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    Clinical Trial Results:
    An Extended Access Program to Assess Long Term Safety of Bardoxolone Methyl in Patients With Chronic Kidney Disease

    Summary
    EudraCT number
    		 2018-003253-24
    Trial protocol
    		 ES   FR   BE   DE   CZ  
    Global end of trial date
    23 Aug 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    402-C-1803
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03749447
    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
    03 Jul 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 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 provide continuing open-label treatment with bardoxolone methyl as part of this extended access program while collecting ongoing safety and tolerability data of bardoxolone methyl.
    Protection of trial subjects
    Written informed consent was obtained from each subject or subject’s legally authorised representative (e.g., legal guardian), as applicable, prior to evaluations performed for eligibility. Subjects or the subject’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
    08 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 215
    Country: Number of subjects enrolled
    Australia: 10
    Country: Number of subjects enrolled
    Japan: 29
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Puerto Rico: 4
    Worldwide total number of subjects
    270
    EEA total number of subjects
    12
    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)
    9
    Adults (18-64 years)
    239
    From 65 to 84 years
    22
    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, Japan, Spain, Puerto Rico and France from 08 March 2019 to 23 August 2023.

    Pre-assignment
    Screening details
    		 A total of 270 eligible participants who participated in the previous qualifying studies i.e., 402-C-1603 (NCT03019185) and 402-C-1808 (NCT03918447) of bardoxolone methyl were enrolled in this study. Data was summarized as per the treatment received in the previous qualifying studies.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prior Placebo to Bardoxolone Methyl
    Arm description
    		 Participants who received placebo in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult 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 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility urine albumin to creatinine ratio (UACR) >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bardoxolone methyl
    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.

    Arm title
    		 Prior Bardoxolone Methyl to Bardoxolone Methyl
    Arm description
    		 Participants who received bardoxolone methyl in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalated to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bardoxolone methyl
    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
    		Prior Placebo to Bardoxolone Methyl Prior Bardoxolone Methyl to Bardoxolone Methyl
    Started
    143
    127
    Completed
    0
    0
    Not completed
    143
    127
         Adverse event, serious fatal
    1
    1
         Protocol-Specified Withdrawal Criteria Met
    1
    3
         Physician decision
    4
    3
         Consent withdrawn by subject
    12
    6
         Adverse event, non-fatal
    11
    3
         Reason Not Specified
    -
    3
         Non-Compliance With Study Drug
    -
    1
         Study Terminated by Sponsor
    112
    105
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prior Placebo to Bardoxolone Methyl
    Reporting group description
    		 Participants who received placebo in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult 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 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility urine albumin to creatinine ratio (UACR) >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

    Reporting group title
    Prior Bardoxolone Methyl to Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalated to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

    Reporting group values
    		 Prior Placebo to Bardoxolone Methyl Prior Bardoxolone Methyl to Bardoxolone Methyl Total
    Number of subjects
    		 143 127
    Age Categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.8 ± 13.26 48.3 ± 13.82 -
    Gender categorical
    Units: Participants
        Male
    		 55 49 104
        Female
    		 88 78 166
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 0 2
        Asian
    		 17 16 33
        Black or African American
    		 9 9 18
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        White
    		 112 96 208
        Other
    		 3 5 8
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 15 12 27
        Non-Hispanic/Latino
    		 128 115 243

    End points

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    End points reporting groups
    Reporting group title
    Prior Placebo to Bardoxolone Methyl
    Reporting group description
    		 Participants who received placebo in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult 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 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility urine albumin to creatinine ratio (UACR) >300 milligrams per gram (mg/g), the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

    Reporting group title
    Prior Bardoxolone Methyl to Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalated to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

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

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    End point title
    		 Number of Participants With Treatment-emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [1]
    End point description
    An AE is any untoward medical occurrence in a participant administered a pharmaceutical product that does not necessarily have a causal relationship with this treatment. An SAE is any untoward medical occurrence that at any dose results in death, places the participant at immediate risk of death, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or is a medically important event. AEs and SAEs that occurred within 30 days after the last dose were considered treatment-emergent. The study follow-up assessment was collected within 14 to 35 days after the last dose. The safety population included all participants who had received at least 1 dose of bardoxolone methyl in the 402-C-1803 study.
    End point type
    Primary
    End point timeframe
    From the first dose of the study drug (baseline) up to the end of the study follow-up (up to 4.2 years)
    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: Only descriptive analysis was planned to be analyzed.
    End point values
    		 Prior Placebo to Bardoxolone Methyl Prior Bardoxolone Methyl to Bardoxolone Methyl
    Number of subjects analysed
    143
    127
    Units: participants
        AEs
    128
    105
        SAEs
    12
    20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of the study drug (baseline) up to the end of the study follow-up (up to 4.2 years)
    Adverse event reporting additional description
    The safety population included all participants who had received at least 1 dose of bardoxolone methyl in the 402-C-1803 study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Prior Placebo to Bardoxolone Methyl
    Reporting group description
    		 Participants who received placebo in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose- escalation to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

    Reporting group title
    Prior Bardoxolone Methyl to Bardoxolone Methyl
    Reporting group description
    		 Participants who received bardoxolone methyl in the previous qualifying studies, 402-C-1603 (NCT03019185) or 402-C-1808 (NCT03918447), and received bardoxolone methyl in this study. Adult participants received bardoxolone methyl capsules, QD at a starting dose of 5 mg, followed by dose-escalated to 10 mg at Week 2 (Day 14 ± 3), and to 20 mg at Week 4 (Day 28 ± 3). Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 (Day 42 ± 3) until the end of the study. Participants under 18 years of age received bardoxolone methyl capsules at a starting dose of 5 mg every other day during the first week and QD during the second week of the study, followed by dose-escalation to 10 mg at Week 2 and to 20 mg at Week 4. Based on the eligibility UACR >300 mg/g, the dose was increased to 30 mg starting from Week 6 until the end of the study.

    Serious adverse events
    		 Prior Placebo to Bardoxolone Methyl Prior Bardoxolone Methyl to Bardoxolone Methyl
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 143 (8.39%)
    20 / 127 (15.75%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Uterine leiomyoma
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (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
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         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
    Respiratory failure
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Biopsy kidney
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         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
    Wrist fracture
         subjects affected / exposed
    1 / 143 (0.70%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (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
    Cerebellar stroke
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid hemorrhage
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis ischaemic
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis acute
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (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
    End stage renal disease
         subjects affected / exposed
    0 / 143 (0.00%)
    3 / 127 (2.36%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 127 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         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 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (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
    Gangrene
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 143 (0.70%)
    0 / 127 (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
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 143 (0.00%)
    1 / 127 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 143 (0.00%)
    2 / 127 (1.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Prior Placebo to Bardoxolone Methyl Prior Bardoxolone Methyl to Bardoxolone Methyl
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 143 (88.81%)
    104 / 127 (81.89%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 143 (16.78%)
    7 / 127 (5.51%)
         occurrences all number
    26
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    37 / 143 (25.87%)
    8 / 127 (6.30%)
         occurrences all number
    38
    9
    Blood creatinine increased
         subjects affected / exposed
    3 / 143 (2.10%)
    7 / 127 (5.51%)
         occurrences all number
    3
    7
    Brain natriuretic peptide increased
         subjects affected / exposed
    11 / 143 (7.69%)
    5 / 127 (3.94%)
         occurrences all number
    18
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    11 / 143 (7.69%)
    0 / 127 (0.00%)
         occurrences all number
    14
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    13 / 143 (9.09%)
    11 / 127 (8.66%)
         occurrences all number
    18
    13
    Vascular disorders
    Hypertension
         subjects affected / exposed
    8 / 143 (5.59%)
    9 / 127 (7.09%)
         occurrences all number
    8
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 143 (11.19%)
    9 / 127 (7.09%)
         occurrences all number
    29
    10
    Dizziness
         subjects affected / exposed
    5 / 143 (3.50%)
    7 / 127 (5.51%)
         occurrences all number
    6
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 143 (6.29%)
    6 / 127 (4.72%)
         occurrences all number
    9
    6
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    10 / 143 (6.99%)
    11 / 127 (8.66%)
         occurrences all number
    11
    15
    Pyrexia
         subjects affected / exposed
    7 / 143 (4.90%)
    7 / 127 (5.51%)
         occurrences all number
    9
    8
    Fatigue
         subjects affected / exposed
    14 / 143 (9.79%)
    8 / 127 (6.30%)
         occurrences all number
    15
    10
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    16 / 143 (11.19%)
    8 / 127 (6.30%)
         occurrences all number
    20
    8
    Abdominal pain
         subjects affected / exposed
    9 / 143 (6.29%)
    5 / 127 (3.94%)
         occurrences all number
    11
    6
    Nausea
         subjects affected / exposed
    12 / 143 (8.39%)
    13 / 127 (10.24%)
         occurrences all number
    12
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 143 (2.80%)
    11 / 127 (8.66%)
         occurrences all number
    4
    13
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    12 / 143 (8.39%)
    12 / 127 (9.45%)
         occurrences all number
    15
    13
    Muscle spasms
         subjects affected / exposed
    57 / 143 (39.86%)
    45 / 127 (35.43%)
         occurrences all number
    96
    75
    Pain in extremity
         subjects affected / exposed
    4 / 143 (2.80%)
    7 / 127 (5.51%)
         occurrences all number
    6
    10
    Infections and infestations
    Sinusitis
         subjects affected / exposed
    5 / 143 (3.50%)
    8 / 127 (6.30%)
         occurrences all number
    5
    9
    Corona virus infection
         subjects affected / exposed
    22 / 143 (15.38%)
    27 / 127 (21.26%)
         occurrences all number
    23
    27
    Nasopharyngitis
         subjects affected / exposed
    5 / 143 (3.50%)
    8 / 127 (6.30%)
         occurrences all number
    8
    11
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 143 (8.39%)
    12 / 127 (9.45%)
         occurrences all number
    13
    15
    Urinary tract infection
         subjects affected / exposed
    8 / 143 (5.59%)
    12 / 127 (9.45%)
         occurrences all number
    9
    22
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    10 / 143 (6.99%)
    11 / 127 (8.66%)
         occurrences all number
    10
    14
    Hypomagnesaemia
         subjects affected / exposed
    10 / 143 (6.99%)
    4 / 127 (3.15%)
         occurrences all number
    11
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2019
    1. Defined qualifying clinical study, as CARDINAL (2016-004395-22). 2. Clarified intent to measure B-type natriuretic peptide (BNP) and N-Terminal prohormone B-type natriuretic peptide (NT-Pro BNP) levels.
    30 Jun 2020
    1. Added FALCON (2018-004651-20) as another qualifying study to enroll in EAGLE. 2. Updated for clarification regarding recording of AEs between prior qualifying study and Day 1 of EAGLE. 3. Updated text to include results of physical examinations as a safety parameter. 4. Updated section to manage transaminases (ALT/AST) elevations. 5. Updated information for resuming drug therapy after temporary discontinuation due to elevated liver enzymes. 6. Updated inclusion and exclusion criteria. 7. COVID-19 Mitigation Appendix was added to describe protocol modifications due to the pandemic. 8. Added section for participants reaching end stage kidney disease.
    08 Nov 2022
    1. Lipid panel and Tanner Staging added to study visits. 2. Defined the qualifying study lab assessments which may be used for eligibility due to the variability of the-off treatment follow-up schedule for studies 402-C-1603 (2016-004395-22)/402-C-1808 (2018-004651-20) protocol v5 and older vs. 402-C-1808 (2018-004651-20) protocol v6 and newer. 3. Differentiated between dose-titration period for adolescent participants enrolling from study 402-C-1603 (2016-004395-22) versus adolescent and adult participants enrolling from study 402-C-1808 (2018-004651-20). 4. Aligned with specific criteria and communication requirements added to study 402-C-1808 (2018-004651-20) protocol v6 related to the weight loss of adolescent and adult patients in the study to monitor for safety. 5. Simplified the instructions provided to investigators in the event of an increase in urinary albumin to creatinine ratios and to clarify that proteinuria is not required to be associated with other concurrent signs to consult with the medical monitor.

    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.
    Early termination of trial due to discontinuation of all bardoxolone chronic kidney disease programs.
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    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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