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    Clinical Trial Results:
    A Feasibility Study of Bezafibrate in Mitochondrial Myopathy

    Summary
    EudraCT number
    		 2015-000508-24
    Trial protocol
    		 GB  
    Global end of trial date
    23 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Nov 2018
    First version publication date
    01 Nov 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    7406
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02398201
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Newcastle upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Queen Victoria Road, Newcastle upon Tyne, United Kingdom, NE1 4LP
    Public contact
    Patrick Chinnery, Newcastle University, +44 01912418611, patrick.chinnery@ncl.ac.uk
    Scientific contact
    Patrick Chinnery, Newcastle University, +44 01912418611, patrick.chinnery@ncl.ac.uk
    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
    20 Mar 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Mar 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To undertake a proof of concept study to determine whether bezafibrate can improve mitochondrial function in individuals with mitochondrial disease; to determine whether further study warranted in an RCT; and to have data to inform any power calculations for potential future studies.
    Protection of trial subjects
    Two data monitoring committee meetings during the course of the study. The first of these discussed adverse events occurring within the study, and due to hypoglycaemic episodes, further monitoring of blood sugars was advised if participants were recruited to higher doses of bezafibrate. Substantial amendment submitted to reflect this.
    Background therapy
    		 None
    Evidence for comparator
    		 No disease modifying treatments currently available.
    Actual start date of recruitment
    09 Nov 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
    United Kingdom: 6
    Worldwide total number of subjects
    6
    EEA total number of subjects
    6
    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)
    6
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were provided with introductory information via i) routine clinic appointments; or ii) the UK mitochondrial disease cohort, inviting them to contact the study team. With further contact from participants, the participant information sheet was provided and questions answered via telephone before a screening visit was arranged.

    Pre-assignment
    Screening details
    		 Screening was undertaken at the Clinical Research Facility, Royal Victoria Infirmary, Newcastle upon Tyne. 9 individuals were screened and 6 were recruited to the study.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bezafibrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52

    Number of subjects in period 1
    		Group 1
    Started
    6
    Completed
    6
    Period 2
    Period 2 title
    Wk 6 Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bezafibrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52

    Number of subjects in period 2
    		Group 1
    Started
    6
    Completed
    6
    Period 3
    Period 3 title
    Wk 12 End of Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Group 1
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bezafibrate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200mg TDS PO for 6/52 followed by 400mg TDS PO for 6/52

    Number of subjects in period 3
    		Group 1
    Started
    6
    Completed
    6

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 6 6
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 6 6
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 50 (44 to 57) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 2 2
    Complex I Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex I/CS
        arithmetic mean (standard deviation)
    		 0.073000 ± 0.014697 -
    Complex II Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex II/CS
        arithmetic mean (standard deviation)
    		 0.203000 ± 0.025965 -
    Complex III Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex III/CS
        arithmetic mean (standard deviation)
    		 1.12800 ± 0.188611 -
    Complex IV Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex IV/CS
        arithmetic mean (standard deviation)
    		 1.406000 ± 0.235151 -
    Citrate synthase
    Citrate synthase activity in muscle tissue homogenate at baseline
    Units: μmol x min-1 x g tissue-1
        arithmetic mean (standard deviation)
    		 690 ± 174.404 -
    mitochondrial DNA copy number
    mitochondrial DNA copy number (muscle tissue)
    Units: Relative mtDNA CN/thousands
        arithmetic mean (standard deviation)
    		 3863.89 ± 625.9426 -
    Serum FGF-21
    Serum Fibroblast growth factor-21
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 415.00 ± 193.51 -
    Serum GDF-15
    Serum Growth Differentiation Factor-15
    Units: pg/ml
        arithmetic mean (standard deviation)
    		 1973 ± 269.93 -
    Muscle PGC-1alpha level
    Muscle PGC-1alpha level determined by immunoblotting
    Units: relative to control = 1.0
        arithmetic mean (standard deviation)
    		 0.615 ± 0.197184 -
    skeletal muscle τ1/2 PCr
    skeletal muscle τ1/2 PCr as determined by 31P-MRS
    Units: τ1/2 PCr seconds
        arithmetic mean (standard deviation)
    		 48.7 ± 39.1 -
    Myocardial PCr/ATP ratio
    Myocardial PCr/ATP ratio as determined by 31P-MRS NB - only 5 individuals had values determined at baseline due to a technical error in MR set up.
    Units: PCr/ATP ratio
        arithmetic mean (standard deviation)
    		 1.69 ± 0.2 -
    Peak cardiac left ventricular torsion
    Peak cardiac left ventricular torsion as determined by cardiac cine scanning
    Units: degrees (°)
        arithmetic mean (standard deviation)
    		 7.66 ± 1.20 -
    Mean peak VO2
    Mean peak VO2 as measured by cycle ergometry
    Units: ml/min
        arithmetic mean (standard deviation)
    		 1214 ± 225 -
    Peak power
    Peak power as determined by cycle ergometry
    Units: watts
        arithmetic mean (standard deviation)
    		 87.2 ± 8.0 -
    peak arterio-venous oxygen differential
    peak arterio-venous oxygen differential as determined by cycle ergometry
    Units: mlO2/dl
        arithmetic mean (standard deviation)
    		 11.4 ± 0.7 -
    Newcastle Mitochondrial Disease Adult Scale (NMDAS) Total
    Units: points
        arithmetic mean (standard deviation)
    		 24 ± 8.0 -
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section I sub-total
    Units: points
        arithmetic mean (standard deviation)
    		 9 ± 5.4 -
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section II sub-total
    Units: points
        arithmetic mean (standard deviation)
    		 10 ± 4.5 -
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section III sub-total
    Units: points
        arithmetic mean (standard deviation)
    		 5.0 ± 2.3 -
    NMQ - mobility
    Newcastle Mitochondrial Quality of Life Scale - mobility domain
    Units: points
        arithmetic mean (standard deviation)
    		 60 ± 14.7 -
    NMQ - ADLs
    Newcastle Mitochondrial Quality of Life Scale - Activity of Daily Living domain
    Units: points
        arithmetic mean (standard deviation)
    		 86 ± 24.2 -
    NMQ - Energy
    Newcastle Mitochondrial Quality of Life Scale - energy domain
    Units: points
        arithmetic mean (standard deviation)
    		 45 ± 15.7 -
    NMQ - Vision
    Newcastle Mitochondrial Quality of Life Scale - vision domain
    Units: points
        arithmetic mean (standard deviation)
    		 78 ± 21.3 -
    NMQ - communication
    Newcastle Mitochondrial Quality of Life Scale - communication domain
    Units: points
        arithmetic mean (standard deviation)
    		 58.0 ± 19.0 -
    NMQ - memory
    Newcastle Mitochondrial Quality of Life Scale - memory domain
    Units: points
        arithmetic mean (standard deviation)
    		 56 ± 12.5 -
    NMQ - Food
    Newcastle Mitochondrial Quality of Life Scale - food domain
    Units: points
        arithmetic mean (standard deviation)
    		 77 ± 17.6 -
    NMQ - pain
    Newcastle Mitochondrial Quality of Life Scale - Pain domain
    Units: points
        arithmetic mean (standard deviation)
    		 66 ± 32.3 -
    NMQ - Muscle
    Newcastle Mitochondrial Quality of Life Scale - Muscle domain
    Units: points
        arithmetic mean (standard deviation)
    		 67 ± 31.2 -
    NMQ - Migraine
    Newcastle Mitochondrial Quality of Life Scale - Migraine domain
    Units: points
        arithmetic mean (standard deviation)
    		 79 ± 25.0 -
    NMQ - Emotion
    Newcastle Mitochondrial Quality of Life Scale - Emotion domain
    Units: points
        arithmetic mean (standard deviation)
    		 56 ± 21.9 -
    NMQ - Stigma
    Newcastle Mitochondrial Quality of Life Scale - Stigma domain
    Units: points
        arithmetic mean (standard deviation)
    		 69 ± 31.5 -
    NMQ - Family Role
    Newcastle Mitochondrial Quality of Life Scale - Family Role domain
    Units: points
        arithmetic mean (standard deviation)
    		 58 ± 19.4 -
    NMQ - Personal Relations
    Newcastle Mitochondrial Quality of Life Scale - Personal Relations domain
    Units: points
        arithmetic mean (standard deviation)
    		 56 ± 26.9 -
    NMQ - Social Role
    Newcastle Mitochondrial Quality of Life Scale - Social Role Domain
    Units: points
        arithmetic mean (standard deviation)
    		 48 ± 33.5 -
    NMQ - Diabetes
    Newcastle Mitochondrial Quality of Life Scale - Diabetes domain
    Units: points
        arithmetic mean (standard deviation)
    		 55 ± 16.8 -
    Physical Component Score
    From NMDAS - Section IV (SF12.2)
    Units: points
        arithmetic mean (standard deviation)
    		 37.5 ± 13.2 -
    Mental Component Score
    From NMDAS - Section IV (SF12.2)
    Units: points
        arithmetic mean (standard deviation)
    		 43.6 ± 7.9 -
    FIS - Total
    Fatigue Impact Scale - Total
    Units: points
        arithmetic mean (standard deviation)
    		 68 ± 28.659 -
    FIS - Physical
    Fatigue Impact Scale - Physical sub-score
    Units: points
        arithmetic mean (standard deviation)
    		 31.00 ± 12.247 -
    FIS - cognitive
    Fatigue Impact Scale - Cognitive sub-score
    Units: points
        arithmetic mean (standard deviation)
    		 19.00 ± 7.348 -
    FIS - social
    Fatigue Impact Scale - Social sub-score
    Units: points
        arithmetic mean (standard deviation)
    		 18.3 ± 9.60 -
    IPAQ score
    International Physical Activity Questionnaire (IPAQ) score
    Units: MET/mins/week
        median (inter-quartile range (Q1-Q3))
    		 1303.5 (185.6 to 2531.25) -
    Daytime acceleration
    Activity Levels Exercise intensity & duration
    Units: milligravity
        arithmetic mean (standard deviation)
    		 33.56 ± 10.28 -
    Time in vigorous activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    		 1.1347 ± 0.80121 -
    Time in Moderate activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    		 70.49 ± 47.41 -
    Time in Light Activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    		 161.73 ± 40.90 -
    Muscle heteroplasmy
    Units: percentage
        arithmetic mean (full range (min-max))
    		 72 (53 to 84) -
    Urine heteroplasmy
    Units: percentage
        arithmetic mean (full range (min-max))
    		 65 (33 to 89) -
    Blood Heteroplasmy
    Uncorrected - raw values
    Units: percentage
        arithmetic mean (full range (min-max))
    		 19 (11 to 27) -
    COX deficient fibres
    Units: percentage
        arithmetic mean (full range (min-max))
    		 5.0 (2.0 to 10.0) -
    Timed up and go
    Units: seconds
        arithmetic mean (full range (min-max))
    		 8.9 (7.13 to 11.47) -
    Subject analysis sets

    Subject analysis set title
    Group 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All recruited participants

    Subject analysis sets values
    		 Group 1
    Number of subjects
    6
    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 (full range (min-max))
    Gender categorical
    Units: Subjects
        Female
        Male
    Complex I Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex I/CS
        arithmetic mean (standard deviation)
    0.073000 ± 0.014697
    Complex II Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex II/CS
        arithmetic mean (standard deviation)
    0.203000 ± 0.025965
    Complex III Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex III/CS
        arithmetic mean (standard deviation)
    ±
    Complex IV Respiratory Chain Enzyme Activity
    Respiratory Chain Enzyme Activity on skeletal muscle tissue homogenate taken at study baseline.
    Units: Complex IV/CS
        arithmetic mean (standard deviation)
    1.406000 ± 0.235151
    Citrate synthase
    Citrate synthase activity in muscle tissue homogenate at baseline
    Units: μmol x min-1 x g tissue-1
        arithmetic mean (standard deviation)
    ±
    mitochondrial DNA copy number
    mitochondrial DNA copy number (muscle tissue)
    Units: Relative mtDNA CN/thousands
        arithmetic mean (standard deviation)
    3863.89 ± 625.9426
    Serum FGF-21
    Serum Fibroblast growth factor-21
    Units: pg/ml
        arithmetic mean (standard deviation)
    415.00 ± 193.51
    Serum GDF-15
    Serum Growth Differentiation Factor-15
    Units: pg/ml
        arithmetic mean (standard deviation)
    1973 ± 269.93
    Muscle PGC-1alpha level
    Muscle PGC-1alpha level determined by immunoblotting
    Units: relative to control = 1.0
        arithmetic mean (standard deviation)
    0.615 ± 0.197184
    skeletal muscle τ1/2 PCr
    skeletal muscle τ1/2 PCr as determined by 31P-MRS
    Units: τ1/2 PCr seconds
        arithmetic mean (standard deviation)
    ±
    Myocardial PCr/ATP ratio
    Myocardial PCr/ATP ratio as determined by 31P-MRS NB - only 5 individuals had values determined at baseline due to a technical error in MR set up.
    Units: PCr/ATP ratio
        arithmetic mean (standard deviation)
    ±
    Peak cardiac left ventricular torsion
    Peak cardiac left ventricular torsion as determined by cardiac cine scanning
    Units: degrees (°)
        arithmetic mean (standard deviation)
    ±
    Mean peak VO2
    Mean peak VO2 as measured by cycle ergometry
    Units: ml/min
        arithmetic mean (standard deviation)
    ±
    Peak power
    Peak power as determined by cycle ergometry
    Units: watts
        arithmetic mean (standard deviation)
    ±
    peak arterio-venous oxygen differential
    peak arterio-venous oxygen differential as determined by cycle ergometry
    Units: mlO2/dl
        arithmetic mean (standard deviation)
    ±
    Newcastle Mitochondrial Disease Adult Scale (NMDAS) Total
    Units: points
        arithmetic mean (standard deviation)
    ±
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section I sub-total
    Units: points
        arithmetic mean (standard deviation)
    ±
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section II sub-total
    Units: points
        arithmetic mean (standard deviation)
    ±
    Newcastle Mitochondrial Disease Adult Scale (NMDAS), Section III sub-total
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - mobility
    Newcastle Mitochondrial Quality of Life Scale - mobility domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - ADLs
    Newcastle Mitochondrial Quality of Life Scale - Activity of Daily Living domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Energy
    Newcastle Mitochondrial Quality of Life Scale - energy domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Vision
    Newcastle Mitochondrial Quality of Life Scale - vision domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - communication
    Newcastle Mitochondrial Quality of Life Scale - communication domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - memory
    Newcastle Mitochondrial Quality of Life Scale - memory domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Food
    Newcastle Mitochondrial Quality of Life Scale - food domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - pain
    Newcastle Mitochondrial Quality of Life Scale - Pain domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Muscle
    Newcastle Mitochondrial Quality of Life Scale - Muscle domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Migraine
    Newcastle Mitochondrial Quality of Life Scale - Migraine domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Emotion
    Newcastle Mitochondrial Quality of Life Scale - Emotion domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Stigma
    Newcastle Mitochondrial Quality of Life Scale - Stigma domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Family Role
    Newcastle Mitochondrial Quality of Life Scale - Family Role domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Personal Relations
    Newcastle Mitochondrial Quality of Life Scale - Personal Relations domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Social Role
    Newcastle Mitochondrial Quality of Life Scale - Social Role Domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    NMQ - Diabetes
    Newcastle Mitochondrial Quality of Life Scale - Diabetes domain
    Units: points
        arithmetic mean (standard deviation)
    ±
    Physical Component Score
    From NMDAS - Section IV (SF12.2)
    Units: points
        arithmetic mean (standard deviation)
    ±
    Mental Component Score
    From NMDAS - Section IV (SF12.2)
    Units: points
        arithmetic mean (standard deviation)
    ±
    FIS - Total
    Fatigue Impact Scale - Total
    Units: points
        arithmetic mean (standard deviation)
    68 ± 28.659
    FIS - Physical
    Fatigue Impact Scale - Physical sub-score
    Units: points
        arithmetic mean (standard deviation)
    ±
    FIS - cognitive
    Fatigue Impact Scale - Cognitive sub-score
    Units: points
        arithmetic mean (standard deviation)
    19.00 ± 7.348
    FIS - social
    Fatigue Impact Scale - Social sub-score
    Units: points
        arithmetic mean (standard deviation)
    18.3 ± 9.60
    IPAQ score
    International Physical Activity Questionnaire (IPAQ) score
    Units: MET/mins/week
        median (inter-quartile range (Q1-Q3))
    Daytime acceleration
    Activity Levels Exercise intensity & duration
    Units: milligravity
        arithmetic mean (standard deviation)
    ±
    Time in vigorous activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    ±
    Time in Moderate activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    ±
    Time in Light Activity
    Activity Levels Exercise intensity & duration
    Units: minutes
        arithmetic mean (standard deviation)
    ±
    Muscle heteroplasmy
    Units: percentage
        arithmetic mean (full range (min-max))
    Urine heteroplasmy
    Units: percentage
        arithmetic mean (full range (min-max))
    Blood Heteroplasmy
    Uncorrected - raw values
    Units: percentage
        arithmetic mean (full range (min-max))
    COX deficient fibres
    Units: percentage
        arithmetic mean (full range (min-max))
    Timed up and go
    Units: seconds
        arithmetic mean (full range (min-max))

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 -
    Reporting group title
    Group 1
    Reporting group description
    		 -
    Reporting group title
    Group 1
    Reporting group description
    		 -

    Subject analysis set title
    Group 1
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All recruited participants

    Primary: Change in Complex I Respiratory Chain Enzyme Activity between baseline & week 12

    		 Close Top of page
    End point title
    		 Change in Complex I Respiratory Chain Enzyme Activity between baseline & week 12
    End point description
    End point type
    Primary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: CI/CS
        arithmetic mean (standard error)
    0.073 ± 0.0060
    0.072 ± 0.0044
    Statistical analysis title
    		 Change in CI between weeks 0 and 12.
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.7
    Method
    		 paired t test
    Confidence interval
    Notes
    [1] - exploratory

    Primary: dChange in Complex II Respiratory Chain Enzyme Activity between baseline & week 12

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    End point title
    		 dChange in Complex II Respiratory Chain Enzyme Activity between baseline & week 12
    End point description
    End point type
    Primary
    End point timeframe
    Measured at weeks 0 and 12
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: CII/CS
        arithmetic mean (standard error)
    0.203 ± 0.0106
    0.227 ± 0.0098
    Statistical analysis title
    		 Change in CII activity between wks 0 and 12
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.02
    Method
    		 paired t test
    Confidence interval
    Notes
    [2] - exploratory

    Primary: Change in Complex III Respiratory Chain Enzyme Activity between baseline & week 12I

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    End point title
    		 Change in Complex III Respiratory Chain Enzyme Activity between baseline & week 12I
    End point description
    End point type
    Primary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: CIII/CS
        arithmetic mean (standard error)
    1.128 ± 0.077
    1.129 ± 0.0744
    Statistical analysis title
    		 Change in CIII activity between weeks 0 and 12
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.99
    Method
    		 paired t test
    Confidence interval
    Notes
    [3] - exploratory

    Primary: Change in Complex IV Respiratory Chain Enzyme Activity between baseline & week 12

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    End point title
    		 Change in Complex IV Respiratory Chain Enzyme Activity between baseline & week 12
    End point description
    End point type
    Primary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: CIVCS
        arithmetic mean (standard error)
    1.406 ± 0.096
    1.399 ± 0.1189
    Statistical analysis title
    		 Change in CIV activity between weeks 0 and 12.
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.96
    Method
    		 paired t test
    Confidence interval
    Notes
    [4] - exploratory

    Secondary: Change in Citrate Synthase

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    End point title
    		 Change in Citrate Synthase
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: μmol x min-1 x g tissue-1
        arithmetic mean (standard error)
    690 ± 71.2
    649 ± 73.6
    Statistical analysis title
    		 Change in CS activity between weeks 0 and 12
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.72
    Method
    		 paired t test
    Confidence interval
    Notes
    [5] - exploratory

    Secondary: Change in mitochondrial DNA copy number

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    End point title
    		 Change in mitochondrial DNA copy number
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: Relative mtDNA CN/thousands
        arithmetic mean (standard error)
    3863.89 ± 255.54
    3991.57 ± 314.53
    Statistical analysis title
    		 change in mtDNA CN between weeks 0 and 12
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.64
    Method
    		 paired t test
    Confidence interval
    Notes
    [6] - exploratory

    Secondary: Change in serum FGF-21

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    End point title
    		 Change in serum FGF-21
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: pg/ml
        arithmetic mean (standard error)
    415 ± 79
    1149 ± 128
    2173 ± 268
    Statistical analysis title
    		 Change in FGF-21
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.021 [8]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [7] - exploratory
    [8] - a priori threshold for significance = <0.05 Greenhouse-Geisser correction Two sided

    Secondary: Change in serum GDF-15

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    End point title
    		 Change in serum GDF-15
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: pg/ml
        arithmetic mean (standard error)
    1973 ± 110.2
    2432 ± 171.8
    2795 ± 160.3
    Statistical analysis title
    		 Change in GDF-15
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.007 [10]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [9] - exploratory
    [10] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in muscle PGC-1alpha level

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    End point title
    		 Change in muscle PGC-1alpha level
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0 and 12 weeks
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: Relative level
        arithmetic mean (standard error)
    0.6150 ± 0.0805
    0.6681 ± 0.0809
    Statistical analysis title
    		 Change in PGC1alpha level
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.63
    Method
    		 paired t test
    Confidence interval
    Notes
    [11] - exploratory

    Secondary: Change in τ 1/2 PCr between 0 and 12 weeks

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    End point title
    		 Change in τ 1/2 PCr between 0 and 12 weeks
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: seconds
        arithmetic mean (standard deviation)
    48.7 ± 39.1
    54.5 ± 31.7
    Statistical analysis title
    		 Change in Ï„ 1/2 PCr between wks 0 & 12
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.345 [13]
    Method
    		 paired t test
    Confidence interval
    Notes
    [12] - exploratory
    [13] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in Myocardial PCr/ATP ratio

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    End point title
    		 Change in Myocardial PCr/ATP ratio
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    4 [14]
    4
    Units: PCr/ATP ratio
        arithmetic mean (standard deviation)
    1.69 ± 0.2
    1.84 ± 0.2
    Notes
    [14] - n=5 participants scanned at baseline due to technical error. 4 individuals had paired samples.
    Statistical analysis title
    		 Change in myocardial PCr/ATP ratio
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    8
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 = 0.035
    Method
    		 paired t test
    Confidence interval
    Notes
    [15] - exploratory

    Secondary: Change in Peak cardiac left ventricular torsion

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    End point title
    		 Change in Peak cardiac left ventricular torsion
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    5
    5
    Units: degrees (°)
        arithmetic mean (standard deviation)
    7.66 ± 1.20
    7.78 ± 1.25
    Statistical analysis title
    		 Change in mean left ventricular torsion
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 = 0.8 [17]
    Method
    		 paired t test
    Confidence interval
    Notes
    [16] - exploratory
    [17] - a priori threshold for significance = <0.05 Two sided

    Secondary: change in mean peak VO2

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    End point title
    		 change in mean peak VO2
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    5
    5
    Units: ml/min
        arithmetic mean (standard deviation)
    1214 ± 225
    1221 ± 221
    Statistical analysis title
    		 Change in peak VO2
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 [18]
    P-value
    		 = 0.91 [19]
    Method
    		 paired t test
    Confidence interval
    Notes
    [18] - exploratory
    [19] - a priori threshold for significance = <0.05 Two sided

    Secondary: change in peak power

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    End point title
    		 change in peak power
    End point description
    End point type
    Secondary
    End point timeframe
    measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    5
    5
    Units: watts
        arithmetic mean (standard deviation)
    87.2 ± 8.0
    88.2 ± 10.1
    Statistical analysis title
    		 Change in mean peak power (W)
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 = 0.87 [21]
    Method
    		 paired t test
    Confidence interval
    Notes
    [20] - exploratory
    [21] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in arterio-venous oxygen differential 0-12wks

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    End point title
    		 Change in arterio-venous oxygen differential 0-12wks
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    5
    5
    Units: mlO2/dl
        arithmetic mean (standard deviation)
    11.4 ± 0.7
    10.4 ± 2.0
    Statistical analysis title
    		 Change in mean peak a-VO2 diff
    Comparison groups
    Group 1 v Group 1
    Number of subjects included in analysis
    10
    Analysis specification
    Pre-specified
    Analysis type
    		 [22]
    P-value
    		 = 0.37 [23]
    Method
    		 paired t test
    Confidence interval
    Notes
    [22] - exploratory
    [23] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in NMDAS Total

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    End point title
    		 Change in NMDAS Total
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    24 ± 8.0
    24 ± 7.7
    21 ± 8.2
    Statistical analysis title
    		 Change in NMDAS_total
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.115 [24]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [24] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in NMQ - mobility

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    End point title
    		 Change in NMQ - mobility
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0,6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    60 ± 14.7
    72 ± 25.3
    69 ± 12.5
    Statistical analysis title
    		 change in NMQ - mobility
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [25]
    P-value
    		 = 0.127
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [25] - exploratory

    Secondary: Change in NMQ - ADLs

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    End point title
    		 Change in NMQ - ADLs
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0,6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    86 ± 24.2
    87 ± 25.0
    91 ± 18.8
    Statistical analysis title
    		 Change in NMQ - ADLs
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [26]
    P-value
    		 = 0.062
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [26] - exploratory

    Secondary: Change in NMQ - Energy

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    End point title
    		 Change in NMQ - Energy
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6, 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    45 ± 15.7
    46 ± 25.9
    49 ± 16.9
    Statistical analysis title
    		 Change in NMQ - Energy
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [27]
    P-value
    		 = 0.127
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [27] - exploratory

    Secondary: Change in NMQ - Vision

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    End point title
    		 Change in NMQ - Vision
    End point description
    End point type
    Secondary
    End point timeframe
    measured at Wk 0, 6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    78 ± 21.3
    81 ± 16.1
    75 ± 14.3
    Statistical analysis title
    		 Change in NMQ _ Vision
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [28]
    P-value
    		 = 0.425
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [28] - exploratory

    Secondary: Change in NMQ - Communication

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    End point title
    		 Change in NMQ - Communication
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    58 ± 19.0
    56 ± 14.3
    55 ± 13.7
    Statistical analysis title
    		 Change in NMQ - Communication
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [29]
    P-value
    		 = 0.746
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [29] - exploratory

    Secondary: Change in NMQ - Memory

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    End point title
    		 Change in NMQ - Memory
    End point description
    End point type
    Secondary
    End point timeframe
    measured at 0,6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    56 ± 12.5
    68.7 ± 23.9
    75 ± 20.4
    Statistical analysis title
    		 Change in NMQ - Memory
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [30]
    P-value
    		 = 0.08
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [30] - exploratory

    Secondary: Change in NMQ - Food

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    End point title
    		 Change in NMQ - Food
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    77 ± 17.6
    85.4 ± 13.8
    75 ± 20.4
    Statistical analysis title
    		 change in NMQ _food
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [31]
    P-value
    		 = 0.094
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [31] - exploratory

    Secondary: Change in NMQ - Pain

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    End point title
    		 Change in NMQ - Pain
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6, 12 weeks
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    66 ± 32.3
    77 ± 40.4
    67.9 ± 36.8
    Statistical analysis title
    		 change in NMQ - Pain
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [32]
    P-value
    		 = 0.514
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [32] - exploratory

    Secondary: Change in NMQ - Muscle

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    End point title
    		 Change in NMQ - Muscle
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    67 ± 31.2
    73 ± 39.3
    69 ± 37.5
    Statistical analysis title
    		 Change in NMQ - Muscle
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [33]
    P-value
    		 = 0.235
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [33] - exploratory

    Secondary: Change in NMQ - Migraine

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    End point title
    		 Change in NMQ - Migraine
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    79 ± 25.0
    77 ± 36.0
    83 ± 23.6
    Statistical analysis title
    		 change in NMQ - Migraine
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [34]
    P-value
    		 = 0.471
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [34] - exploratory

    Secondary: Change in NMQ - Emotions

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    End point title
    		 Change in NMQ - Emotions
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    56 ± 21.9
    66.5 ± 32.6
    66 ± 32.6
    Statistical analysis title
    		 change in NMQ - Emotions
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [35]
    P-value
    		 = 0.173
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [35] - exploratory

    Secondary: Change in NMQ - Stigma

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    End point title
    		 Change in NMQ - Stigma
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    69 ± 31.5
    73 ± 23.0
    64 ± 33.5
    Statistical analysis title
    		 Change in NMQ - Stigma
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [36]
    P-value
    		 = 0.47
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [36] - exploratory

    Secondary: Change in NMQ - Family Role

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    End point title
    		 Change in NMQ - Family Role
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    58 ± 19.4
    62.5 ± 27.0
    56 ± 15.5
    Statistical analysis title
    		 Change in NMQ - Family role
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [37]
    P-value
    		 = 0.546
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [37] - exploratory

    Secondary: Change in NMQ - Personal Relations

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    End point title
    		 Change in NMQ - Personal Relations
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    56 ± 26.9
    63.5 ± 35.2
    64 ± 31.9
    Statistical analysis title
    		 Change in NMQ - Personal Relations
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [38]
    P-value
    		 = 0.277
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [38] - exploratory

    Secondary: Change in NMQ - Social Role

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    End point title
    		 Change in NMQ - Social Role
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    48 ± 33.5
    60 ± 42.7
    54 ± 41.7
    Statistical analysis title
    		 Change in NMQ - social role
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [39]
    P-value
    		 = 0.258
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [39] - exploratory

    Secondary: Change in Physical Component Score

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    End point title
    		 Change in Physical Component Score
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    37.5 ± 13.2
    34 ± 9.9
    34 ± 8.6
    Statistical analysis title
    		 Change in Physical Component Score
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [40]
    P-value
    		 = 0.663
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [40] - exploratory

    Secondary: Change in Mental Component Score

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    End point title
    		 Change in Mental Component Score
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard deviation)
    43.6 ± 7.9
    47 ± 7.4
    49 ± 7.6
    Statistical analysis title
    		 Change in Mental Component Score
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [41]
    P-value
    		 = 0.028
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [41] - exploratory

    Secondary: Change in Fatigue Impact Score_Total

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    End point title
    		 Change in Fatigue Impact Score_Total
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard error)
    68 ± 11.7
    57 ± 13.9
    57 ± 7.7
    Statistical analysis title
    		 Change in FIS - Total
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [42]
    P-value
    		 = 0.252
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [42] - exploratory

    Secondary: Change in Fatigue Impact Score_Physical

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    End point title
    		 Change in Fatigue Impact Score_Physical
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard error)
    31 ± 5.0
    25 ± 4.8
    26 ± 3.0
    Statistical analysis title
    		 Change in FIS - Physical
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [43]
    P-value
    		 = 0.127
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [43] - exploratory

    Secondary: Change in Fatigue Impact Score_Cognitive

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    End point title
    		 Change in Fatigue Impact Score_Cognitive
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard error)
    19 ± 3.0
    16 ± 4.1
    14 ± 1.1
    Statistical analysis title
    		 Change in FIS - Cognitive
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [44]
    P-value
    		 = 0.289
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [44] - exploratory

    Secondary: Change in Fatigue Impact Score_Social

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    End point title
    		 Change in Fatigue Impact Score_Social
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 , 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: score
        arithmetic mean (standard error)
    18 ± 3.9
    16 ± 5.2
    17 ± 3.9
    Statistical analysis title
    		 Change in FIS - Social
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [45]
    P-value
    		 = 0.602
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [45] - exploratory

    Secondary: Change in IPAQ Score

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    End point title
    		 Change in IPAQ Score
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: MET/mins/week
        median (standard error)
    1303 ± 531.8
    787.5 ± 575.3
    132.0 ± 324.4
    Statistical analysis title
    		 Change in IPAQ score
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other [46]
    P-value
    		 = 0.084 [47]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [46] - exploratory
    [47] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in Daytime Acceleration

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    End point title
    		 Change in Daytime Acceleration
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 , 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    5
    6
    Units: milligravity
        arithmetic mean (standard error)
    33.56 ± 4.6
    31.35 ± 5.7
    28.33 ± 4.7
    Statistical analysis title
    		 Change in daytime acceleration
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [48]
    P-value
    		 = 0.074 [49]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [48] - exploratory
    [49] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in Vigorous Activity

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    End point title
    		 Change in Vigorous Activity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    5
    6
    Units: mins
        arithmetic mean (standard error)
    1.14 ± 0.33
    1.09 ± 0.31
    0.68 ± 0.19
    Statistical analysis title
    		 Change in vigorous activity
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [50]
    P-value
    		 = 0.021 [51]
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [50] - exploratory
    [51] - a priori threshold for significance = <0.05 Two sided

    Secondary: Change in Moderate Activity

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    End point title
    		 Change in Moderate Activity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    5
    6
    Units: seconds
        arithmetic mean (standard error)
    70.49 ± 19.35
    60.51 ± 25.41
    54.98 ± 20.45
    Statistical analysis title
    		 Change in time in moderate activity
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [52]
    P-value
    		 = 0.165
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [52] - exploratory

    Secondary: Change in Light Activity

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    End point title
    		 Change in Light Activity
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0, 6 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    5
    6
    Units: minutes
        arithmetic mean (standard error)
    161.74 ± 16.7
    148.42 ± 20.05
    133.14 ± 15.07
    Statistical analysis title
    		 Change in time in light activity
    Comparison groups
    Group 1 v Group 1 v Group 1
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 other [53]
    P-value
    		 = 0.041
    Method
    		 Repeated measures ANOVA
    Confidence interval
    Notes
    [53] - exploratory

    Secondary: Change in Muscle heteroplasmy

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    End point title
    		 Change in Muscle heteroplasmy
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: percentage
        arithmetic mean (full range (min-max))
    72 (53 to 84)
    71 (56 to 87)
    No statistical analyses for this end point

    Secondary: Change in Urine Heteroplasmy

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    End point title
    		 Change in Urine Heteroplasmy
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: percentage
        arithmetic mean (full range (min-max))
    65 (33 to 89)
    61 (38 to 83)
    72 (46 to 92)
    No statistical analyses for this end point

    Secondary: Change in Blood Heteroplasmy

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    End point title
    		 Change in Blood Heteroplasmy
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: percentage
        arithmetic mean (full range (min-max))
    19 (11 to 27)
    19 (13 to 30)
    No statistical analyses for this end point

    Secondary: Change in COX deficient Fibres

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    End point title
    		 Change in COX deficient Fibres
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at weeks 0 and 12.
    End point values
    		 Group 1 Group 1
    Number of subjects analysed
    6
    6
    Units: percentage
        arithmetic mean (full range (min-max))
    5.0 (2.0 to 10.0)
    6.0 (3.0 to 12.0)
    No statistical analyses for this end point

    Secondary: Change in Timed Up and Go

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    End point title
    		 Change in Timed Up and Go
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at 0, 6 and 12 weeks.
    End point values
    		 Group 1 Group 1 Group 1
    Number of subjects analysed
    6
    6
    6
    Units: seconds
        arithmetic mean (full range (min-max))
    8.9 (7.13 to 11.47)
    8.71 (6.22 to 11.7)
    8.46 (6.46 to 10.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Enrolment in study up to 2 weeks after taking final dose of IMP.
    Adverse event reporting additional description
    Given the multi-systemic feature of mitochondrial disorders, and the low numbers of participants, all adverse events were captured during the study period.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Group 1
    Reporting group description
    		 All participants recruited to study, who it was anticipated at onset would take 6 weeks bezafibrate at 200mg TDS; followed by 400mg TDS for 6 weeks.

    Serious adverse events
    		 Group 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 6 (16.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Constipation
    Additional description: Participant attended hospital on morning of planned week 12 muscle biopsy with acute onset abdominal pain. Admitted under surgeons for assessment. Abdominal X-Ray confirmed faecal loading. Pain improved following passing stool.
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    Vascular disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Increased appetite
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Improved sleep
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Feeling hot
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Muscle tingling
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Energy increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Improved myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Post-menopausal haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    3
    Blood creatine increased
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    2
    Elevated creatine phosphokinase
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    White blood cell count decreased
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    2
    Neutrophil count decreased
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Migraine
         subjects affected / exposed
    5 / 6 (83.33%)
         occurrences all number
    40
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Eye disorders
    Refraction disorder
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    3
    Flatulence
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Oral dryness and saliva altered
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Abdominal Pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rosaceas
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Pruritis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Skin odour abnormal
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Incision site dermatitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Endocrine disorders
    Hypoglycaemia
         subjects affected / exposed
    5 / 6 (83.33%)
         occurrences all number
    44
    Decreased insulin requirement
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Increased insulin requirement
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    2
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    5 / 6 (83.33%)
         occurrences all number
    9
    Spondylitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    7
    Muscle spasms
         subjects affected / exposed
    2 / 6 (33.33%)
         occurrences all number
    5
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Metatarsalgia
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    4 / 6 (66.67%)
         occurrences all number
    12
    Viral sinusitis
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 6 (16.67%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    3 / 6 (50.00%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Jun 2015
    MHRA approval for use of protocol V2.0 obtained 11 June 2015. REC Approval for protocol V2.0 24 July 2015. Protocol updated from V1.0 to reflect changes in eligibility criteria to make sure the study was relevant to the patient population. MHRA only approved V2.0 protocol. Amendment submitted to ensure REC approval in place for V2.0 protocol also.
    09 Dec 2015
    REC approval for addition of Prof Horvath as PI; increased time between screen and baseline; change in accelerometry equipment; addition of statin washout; removal of site specific muscle biopsy details; clarification that potential biomarkers will be analysed in muscle tissue and serum; streamlining information within the protocol.
    19 Apr 2016
    Updated following Trial Oversight Committee meeting, to improve blood glucose monitoring for participants in light of hypoglycaemic episodes.

    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.
    Adverse event profile in the first six participants, and in particular hypoglycaemic episodes, led to discontinuation of study after 6 individuals. It was not thought that persons would tolerate a higher dose.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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