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    Clinical Trial Results:
    EFFICACY OF EGb 761® 120 mg bid VERSUS PLACEBO IN PATIENTS SUFFERING FROM FRIEDREICH ATAXIA A 3 months, phase II, randomised, double blind, placebo-controlled, parallel groups, clinical study.

    Summary
    EudraCT number
    		 2007-005371-34
    Trial protocol
    		 FR  
    Global end of trial date
    20 Oct 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 May 2016
    First version publication date
    05 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2-39-00240-133
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00824512
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ipsen Pharma
    Sponsor organisation address
    65 Quai George Gorse, Boulogne-Billancourt, Cedex, France, 92100
    Public contact
    Medical Director, Neurology, Ipsen Pharma, clinical.trials@ipsen.com
    Scientific contact
    Medical Director, Neurology, Ipsen Pharma, clinical.trials@ipsen.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
    12 Jun 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    20 Oct 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Oct 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate an improvement in skeletal muscle energetics and particularly in mitochondrial oxidative phosphorylation.
    Protection of trial subjects
    This clinical study was designed and implemented and reported in accordance with the InternationalConference on Harmonisation (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC, US Code of Federal Regulations Title 21, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 22
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    17
    Adults (18-64 years)
    5
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited at a single centre investigational site in France.

    Pre-assignment
    Screening details
    		 From the 22 randomised patients, 21 were included in the modified Intention-To-Treat (mITT) population. 1 patient in the placebo group did not meet the primary criteria and thus excluded from the analysis. All patient were included in the safety population.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 EGb 761® 120 mg
    Arm description
    		 EGb 761 120 mg : EGb 761® 120 mg BID, orally for 12 to 14 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    EGB 761 (r) 120 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg

    Arm title
    		 Placebo
    Arm description
    		 Placebo : Placebo 1 tablet BID, orally for 12 to 14 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    NA

    Number of subjects in period 1 [1]
    		EGb 761® 120 mg Placebo
    Started
    11
    10
    Completed
    11
    10
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Worldwide details are for all randomized subjects, however baseline details are for mITT population (1 subject in Placebo arm was excluded from the mITT population due to Test or examination not done)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EGb 761® 120 mg
    Reporting group description
    		 EGb 761 120 mg : EGb 761® 120 mg BID, orally for 12 to 14 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo : Placebo 1 tablet BID, orally for 12 to 14 weeks

    Reporting group values
    		 EGb 761® 120 mg Placebo Total
    Number of subjects
    		 11 10 21
    Age categorical
    Units: Subjects
        12-15 years
    		 5 4 9
        16-22 years
    		 6 6 12
    Age continuous
    Units: years
        median (full range (min-max))
    		 16 (12 to 20) 16 (12 to 22) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5 10
        Male
    		 6 5 11
    Duration since first symptoms
    Units: Years
        median (full range (min-max))
    		 8.1 (3 to 15) 7.7 (4 to 18) -
    Number of repeats of Guanine Adenine Adenine (GAA) sequence
    Units: GAA sequence repetitions
        median (full range (min-max))
    		 700 (500 to 950) 810 (100 to 1000) -

    End points

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    End points reporting groups
    Reporting group title
    EGb 761® 120 mg
    Reporting group description
    		 EGb 761 120 mg : EGb 761® 120 mg BID, orally for 12 to 14 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo : Placebo 1 tablet BID, orally for 12 to 14 weeks

    Primary: Creatine Rephosphorylation Rate Post Exercise

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    End point title
    		 Creatine Rephosphorylation Rate Post Exercise
    End point description
    The primary efficacy endpoint is the evolution of the Creatine Rephosphorylation rate post-exercise corrected by pH (sec-1) using Phosphorus 31 Nuclear Magnetic Resonance (P-31 NMR) spectroscopy between the W0 and W12 visits. As this study is evaluating an orphan pathology with only few patients in France known to be affected by Friedreich ataxia, and considering there are no specific studies in this population with EGb761, the use of a statistical hypothesis for a sample size calculation was not possible. Primary efficacy analyses performed on the mITT population and analysis of safety performed on the safety population.
    End point type
    Primary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: pH per second
    median (full range (min-max))
        Baseline (Week 0)
    0.024 (0.013 to 0.037)
    0.029 (0.018 to 0.04)
        Week 12
    0.022 (0.015 to 0.043)
    0.029 (0.014 to 0.035)
        Change from Baseline (Week 0) to Week 12
    0.001 (-0.009 to 0.009)
    0 (-0.013 to 0.005)
    Statistical analysis title
    		 Creatine Rephosphorylation Rate Post Exercise
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9133
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Peak Post Exercise Perfusion

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    End point title
    		 Peak Post Exercise Perfusion
    End point description
    Peak post exercise perfusion (mL/mn/100 g of tissue) was assessed using Arterial spin labelling combined with Nuclear Magnetic Resonance imaging.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: ml/mn/100 g of tissue
    median (full range (min-max))
        Baseline (Week 0)
    54.3 (33.9 to 91)
    51.8 (10.8 to 81.4)
        Week 12
    58.8 (37.6 to 88.8)
    46.6 (30.7 to 63.1)
        Change from Baseline (Week 0) to Week 12
    3.6 (-29.5 to 31.2)
    -1.55 (-20.9 to 23.2)
    Statistical analysis title
    		 Peak Post Exercise Perfusion
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0661
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Time to Peak Perfusion

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    End point title
    		 Time to Peak Perfusion
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: seconds
    median (full range (min-max))
        Baseline (Week 0)
    38.3 (0.8 to 269.3)
    58.55 (5.3 to 317.3)
        Week 12
    39.8 (0.8 to 119.3)
    76.55 (0.8 to 384.8)
        Change from Baseline (Week 0) to Week 12
    8.5 (-267 to 94.5)
    14.25 (-232.5 to 274.5)
    Statistical analysis title
    		 Time to Peak Perfusion
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2725
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Perfusion-time Integral During the First 9 Minutes Post Exercise

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    End point title
    		 Perfusion-time Integral During the First 9 Minutes Post Exercise
    End point description
    The integral of 'peak perfusion' over a period of 9 minutes post exercise.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: mL/100 g of tissue
    median (full range (min-max))
        Baseline (Week 0)
    166.9 (83.6 to 353)
    157.2 (11.8 to 373)
        Week 12
    191.6 (86.1 to 417.3)
    185.7 (22 to 396.7)
        Change from Baseline (Week 0) to Week 12
    -5.2 (-138.2 to 237.4)
    0.05 (-156.7 to 212.9)
    Statistical analysis title
    		 Perfusion Time Integral
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9198
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Muscle Reoxygenation Rate Post Exercise.

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    End point title
    		 Muscle Reoxygenation Rate Post Exercise.
    End point description
    Muscle reoxygenation rate post exercise was assessed using Myoglobin Hydrogen-1 Nuclear Magnetic Resonance spectroscopy. n values for EGb 761 120 mg = 7, 10, 7 and for Placebo = 9, 9 8
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: 1/second
    median (full range (min-max))
        Baseline (Week 0)
    0.087 (0.035 to 0.156)
    0.054 (0.024 to 0.123)
        Week 12
    0.058 (0.03 to 0.114)
    0.062 (0.021 to 0.087)
        Change from Baseline (Week 0) to Week 12
    -0.035 (-0.124 to 0.039)
    -0.0035 (-0.058 to 0.049)
    Statistical analysis title
    		 Muscle Reoxygenation Rate Post Exercise
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5885
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Muscle Trophicity: Maximum Cross Section of Muscle

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    End point title
    		 Muscle Trophicity: Maximum Cross Section of Muscle
    End point description
    Muscle trophicity measured using Phosphorus 31 Nuclear Magnetic Resonance (P-31 NMR)spectroscopy and calculated based on maximum cross section of muscle (cm^2)
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: cm^2
    median (full range (min-max))
        Baseline (Week 0)
    28.1 (16.6 to 33.1)
    28.95 (23.4 to 42.4)
        Week 12
    26.8 (16.7 to 33.2)
    29.85 (24 to 42.9)
        Change from Baseline (Week 0) to Week 12
    0.1 (-1.3 to 0.7)
    0.55 (-2.1 to 2.1)
    Statistical analysis title
    		 Muscle Trophicity
    Statistical analysis description
    Muscle Trophicity - Maximum Cross Section of Muscle
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.296
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Developed Force During the Exercise Bout

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    End point title
    		 Developed Force During the Exercise Bout
    End point description
    Developed force during the exercise bout measured using Phosphorus 31 Nuclear Magnetic Resonance (P-31 NMR)spectroscopy n values for EGb 761 120 mg = 11, 9, 9 and for Placebo = 10, 10, 10
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: Joules
    median (full range (min-max))
        Baseline (Week 0)
    305.3 (177 to 822.9)
    358.1 (207.2 to 1172.8)
        Week 12
    277.5 (136.9 to 750.9)
    354.35 (200.9 to 1002.1)
        Change from Baseline (Week 0) to Week 12
    -32.4 (-146.9 to 56.6)
    19.2 (-191.8 to 109.8)
    Statistical analysis title
    		 Developed Force during the Exercise Bout
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3024
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Normalised Work Developed During the Exercise

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    End point title
    		 Normalised Work Developed During the Exercise
    End point description
    Normalised work developed during the exercise was derived as Work developed during the exercise/([60 X Maximum cross section of muscle]-1100). Normalised work measured using Phosphorus 31 Nuclear Magnetic Resonance (P-31 NMR)spectroscopy. n values for EGb 761 120 mg = 11, 9, 9 and for Placebo = 10, 10, 10
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: Joules/cm^2
    median (full range (min-max))
        Baseline (Week 0)
    12.07 (6.3 to 26)
    12 (8.6 to 30.5)
        Week 12
    9.23 (7.6 to 24)
    11.53 (6.1 to 25.7)
        Change from Baseline (Week 0) to Week 12
    -1.03 (-6.3 to 2.6)
    0.47 (-4.8 to 4.6)
    Statistical analysis title
    		 Normalised Work Developed during the Exercise
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6641
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Metabolism Efficacy Index

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    End point title
    		 Metabolism Efficacy Index
    End point description
    The metabolism efficacy index was derived as Normalised work x creatine phosphorylation rate (sec-1). [Normalised work was derived as Work developed during the exercise/(60 X Maximum cross section of muscle-1100)]. Greater values of Metabolism Efficacy index indicate improvement in skeletal muscle energetics while lower values indicate the reverse. Negative values obtained using the formula indicated severe levels of muscle weakness. n values for EGb 761 120 mg = 11, 9, 9 and for Placebo = 10, 10, 10
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: per second
    median (full range (min-max))
        Baseline (Week 0)
    0.018 (-0.042 to 0.038)
    0.015 (0.01 to 0.029)
        Week 12
    0.013 (-0.021 to 0.042)
    0.0145 (0.007 to 0.028)
        Change from Baseline (Week 0) to Week 12
    0.001 (-0.021 to 0.021)
    -0.001 (-0.007 to 0.001)
    Statistical analysis title
    		 Metabolism Efficacy Index
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1415
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: International Cooperative Ataxia Rating Scale [ICARS] (Total Score)

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    End point title
    		 International Cooperative Ataxia Rating Scale [ICARS] (Total Score)
    End point description
    The ICARS was used to measure the general clinical symptoms of Friedreich ataxia using four subscales (i.e. Posture and gait disturbances, Kinetic functions, Speech disorders, & Oculomotor disorders). Scores for each subscale quantify the extent of ataxia in each clinically important area and subscale scores are also summed to give a total score ranging from 0 to 100, with 100 indicative of the most severely affected outcome.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: score on a scale
    median (full range (min-max))
        Baseline (Week 0)
    35 (21 to 54)
    26.5 (20 to 58)
        Week 12
    33 (26 to 60)
    29 (22 to 54)
        Change from Baseline (Week 0) to Week 12
    0 (-9 to 6)
    0.5 (-4 to 11)
    Statistical analysis title
    		 ICARS - Total Scores
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.728
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: ICARS (Posture and Gait Disturbance Score)

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    End point title
    		 ICARS (Posture and Gait Disturbance Score)
    End point description
    The ICARS was used to measure the general clinical symptoms of Friedreich ataxia using four subscales including Posture and gait disturbances. Posture and gait disturbances score range from 0 to 34 (Higher scores indicate higher levels of impairment).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: score on a scale
    median (full range (min-max))
        Baseline (Week 0)
    19 (8 to 29)
    12.5 (7 to 31)
        Week 12
    18 (10 to 32)
    12 (10 to 29)
        Change from Baseline (Week 0) to Week 12
    1 (-6 to 3)
    2.8 (-3 to 4)
    Statistical analysis title
    		 ICARS (Posture and Gait Disturbance Score)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8639
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: ICARS (Kinetic Function Score)

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    End point title
    		 ICARS (Kinetic Function Score)
    End point description
    The ICARS was used to measure the general clinical symptoms of Friedreich ataxia using four subscales including Kinetic Function. Kinetic Function score range from 0 to 52 (Higher scores indicate higher levels of impairment).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: score on a scale
    median (full range (min-max))
        Baseline (Week 0)
    15 (11 to 19)
    11.5 (9 to 22)
        Week 12
    13 (11 to 24)
    13 (11 to 22)
        Change from Baseline (Week 0) to Week 12
    0 (-6 to 5)
    0.5 (-2 to 5)
    Statistical analysis title
    		 ICARS (Kinetic Function Score)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.951
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: ICARS (Speech Disorders Score)

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    End point title
    		 ICARS (Speech Disorders Score)
    End point description
    The ICARS was used to measure the general clinical symptoms of Friedreich ataxia using four subscales including Speech Disorders. Speech Disorders Score range from 0 to 8 (Higher scores indicate higher levels of impairment).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: score on a scale
    median (full range (min-max))
        Baseline (Week 0)
    2 (0 to 4)
    0.5 (0 to 3)
        Week 12
    1 (0 to 2)
    1 (0 to 2)
        Change from Baseline (Week 0) to Week 12
    0 (-3 to 1)
    0 (-1 to 2)
    Statistical analysis title
    		 ICARS (Speech Disorders Score)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8736
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: ICARS (Oculomotor Disorders Score)

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    End point title
    		 ICARS (Oculomotor Disorders Score)
    End point description
    The ICARS was used to measure the general clinical symptoms of Friedreich ataxia using four subscales including Oculomotor Disorders. Oculomotor Disorders score range from 0 to 6 (Higher scores indicate higher levels of impairment).
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: score on a scale
    median (full range (min-max))
        Baseline (Week 0)
    1 (0 to 2)
    1.5 (0 to 3)
        Week 12
    2 (1 to 3)
    2 (1 to 2)
        Change from Baseline (Week 0) to Week 12
    0 (0 to 1)
    0 (-1 to 2)
    Statistical analysis title
    		 ICARS (Oculomotor Disorders Score)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4005
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Timed 25-foot Walk Test

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    End point title
    		 Timed 25-foot Walk Test
    End point description
    n values for EGb 761 120 mg = 8, 8, 8 and for Placebo = 8, 8, 8
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: seconds
    median (full range (min-max))
        Baseline (Week 0)
    8.5 (6 to 16)
    6.75 (5 to 29.5)
        Week 12
    9 (7 to 15.5)
    6.75 (5.5 to 29.5)
        Change from Baseline (Week 0) to Week 12
    0.5 (-1 to 2)
    0 (-2.5 to 0.5)
    Statistical analysis title
    		 Timed 25-foot Walk Test
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0387
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Nine Hole Peg Test (Dominant Hand)

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    End point title
    		 Nine Hole Peg Test (Dominant Hand)
    End point description
    The nine hole peg test was used to assess cognitive function and in particular, fine motor coordination. The patient was asked to place nine pegs in nine holes and was scored on the amount of time it took to place and remove all nine pegs.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: seconds
    median (full range (min-max))
        Baseline (Week 0)
    38.5 (31.5 to 71.5)
    43.5 (33.5 to 91.5)
        Week 12
    42 (29.5 to 86)
    40.75 (32 to 89.5)
        Change from Baseline (Week 0) to Week 12
    1.5 (-2.5 to 15.5)
    -1.5 (-4 to 6.5)
    Statistical analysis title
    		 Nine Hole Peg Test (Dominant Hand)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2359
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Nine Hole Peg Test (Nondominant Hand)

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    End point title
    		 Nine Hole Peg Test (Nondominant Hand)
    End point description
    The nine hole peg test was used to assess cognitive function and in particular, fine motor coordination. The patient was asked to place nine pegs in nine holes and was scored on the amount of time it took to place and remove all nine pegs.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: seconds
    median (full range (min-max))
        Baseline (Week 0)
    47.5 (39.5 to 113)
    48.5 (34.5 to 117.5)
        Week 12
    53 (36 to 113.5)
    46.5 (36.5 to 100.5)
        Change from Baseline (Week 0) to Week 12
    0.5 (-11 to 7)
    1.75 (-17 to 7)
    Statistical analysis title
    		 Nine Hole Peg Test (Nondominant Hand)
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9681
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Choice Reaction Time Test- Reaction Time

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    End point title
    		 Choice Reaction Time Test- Reaction Time
    End point description
    The choice reaction time test was used to assess cognitive functioning. On random presentation of one of six signal lights, the patient was asked to respond as quickly and accurately as possible by removing their index finger of the dominant hand from the bottom key and pressing whichever of the top six keys was indicated by the signal. Reaction time was the time elapsed between the presentation of the stimulus and the release of the finger and movement time was defined as the time elapsed between release of the finger and pressure of the second key. n values for EGb 761 120 mg = 10, 11, 10 and for Placebo = 9, 10, 9
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: millisecond
    median (full range (min-max))
        Baseline (Week 0)
    513.5 (392 to 1594)
    536 (461 to 692)
        Week 12
    491 (417 to 899)
    531 (446 to 865)
        Change from Baseline (Week 0) to Week 12
    8.5 (-1032 to 40)
    9 (-89 to 173)
    Statistical analysis title
    		 Choice Reaction Time Test- Reaction Time
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3607
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Choice Reaction Time Test- Movement Time

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    End point title
    		 Choice Reaction Time Test- Movement Time
    End point description
    The choice reaction time test was used to assess cognitive functioning. On random presentation of one of six signal lights, the patient was asked to respond as quickly and accurately as possible by removing their index finger of the dominant hand from the bottom key and pressing whichever of the top six keys was indicated by the signal. Reaction time was the time elapsed between the presentation of the stimulus and the release of the finger and movement time was defined as the time elapsed between release of the finger and pressure of the second key. n values for EGb 761 120 mg = 10, 11, 10 and for Placebo = 9, 10, 9
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: millisecond
    median (full range (min-max))
        Baseline (Week 0)
    561.5 (344 to 1452)
    531 (390 to 986)
        Week 12
    555 (406 to 1107)
    496.5 (396 to 1419)
        Change from Baseline (Week 0) to Week 12
    4.5 (-998 to 190)
    -31 (-124 to 433)
    Statistical analysis title
    		 Choice Reaction Time Test- Movement Time
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1683
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Visual Assessment Scale (VAS) of Global Impression - Patient

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    End point title
    		 Visual Assessment Scale (VAS) of Global Impression - Patient
    End point description
    The VAS used a 10-cm scoring scale in which values were reported in mm such that 0=bad and 100=good. Total score range on VAS is from 0 to 100.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: mm
    median (full range (min-max))
        Baseline (Week 0)
    60 (18 to 80)
    68.5 (12 to 100)
        Week 12
    67 (12 to 82)
    63 (26 to 100)
        Change from Baseline (Week 0) to Week 12
    -2 (-47 to 30)
    -2 (-20 to 59)
    Statistical analysis title
    		 VAS of Global Impression - Patient
    Statistical analysis description
    Visual Assessment Scale (VAS) of Global Impression - Patient
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8415
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Visual Assessment Scale (VAS) of Global Impression - Parents

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    End point title
    		 Visual Assessment Scale (VAS) of Global Impression - Parents
    End point description
    The VAS used a 10-cm scoring scale in which values were reported in mm such that 0=bad and 100=good. Total score range on VAS is from 0 to 100. n values for EGb 761 120 mg = 9, 9, 9 and for Placebo = 9, 9, 9
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: mm
    median (full range (min-max))
        Baseline (Week 0)
    64 (45 to 96)
    62 (16 to 87)
        Week 12
    64 (31 to 95)
    57 (11 to 72)
        Change from Baseline (Week 0) to Week 12
    -7 (-14 to 13)
    -10 (-25 to 14)
    Statistical analysis title
    		 VAS of Global Impression - Parents
    Statistical analysis description
    Visual Assessment Scale (VAS) of Global Impression - Parents
    Comparison groups
    Placebo v EGb 761® 120 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1647
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Secondary: Visual Assessment Scale (VAS) of Global Impression - Investigator

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    End point title
    		 Visual Assessment Scale (VAS) of Global Impression - Investigator
    End point description
    The VAS used a 10-cm scoring scale in which values were reported in mm such that 0=bad and 100=good. Total score range on VAS is from 0 to 100.
    End point type
    Secondary
    End point timeframe
    Baseline (Week 0) to Week 12
    End point values
    		 EGb 761® 120 mg Placebo
    Number of subjects analysed
    11
    10
    Units: mm
    median (full range (min-max))
        Baseline (Week 0)
    78 (67 to 90)
    76 (25 to 90)
        Week 12
    80 (46 to 87)
    74 (46 to 86)
        Change from Baseline (Week 0) to Week 12
    -2 (-36 to 13)
    -1 (-23 to 52)
    Statistical analysis title
    		 VAS of Global Impression - Investigator
    Statistical analysis description
    Visual Assessment Scale (VAS) of Global Impression - Investigator
    Comparison groups
    EGb 761® 120 mg v Placebo
    Number of subjects included in analysis
    21
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6265
    Method
    		 Non parametric ANCOVA on the rank test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to month 18
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    11.1
    Reporting groups
    Reporting group title
    EGb 761® 120 mg
    Reporting group description
    		 EGb 761 120 mg : EGb 761® 120 mg BID, orally for 12 to 14 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo : Placebo 1 tablet BID, orally for 12 to 14 weeks

    Serious adverse events
    		 EGb 761® 120 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Sciatica
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Varicella
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EGb 761® 120 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 11 (72.73%)
    7 / 11 (63.64%)
    Surgical and medical procedures
    Orthopedic procedure
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 11 (27.27%)
    2 / 11 (18.18%)
         occurrences all number
    3
    3
    Tremor
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 11 (18.18%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    Toothache
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Scoliosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    Influenza
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Mar 2008
    • Corrections to inconsistencies between the synopsis and body of the protocol • Improvement to the presentation of the selection criteria • Precision to the primary endpoint by adding a PCr depletion threshold for patients at the inclusion visit • Clarification of the NMR contraindication wording: addition of exclusion criteria for patients who did not deplete the PCr pool by more than 40% during the exercise bout and exclusion of patients with implanted iron or magnetic objects • Completion of the ICF
    08 Jul 2008
    • Change to the exclusion criteria such that patients who did not deplete the PCr pool by more than 30% during the exercise bout were excluded whereas previously those who did not deplete the pool by more than 40% were excluded. • Change to the forbidden medications list in the exclusion criteria: deferiprone (Ferriprox®) added • Correction to the number of code break envelope sets • Clarification in the ICF on the change of visit order between the two hospitals • Revision to the Pharmacovigilance and Ipsen contact details
    19 Feb 2009
    • Modification to the Ipsen Pharma BIP contact details • Addition of the “not assessable patient” definition i.e. patients who were considered as noncompliant with the study treatment and/or took forbidden treatment and/or didn’t perform the baseline and final assessment of the primary efficacy endpoint • Addition of the replacement patients procedure • Clarification of the primary endpoint to include correction of the rate according to the muscular pH • Correction of the unit for perfusion time integral to mL/100 g of tissue during the first 9 minutes post exercise • Change to the inclusion criteria related to age
    07 Dec 2009
    • Addition of safety criteria (physical examination and vital signs) • Addition of other muscle improvements in peak post exercise • Deletion of the secondary criteria “post exercise skeletal muscle perfusion” (“peak post exercise perfusion” retained) • Addition of “ataxia history” to the inclusion criteria • Addition of concomitant medication Pioglitazone to the exclusion criteria • The mITT population was defined • Update to statistical section • Modifications to the emergency contact details

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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