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    Clinical Trial Results:
    A PHASE 2 STUDY OF THE SAFETY, EFFICACY, AND PHARMACODYNAMICS OF RTA 408 IN THE TREATMENT OF MITOCHONDRIAL MYOPATHY

    Summary
    EudraCT number
    		 2014-003501-15
    Trial protocol
    		 DK  
    Global end of trial date
    30 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Jul 2021
    First version publication date
    11 Jul 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    408-C-1403
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02255422
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Reata Pharmaceuticals, Inc.
    Sponsor organisation address
    5320 Legacy Drive, Plano, United States, 75024
    Public contact
    Clinical Operations, Reata Pharmaceuticals, 1 9728652219, 408C1403DNK@reatapharma.com
    Scientific contact
    Clinical Operations, Reata Pharmaceuticals, 1 9728652219, 408C1403DNK@reatapharma.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
    05 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Primary: • To evaluate the change in peak work during maximal exercise testing • To evaluate the safety and tolerability of RTA 408
    Protection of trial subjects
    The DSMB consisted of external clinical experts supported by an independent statistical group who reviewed unblinded safety data throughout the study and made recommendations as appropriate regarding the opening of cohorts and subsequent parts of the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2015
    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
    Denmark: 15
    Country: Number of subjects enrolled
    United States: 38
    Worldwide total number of subjects
    53
    EEA total number of subjects
    15
    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)
    50
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Patients with Mitochondrial myopathy as evidenced by a history of exercise intolerance with/without weakness and/or progressive exercise intolerance and have a known primary mitochondrial DNA mutation or nuclear DNA defect associated with reduced activity of at least 1 mitochondrially encoded respiratory chain complex were recruited per protocol.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Placebo capsules
    Arm description
    		 Placebo capsules administered orally once daily for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo Capsules
    Investigational medicinal product code
    Placebo
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsules administered orally once daily for 12 weeks

    Arm title
    		 Omaveloxolone Capsules 2.5 and 5 mg
    Arm description
    		 Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5mg administered orally once daily for 10 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 2.5 and 5 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5mg administered orally once daily for 10 weeks

    Arm title
    		 Omaveloxolone Capsules 10 mg
    Arm description
    		 Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 10 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks

    Arm title
    		 Omaveloxolone Capsules 20 mg
    Arm description
    		 Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 20 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks

    Arm title
    		 Omaveloxolone Capsules 40 mg
    Arm description
    		 Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 40 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks

    Arm title
    		 Omaveloxolone Capsules 80 mg
    Arm description
    		 Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 80 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks

    Arm title
    		 Omaveloxolone Capsules 160 mg
    Arm description
    		 Omaveloxolone (RTA 408) 160 mg capsules administered orally once daily for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omaveloxolone Capsules 160 mg
    Investigational medicinal product code
    RTA 408
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Omaveloxolone (RTA 408) 160 mg capsules administered orally once daily for 12 weeks

    Number of subjects in period 1
    		Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg
    Started
    13
    6
    6
    6
    6
    6
    10
    Completed
    13
    6
    5
    6
    6
    6
    8
    Not completed
    0
    0
    1
    0
    0
    0
    2
         Consent withdrawn by subject
    -
    -
    -
    -
    -
    -
    2
         Lost to follow-up
    -
    -
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo capsules
    Reporting group description
    		 Placebo capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 2.5 and 5 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5mg administered orally once daily for 10 weeks

    Reporting group title
    Omaveloxolone Capsules 10 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 20 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 40 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 80 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 160 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 160 mg capsules administered orally once daily for 12 weeks

    Reporting group values
    		 Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg Total
    Number of subjects
    		 13 6 6 6 6 6 10
    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)
    		 41.1 ( 11.86 ) 52.3 ( 9.61 ) 49.8 ( 14.05 ) 45.5 ( 14.08 ) 45.2 ( 4.71 ) 30.7 ( 10.25 ) 39.8 ( 15.27 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 1 3 4 5 4 6 32
        Male
    		 4 5 3 2 1 2 4 21
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 0 1 0 0 0 3 6
        Not Hispanic or Latino
    		 11 6 5 6 6 6 7 47
        Unknown or Not Reported
    		 0 0 0 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo capsules
    Reporting group description
    		 Placebo capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 2.5 and 5 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5mg administered orally once daily for 10 weeks

    Reporting group title
    Omaveloxolone Capsules 10 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 20 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 40 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 80 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 160 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 160 mg capsules administered orally once daily for 12 weeks

    Primary: Change of Peak Workload (in Watts/kg) During Exercise Testing

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    End point title
    		 Change of Peak Workload (in Watts/kg) During Exercise Testing
    End point description
    Cycle ergometry using a stationary recumbent bike was used to conduct maximal exercise testing. Peak work is defined as the workload at which patients reach maximal volition (defined as an inability to continue to exercise due to exhaustion). Change of peak workload during exercise testing was measured at baseline, Week 4, and Week 12. Change from baseline at Week 12 reported
    End point type
    Primary
    End point timeframe
    12 Weeks
    End point values
    		 Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg
    Number of subjects analysed
    13 [1]
    6 [2]
    6 [3]
    6 [4]
    6 [5]
    6 [6]
    9 [7]
    Units: Watts/kg
        least squares mean (standard error)
    0.0090 ( 0.0388 )
    0.020 ( 0.0544 )
    -0.0300 ( 0.0544 )
    0.1050 ( 0.0596 )
    -0.0520 ( 0.0544 )
    -0.0660 ( 0.0544 )
    0.0020 ( 0.0465 )
    Notes
    [1] - Placebo capsules administered orally once daily for 12 weeks
    [2] - Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5 mg adminis
    [3] - Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks
    [4] - Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 week
    [5] - Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks
    [6] - Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks
    [7] - Omaveloxolone (RTA 408) 160 mg capsules administered once daily for 12 weeks
    Statistical analysis title
    		 Primary Objective
    Statistical analysis description
    Primary Objective: To evaluate the change in peak work during maximal exercise testing in the following comparison groups: Placebo, Omaveloxolone Capsules 2.5 and 5 mg, Omaveloxolone Capsules 10 mg, Omaveloxolone Capsules 20 mg, Omaveloxolone Capsules 40 mg, Omaveloxolone Capsules 80 mg, Omaveloxolone Capsules 160 mg
    Comparison groups
    Placebo capsules v Omaveloxolone Capsules 2.5 and 5 mg v Omaveloxolone Capsules 10 mg v Omaveloxolone Capsules 20 mg v Omaveloxolone Capsules 40 mg v Omaveloxolone Capsules 80 mg v Omaveloxolone Capsules 160 mg
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7321 [8]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.015
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1051
         upper limit
    		 0.0743
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0446
    Notes
    [8] - P-Value relates to difference in change in peak work from baseline relative to placebo for all doses pooled. Statistical significance was defined as p<0.05

    Secondary: Change in 6-minute Walk Test (6MWT) Distance

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    End point title
    		 Change in 6-minute Walk Test (6MWT) Distance
    End point description
    Patients were instructed to walk as far as they could along a marked path for 6 minutes. Distance walked was measured. If patients used a cane or walking assist device at Screening, the same walking assist device was to be used for all 6MWT assessments.
    End point type
    Secondary
    End point timeframe
    6MWT was assessed at Week 4, Week 8, and Week 12 and compared to baseline
    End point values
    		 Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg
    Number of subjects analysed
    13 [9]
    6 [10]
    6 [11]
    6 [12]
    6 [13]
    6 [14]
    9 [15]
    Units: Meters
    least squares mean (standard error)
        Week 4
    40.462 ( 10.0539 )
    19.333 ( 14.9658 )
    18.2500 ( 14.9658 )
    -9.2000 ( 16.3942 )
    -11.6670 ( 14.9658 )
    9.9170 ( 14.9658 )
    10.8330 ( 12.2195 )
        Week 8
    24.923 ( 9.9381 )
    12.865 ( 15.7374 )
    33.9170 ( 15.1418 )
    13.8000 ( 16.5870 )
    11.0000 ( 15.1418 )
    17.5830 ( 15.1418 )
    28.9440 ( 12.3633 )
        Week 12
    29.846 ( 12.9276 )
    17.167 ( 19.6519 )
    17.7500 ( 19.6519 )
    28.2000 ( 21.5275 )
    -7.833 ( 19.6519 )
    6.2500 ( 19.6519 )
    8.5710 ( 16.4721 )
    Notes
    [9] - Placebo capsules administered orally once daily for 12 weeks
    [10] - Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5 mg adminis
    [11] - Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks
    [12] - Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks
    [13] - Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks
    [14] - Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks
    [15] - Omaveloxolone (RTA 408) 160 mg capsules administered once daily for 12 weeks
    Statistical analysis title
    		 Secondary Objective: Wk 4 change in 6MWT
    Statistical analysis description
    Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 4
    Comparison groups
    Placebo capsules v Omaveloxolone Capsules 2.5 and 5 mg v Omaveloxolone Capsules 10 mg v Omaveloxolone Capsules 20 mg v Omaveloxolone Capsules 40 mg v Omaveloxolone Capsules 80 mg v Omaveloxolone Capsules 160 mg
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.006 [16]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -33.448
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -56.855
         upper limit
    		 -10.042
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.6473
    Notes
    [16] - P-value comparison is for difference in change in six minute walk distance from baseline within each dosage group relative to placebo. Statistical significance defined as p<0.05.
    Statistical analysis title
    		 Secondary Objective: Wk 8 change in 6MWT
    Statistical analysis description
    Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 8
    Comparison groups
    Placebo capsules v Omaveloxolone Capsules 2.5 and 5 mg v Omaveloxolone Capsules 10 mg v Omaveloxolone Capsules 20 mg v Omaveloxolone Capsules 40 mg v Omaveloxolone Capsules 80 mg v Omaveloxolone Capsules 160 mg
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7325 [17]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.963
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.133
         upper limit
    		 19.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    11.53
    Notes
    [17] - Statistical significance was defined as p<0.05. The p-value comparison is for the difference in change in 6MWD from baseline within each dosage group relative to placebo.
    Statistical analysis title
    		 Secondary Objective: Wk 12 change in 6MWT
    Statistical analysis description
    Secondary Objective: To evaluate the change in 6-minute walk test (6MWT) distance at Week 12
    Comparison groups
    Placebo capsules v Omaveloxolone Capsules 2.5 and 5 mg v Omaveloxolone Capsules 10 mg v Omaveloxolone Capsules 20 mg v Omaveloxolone Capsules 40 mg v Omaveloxolone Capsules 80 mg v Omaveloxolone Capsules 160 mg
    Number of subjects included in analysis
    52
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.221 [18]
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -18.594
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -48.739
         upper limit
    		 11.55
    Variability estimate
    Standard error of the mean
    Dispersion value
    15.0004
    Notes
    [18] - Statistical significance was defined as p<0.05. The p-value comparison is for the difference in change in 6MWD from baseline within each dosage group relative to placebo.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    16 weeks
    Adverse event reporting additional description
    Significant adverse events are collected from the time of the first dose of study drug until the final visit or 30 days following final study dose for patients who terminated early. Both investigator assessment/questioning (systematic) and patient self reporting (non-systematic) are used in this study but were reported by the investigators as a con
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Placebo capsules
    Reporting group description
    		 Placebo capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 2.5 and 5 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 2.5 mg capsules administered orally once daily for 2 weeks then 5mg administered orally once daily for 10 weeks

    Reporting group title
    Omaveloxolone Capsules 10 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 10 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 20 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 20 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 40 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 40 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 80 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 80 mg capsules administered orally once daily for 12 weeks

    Reporting group title
    Omaveloxolone Capsules 160 mg
    Reporting group description
    		 Omaveloxolone (RTA 408) 160 mg capsules administered orally once daily for 12 weeks

    Serious adverse events
    		 Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Atrioventricular dissociation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Tonic convulsion
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo capsules Omaveloxolone Capsules 2.5 and 5 mg Omaveloxolone Capsules 10 mg Omaveloxolone Capsules 20 mg Omaveloxolone Capsules 40 mg Omaveloxolone Capsules 80 mg Omaveloxolone Capsules 160 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    4 / 6 (66.67%)
    6 / 6 (100.00%)
    5 / 6 (83.33%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    8 / 10 (80.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    Surgical and medical procedures
    Eyelid operation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    4 / 13 (30.77%)
    0 / 6 (0.00%)
    3 / 6 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
         occurrences all number
    4
    0
    3
    0
    0
    2
    1
    Feeling abnormal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Energy increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    1
    Immune system disorders
    Nasopharyngitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 10 (20.00%)
         occurrences all number
    2
    0
    0
    1
    0
    1
    2
    Localised infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Menorrhagia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    5
    Menstruation irregular
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Productive cough
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Sinus congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Dysphemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Tachyphrenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Electrocardiogram PR prologation
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Brain natriuretic peptide increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Electrocardiogram T wave amplitude decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Serum ferritin decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    0
    Ankle fracture
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Concussion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    1
    Ligament sprain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Muscle strain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    Penis injury
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Cardiac disorder
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    1
    2
    0
    0
    1
    Dizziness
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    2
    0
    1
    0
    0
    Migraine
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    7
    0
    0
    0
    Restless leg syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Head titubation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Myoclonus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    0
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Ear discomfort
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Photophobia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 10 (20.00%)
         occurrences all number
    3
    1
    1
    5
    1
    1
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    2
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    2
    Abdominal distension
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Dry mouth
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Retching
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Asthenia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    2
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Pruritus generalized
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    1
    Back pain
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    3
    0
    0
    0
    0
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Muscle twitching
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    4 / 6 (66.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    0
    Neck pain
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    1
    1
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    2
    1
    0
    1
    1
    0
    3
    Laryngitis
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Sialoadenitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Blister infected
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    Dehydration
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    Iron deficiency
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    Abnormal loss of weight
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Sep 2014
    Version 2.0 (No patients were enrolled under Protocol v1 or v2 of the protocol.): Modified to reflect study centers in the European Union; Updated estimated timeline based on revised study design and Changed to peak work (specified in watts/kg) instead of peak workload (specified in watts)
    13 Oct 2014
    Version 3.0: PK characterization added as an objective of the study, per FDA recommendation; Additional samples collected for PK analysis purposes; Added moderate or strong inhibitors or inducers of cytochrome P450 3A4 as excluded medications, per FDA recommendation: exclude patients with clinically significant liver disease, per FDA recommendation; Clarifications made throughout
    23 Jun 2015
    Version 4.0: Enrollment of up to 2 additional cohorts in Part 1 may require more sites; Assigned new study manager; Modify Part 1 of the study to allow for up to 2 additional cohorts of patients; Modify Part 2 to allow the 2 doses of RTA 408 to be selected from doses cleared by the DSMB in Part 1; Allow approximately 16 additional patients (2 cohorts of approximately 8 patients each); Clarifications given changes to study design; added guidance to maintain assessment order across visits to limit impact on functional assessments; screening window widened to accommodate operational complexities including patient travel and genetic testing confirmation if needed; clarification regarding maximal exercise assessments; clarification regarding timing for PK collections for Cohort 3 and Cohort 4; added ethics committee references for ex-US sites; minor clarification throughout.
    29 Oct 2015
    Version 5.0: Change in clinical manager; Added serious adverse event report hotline phone number for Europe; Update study duration due to additional cohorts included in Part 1 of the study; Modify Part 1 of the study to allow for up to 8 cohorts of patients; condensed the description of each dosing cohort within Part 1 of the study; Modified the description of each dosing cohort and specified that the maximum RTA 408 dose will be 160 mg; Number of patients increased with the addition of more cohorts in Part 1; Clarification that cohorts 2 through 8 will be a randomized to a cohort-specific dose or placebo; Clarification that two dose levels of RTA 408 and placebo will be used in Part 2; Updated dose levels in Part 1 and clarification regarding dose selection in Part 2; Clarification of randomization in Part 1 for additional cohorts; Explicit exclusion that patients who are pregnant or breastfeeding may not participate in the study; Clarification of randomization in Part 1 for additional cohorts; Updated to allow for use of 50-mg capsule; Clarification for sites outside of the US regarding expiry information being provided on treatment kits intended for use in the EU; Updated Safety CRO international reporting information; Clarifications made throughout.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31896620
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