoxolone methyl matching-placebo capsules, orally, QD up to Week 100, with sham titration to maintain the blinding. Participants did not receive a bardoxolone methyl matching placebo capsule during the off-treatment period between Weeks 100 and 112.

    Reporting group title
    Bardoxolone Methyl
    Reporting group description
    		 During the treatment period, the participants received bardoxolone methyl capsules, once daily (QD) at a starting dose of 5 milligrams (mg), followed by dose-escalation to 10 mg at Week 2, and to 20 mg at Week 4. If the eligibility urine albumin to creatinine ratio (UACR) was >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 until Week 100. Participants continued to be assessed during the off-treatment period up to Week 112.

    Serious adverse events
    		 Placebo Bardoxolone Methyl
    Total subjects affected by serious adverse events
         subjects affected / exposed
    26 / 331 (7.85%)
    38 / 335 (11.34%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Prostate cancer
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Incarcerated hernia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cyst rupture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic haematoma
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Nasal septum deviation
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 331 (0.00%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accident
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Anastomotic ulcer
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic injury
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon injury
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic renal injury
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Transient global amnesia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Splenic cyst
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular degeneration
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute abdomen
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated umbilical hernia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cyst
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus urinary
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst ruptured
         subjects affected / exposed
    0 / 331 (0.00%)
    3 / 335 (0.90%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis streptococcal
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    2 / 331 (0.60%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 331 (0.30%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 331 (0.00%)
    1 / 335 (0.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain abscess
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast abscess
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Labyrinthitis
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Obesity
         subjects affected / exposed
    0 / 331 (0.00%)
    2 / 335 (0.60%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 331 (0.30%)
    0 / 335 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Bardoxolone Methyl
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    255 / 331 (77.04%)
    299 / 335 (89.25%)
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 331 (0.30%)
    46 / 335 (13.73%)
         occurrences all number
    1
    56
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 331 (1.21%)
    47 / 335 (14.03%)
         occurrences all number
    6
    60
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 331 (0.91%)
    76 / 335 (22.69%)
         occurrences all number
    3
    92
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    23 / 331 (6.95%)
    32 / 335 (9.55%)
         occurrences all number
    26
    47
    Brain natriuretic peptide increased
         subjects affected / exposed
    16 / 331 (4.83%)
    31 / 335 (9.25%)
         occurrences all number
    18
    41
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 331 (0.91%)
    24 / 335 (7.16%)
         occurrences all number
    3
    24
    Weight decreased
         subjects affected / exposed
    4 / 331 (1.21%)
    28 / 335 (8.36%)
         occurrences all number
    4
    28
    Vascular disorders
    Hypertension
         subjects affected / exposed
    34 / 331 (10.27%)
    25 / 335 (7.46%)
         occurrences all number
    37
    27
    Nervous system disorders
    Headache
         subjects affected / exposed
    41 / 331 (12.39%)
    55 / 335 (16.42%)
         occurrences all number
    70
    74
    Dizziness
         subjects affected / exposed
    13 / 331 (3.93%)
    25 / 335 (7.46%)
         occurrences all number
    15
    35
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    19 / 331 (5.74%)
    22 / 335 (6.57%)
         occurrences all number
    23
    25
    Oedema peripheral
         subjects affected / exposed
    35 / 331 (10.57%)
    27 / 335 (8.06%)
         occurrences all number
    38
    39
    Fatigue
         subjects affected / exposed
    29 / 331 (8.76%)
    47 / 335 (14.03%)
         occurrences all number
    30
    60
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    40 / 331 (12.08%)
    49 / 335 (14.63%)
         occurrences all number
    52
    79
    Vomiting
         subjects affected / exposed
    9 / 331 (2.72%)
    23 / 335 (6.87%)
         occurrences all number
    13
    32
    Constipation
         subjects affected / exposed
    16 / 331 (4.83%)
    38 / 335 (11.34%)
         occurrences all number
    17
    44
    Diarrhoea
         subjects affected / exposed
    31 / 331 (9.37%)
    35 / 335 (10.45%)
         occurrences all number
    40
    45
    Abdominal pain
         subjects affected / exposed
    21 / 331 (6.34%)
    32 / 335 (9.55%)
         occurrences all number
    22
    42
    Abdominal distension
         subjects affected / exposed
    9 / 331 (2.72%)
    22 / 335 (6.57%)
         occurrences all number
    11
    31
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 331 (5.74%)
    26 / 335 (7.76%)
         occurrences all number
    21
    29
    Oropharyngeal pain
         subjects affected / exposed
    9 / 331 (2.72%)
    18 / 335 (5.37%)
         occurrences all number
    9
    21
    Renal and urinary disorders
    Renal pain
         subjects affected / exposed
    18 / 331 (5.44%)
    12 / 335 (3.58%)
         occurrences all number
    25
    13
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    53 / 331 (16.01%)
    164 / 335 (48.96%)
         occurrences all number
    73
    334
    Flank pain
         subjects affected / exposed
    21 / 331 (6.34%)
    43 / 335 (12.84%)
         occurrences all number
    26
    48
    Back pain
         subjects affected / exposed
    36 / 331 (10.88%)
    39 / 335 (11.64%)
         occurrences all number
    43
    53
    Arthralgia
         subjects affected / exposed
    15 / 331 (4.53%)
    35 / 335 (10.45%)
         occurrences all number
    19
    45
    Pain in extremity
         subjects affected / exposed
    14 / 331 (4.23%)
    23 / 335 (6.87%)
         occurrences all number
    16
    36
    Myalgia
         subjects affected / exposed
    12 / 331 (3.63%)
    17 / 335 (5.07%)
         occurrences all number
    13
    23
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 331 (3.93%)
    26 / 335 (7.76%)
         occurrences all number
    15
    32
    Nasopharyngitis
         subjects affected / exposed
    31 / 331 (9.37%)
    39 / 335 (11.64%)
         occurrences all number
    47
    48
    Corona virus infection
         subjects affected / exposed
    89 / 331 (26.89%)
    76 / 335 (22.69%)
         occurrences all number
    95
    87
    Urinary tract infection
         subjects affected / exposed
    21 / 331 (6.34%)
    24 / 335 (7.16%)
         occurrences all number
    28
    33
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 331 (3.63%)
    26 / 335 (7.76%)
         occurrences all number
    12
    28
    Hypomagnesaemia
         subjects affected / exposed
    5 / 331 (1.51%)
    19 / 335 (5.67%)
         occurrences all number
    6
    21

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Mar 2019
    1. Limited total enrollment of participants with higher baseline eGFR. 2. Updated inclusion criteria to add requirement for evidence of ADPKD progression and inclusion requirements for participants currently receiving tolvaptan. 3. Updated participant exclusion criteria. 4. Updated protocol for participant unblinding. 5. Added eGFR ≤ 15 to the list of reasons for unscheduled visits. 6. Expanded AE reporting window to extend throughout study follow-up, irrespective of date of last dose. 7. Updated SAE reporting guidelines for specified events due to CKD disease progression.
    16 Jul 2019
    1. Updated the inclusion and exclusion criteria: participants receiving concomitant use of tolvaptan are excluded from the study. 2. Added tolvaptan (participants on tolvaptan who have already enrolled in FALCON under Version 2 of the protocol may remain in the trial) to the Excluded Medications section. 3. Primary analysis of efficacy and Sample size sections were updated to add Analysis of Covariance (ANCOVA) analysis for off-treatment efficacy endpoints (i.e., Week 52 and Week 104). 4. Added on-treatment efficacy endpoints of change from baseline in eGFR at Week 48 and Week 100 in the primary analysis of efficacy section.
    25 Jun 2020
    1. Updated data for the Cross-study comparison of increases in eGFR, inulin clearance, and creatinine clearance with bardoxolone methyl treatment. 2. Added ‘off-treatment’ change from baseline and specified the year of treatment in primary objective and endpoint. 3. Added ‘off-treatment’ change from baseline and specified the year of treatment in key secondary objective and endpoint. 4. Modifications made due to the COVID-19 pandemic.
    24 Feb 2021
    1. Increased sample size. 2. Updated efficacy endpoints analysis visit week from Week 52 to Week 104. 3. Updated inclusion criteria for screening eGFR. 4. Addition of exclusion criterion for COVID-19 diagnosis. 5. Shortened screening window to ensure stable clinical status from Screen A to randomisation. 6. Clarification of follow-up visit window and AE/SAE reporting.
    03 Feb 2022
    1. Updated schema for study of bardoxolone methyl in participants with autosomal dominant polycystic kidney disease (ADPKD) to reflect the removal of the off-treatment period between Weeks 48 to 52, the extended off-treatment period that follows Week 100, from a 4-week duration to a 12-week duration. 2. Changed primary objective and endpoint to evaluate efficacy at end of Year 2 (instead of at end of Year 1). 3. Removal of the key secondary objective and endpoint, and adjustment of the remaining secondary objective and endpoint. 4. Overall study design and assessment schedule updated to omit the off-treatment period between Week 48 and Week 52 based on updated endpoints. Increased sample size to reflect updated primary endpoint analysis.
    25 May 2022
    1. Updated inclusion criteria, to reflect that participants taking sodium-glucose co-transporter 2 (SGLT2) inhibitor must be on a stable dose for at least 4 weeks prior to the Screen A visit. 2. Clarification added to specify both adults and adolescents will follow the same dose escalation plan. 3. Updated section to clarify that 5mg restarting dose must be used when interruption criteria are met. 4. Clarification on the duration of AE reporting. Extended AE reporting period from 30 days following the last dose to 12 weeks following the last dose of drug, due to the collection of endpoint data through that period.

    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.
    Due to discontinuation of all bardoxolone chronic kidney disease programs, study was terminated early.
    For support, Contact us.
    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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