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    Clinical Trial Results:
    Myomet: A randomized, double blind, placebo-controlled phase II study of metformin in myotonic dystrophy type 1 patients

    Summary
    EudraCT number
    		 2013-001732-21
    Trial protocol
    		 FR  
    Global end of trial date
    17 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Oct 2019
    First version publication date
    16 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MET001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    CECS/Istem
    Sponsor organisation address
    CRCT, 28 rue Henri Desbruères, Corbeil-Essonnes, France, 91100
    Public contact
    M. Raymond ZAKHIA , CECS/Istem, +33 (0)169908535, rzakhia@istem.fr
    Scientific contact
    Dr Marc PESCHANSKI, CECS/Istem, +33 (0)169908517, mpeschanski@istem.fr
    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
    17 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of metformin on ambulation in patients with myotonic dystrophy type 1.
    Protection of trial subjects
    After the enrolment of the first 5 patients in each arm, a blinded assessment of the tolerance has been performed in order to take appropriate measures if required. Additionally, blinded safety reviews have occurred on a regular basis during the course of the study for the same purpose.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Feb 2014
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 40 patients with myotonic dystrophy type I (DM1) was included in order to evaluate 30 patients (expected dropout rate of 25%). Patients were to be aged between 18 and 60 years.

    Pre-assignment
    Screening details
    		 Screening included: - informed consent process - diagnosis of DM1 confirmed by DM1 genetic mutation - Muscular Impairment Rating Scale (MIRS) score 2 or 3 - ambulatory, able to perform the 6MWT

    Period 1
    Period 1 title
    Controlled phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 metformin group - Controlled phase
    Arm description
    		 All enrolled randomised patients in the controlled phase in the metformin arm who actually received at least one dose of study drug
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    - From D1 to D14, the patient received 500 mg oral tablets of metformin BID at the total daily dose of 1,000 mg/d for 14 days - From D15 to D28, the patient received 2 oral tablets of 500 mg BID of metformin at the total daily dose of 2,000 mg/d for 14 days - From D29 to the end of the study period, the patient received 2 oral tablets of 500 mg TID of metformin at the total daily dose of 3,000 mg/d for 48 weeks

    Arm title
    		 Placebo group
    Arm description
    		 All enrolled randomised patients in the controlled phase in the placebo arm who actually received at least one dose of placebo
    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
    - From D1 to D14, the patient received one oral tablet of placebo BID for 14 days - From D15 to D28, the patient received 2 oral tablets of placebo BID for 14 days - From D29 to the end of the study period, the patient received 2 oral tablets of 500 mg TID of placebo for 48 weeks

    Number of subjects in period 1
    		metformin group - Controlled phase Placebo group
    Started
    20
    20
    Completed
    12
    17
    Not completed
    8
    3
         Non-Compliance
    1
    -
         Consent withdrawn by subject
    -
    1
         Patient's Decision
    4
    2
         Adverse event, non-fatal
    3
    -
    Period 2
    Period 2 title
    Open-label extension phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 metformin group - Extension phase
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Metformin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    - From D1 to D14, the patient received 500 mg oral tablets of metformin BID at the total daily dose of 1,000 mg/d for 14 days - From D15 to D28, the patient received 2 oral tablets of 500 mg BID of metformin at the total daily dose of 2,000 mg/d for 14 days - From D29 to the end of the study period, the patient received 2 oral tablets of 500 mg TID of metformin at the total daily dose of 3,000 mg/d for 48 weeks

    Number of subjects in period 2 [1]
    		metformin group - Extension phase
    Started
    20
    Completed
    13
    Not completed
    7
         Consent withdrawn by subject
    4
         Adverse event, non-fatal
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: At the end of the 52 weeks study period, all patients were proposed to enter in the open-label extension phase in which they received the active treatment according to the same dose escalation performed at study entry. 20 patients consented to participate.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    metformin group - Controlled phase
    Reporting group description
    		 All enrolled randomised patients in the controlled phase in the metformin arm who actually received at least one dose of study drug

    Reporting group title
    Placebo group
    Reporting group description
    		 All enrolled randomised patients in the controlled phase in the placebo arm who actually received at least one dose of placebo

    Reporting group values
    		 metformin group - Controlled phase Placebo group Total
    Number of subjects
    		 20 20 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 20 20 40
    Gender categorical
    Units: Subjects
        Female
    		 11 11 22
        Male
    		 8 8 16
        Not reported
    		 1 1 2
    Subject analysis sets

    Subject analysis set title
    ITT Complete D1-W52_Metformin controlled phase
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients having received metformin and completed the controlled phase of the Study (ie from D1 until Week 52 visit)

    Subject analysis set title
    ITT Complete D1-W52_Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients having received the placebo and completed the controlled phase of the Study (ie from D1 until Week 52 visit)

    Subject analysis set title
    Per protocol population N°1_Metformin controlled phase
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who did not substantially deviate from the protocol as to be determined on a per-subject basis discussed with the Investigator regarding any protocol deviation related to study inclusion or exclusion criteria, conduct of the trial, patient management, or patient assessment in the metformin arm

    Subject analysis set title
    Per protocol population N°1_Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who did not substantially deviate from the protocol as to be determined on a per-subject basis discussed with the Investigator regarding any protocol deviation related to study inclusion or exclusion criteria, conduct of the trial, patient management, or patient assessment in the placebo arm

    Subject analysis sets values
    		 ITT Complete D1-W52_Metformin controlled phase ITT Complete D1-W52_Placebo Per protocol population N°1_Metformin controlled phase Per protocol population N°1_Placebo
    Number of subjects
    12
    17
    9
    14
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    12
    17
    9
    14
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male
        Not reported
    12
    17
    9
    14

    End points

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    End points reporting groups
    Reporting group title
    metformin group - Controlled phase
    Reporting group description
    		 All enrolled randomised patients in the controlled phase in the metformin arm who actually received at least one dose of study drug

    Reporting group title
    Placebo group
    Reporting group description
    		 All enrolled randomised patients in the controlled phase in the placebo arm who actually received at least one dose of placebo
    Reporting group title
    metformin group - Extension phase
    Reporting group description
    		 -

    Subject analysis set title
    ITT Complete D1-W52_Metformin controlled phase
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients having received metformin and completed the controlled phase of the Study (ie from D1 until Week 52 visit)

    Subject analysis set title
    ITT Complete D1-W52_Placebo
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients having received the placebo and completed the controlled phase of the Study (ie from D1 until Week 52 visit)

    Subject analysis set title
    Per protocol population N°1_Metformin controlled phase
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who did not substantially deviate from the protocol as to be determined on a per-subject basis discussed with the Investigator regarding any protocol deviation related to study inclusion or exclusion criteria, conduct of the trial, patient management, or patient assessment in the metformin arm

    Subject analysis set title
    Per protocol population N°1_Placebo
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects who did not substantially deviate from the protocol as to be determined on a per-subject basis discussed with the Investigator regarding any protocol deviation related to study inclusion or exclusion criteria, conduct of the trial, patient management, or patient assessment in the placebo arm

    Primary: Ambulation measured by the 6 Minute Walk Test (6MWT): absolute changes from baseline

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    End point title
    		 Ambulation measured by the 6 Minute Walk Test (6MWT): absolute changes from baseline
    End point description
    At week 52, absolute change from baseline in distance walked at the 6MWT: Delta W52 - W0
    End point type
    Primary
    End point timeframe
    52 weeks (change from baseline)
    End point values
    		 metformin group - Controlled phase metformin group - Extension phase Placebo group ITT Complete D1-W52_Metformin controlled phase ITT Complete D1-W52_Placebo Per protocol population N°1_Metformin controlled phase Per protocol population N°1_Placebo
    Number of subjects analysed
    12
    17
    17
    12
    17
    9
    14
    Units: meters
        arithmetic mean (standard deviation)
    14.6 ± 47.6
    -13.0 ± 25.7
    3.1 ± 32.0
    14.6 ± 47.6
    3.1 ± 32.0
    32.9 ± 32.8
    3.7 ± 32.4
    Statistical analysis title
    		 Primary analysis ITT population
    Statistical analysis description
    6MWT: absolute changes from baseline
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [1]
    Method
    		 t-test, 2-sided
    Confidence interval
         level
    		 95%
    Notes
    [1] - No statistically significant differences were detected (p=0.441)
    Statistical analysis title
    		 Primary analysis PP1 population
    Comparison groups
    Per protocol population N°1_Placebo v Per protocol population N°1_Metformin controlled phase
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [2]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [2] - Statistically significant differences were detected (p=0.048)

    Secondary: Ambulation measured by the 6 Minute Walk Test (6MWT): relative changes from baseline

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    End point title
    		 Ambulation measured by the 6 Minute Walk Test (6MWT): relative changes from baseline
    End point description
    Relative change from baseline in 6MWT at week 52 (% Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase metformin group - Extension phase Placebo group Per protocol population N°1_Metformin controlled phase Per protocol population N°1_Placebo
    Number of subjects analysed
    12
    17
    17
    9
    14
    Units: meters
        arithmetic mean (standard deviation)
    3.6 ± 9.2
    -3.0 ± 5.3
    0.9 ± 8.1
    7.1 ± 6.9
    0.9 ± 8.3
    Statistical analysis title
    		 6MWT: relative change from baseline_ITT population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [3]
    Method
    		 t-test, 2-sided
    Confidence interval
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - No statistically significant differences were detected (p=0.419)
    Statistical analysis title
    		 6MWT: relative change from baseline_PP1 population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [4]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [4] - No statistically significant differences were detected (p=0.07)

    Secondary: Myotone at W52: grip strength_changes from baseline

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    End point title
    		 Myotone at W52: grip strength_changes from baseline
    End point description
    MIE Handgrip: changes from baseline (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: mm
        arithmetic mean (standard deviation)
    0.0 ± 0.0
    0.0 ± 0.0
    No statistical analyses for this end point

    Secondary: Handgrip Relaxation Time (RT) 90

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    End point title
    		 Handgrip Relaxation Time (RT) 90
    End point description
    Myotonia RT 90 (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    11
    18
    Units: ms
        median (inter-quartile range (Q1-Q3))
    -11.2 (-31.3 to 121.5)
    5.40 (-28.6 to 48.1)
    Statistical analysis title
    		 Myotonia RT 90 change from baseline_ITT population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [5]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [5] - No statistically significant differences were detected (p=0.637)

    Secondary: Handgrip Relaxation Time (RT) 10

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    End point title
    		 Handgrip Relaxation Time (RT) 10
    End point description
    Myotonia RT10 (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    11
    18
    Units: ms
        median (inter-quartile range (Q1-Q3))
    2.1 (-25.2 to 70.3)
    28.5 (2.5 to 74.9)
    Statistical analysis title
    		 Myotonia RT 10 change from baseline_ITT population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [6]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [6] - No statistically significant differences were detected (p=0.337)

    Secondary: HandHeld Test_fingers extension

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    End point title
    		 HandHeld Test_fingers extension
    End point description
    Extension of fingers: changes from baseline (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: N.m
        median (inter-quartile range (Q1-Q3))
    0.1 (-0.32 to 0.42)
    -0.1 (-0.32 to 0.06)
    Statistical analysis title
    		 Fingers extension (W52-W0)_ITT population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [7]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [7] - No statistically significant differences were detected (p=0.969)

    Secondary: HandHeld Test_knee extension

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    End point title
    		 HandHeld Test_knee extension
    End point description
    Extension of knee: changes from baseline (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: N.m
        median (inter-quartile range (Q1-Q3))
    2.9 (-31.2 to 8.5)
    -5.0 (-15.5 to 1.0)
    Statistical analysis title
    		 Knee extension (W52-W0)_ITT population
    Comparison groups
    Placebo group v metformin group - Controlled phase
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [8]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [8] - No statistically significant differences were detected (p=0.382)

    Secondary: HandHeld Test_elbow flexion

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    End point title
    		 HandHeld Test_elbow flexion
    End point description
    Flexion of elbow: changes from baseline (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (changes from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: N.m
        median (inter-quartile range (Q1-Q3))
    -0.8 (-20.9 to 1.6)
    -0.7 (-6.3 to 3.1)
    Statistical analysis title
    		 Elbow flexion (W52-W0)_ITT population
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [9]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [9] - No statistically significant differences were detected (p=0.266)

    Secondary: Proportion of patients with an improvement ≥5% of the muscle strength for fingers extension

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    End point title
    		 Proportion of patients with an improvement ≥5% of the muscle strength for fingers extension
    End point description
    % of patients with an improvement ≥5% of the muscle strength for fingers extension (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: Percentage
    50
    16
    No statistical analyses for this end point

    Secondary: Muscle MRI right side for VL

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    End point title
    		 Muscle MRI right side for VL
    End point description
    Muscle MRI of Vastus Lateralis (right side): Delta W52-W0
    End point type
    Secondary
    End point timeframe
    W52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    6
    13
    Units: muscle fat fraction
        arithmetic mean (standard deviation)
    -2.0 ± 5.0
    -4.0 ± 23.5
    Statistical analysis title
    		 MRI right side (VL) (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [10]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [10] - No statistically significant differences were detected (p=0.846)

    Secondary: Muscle MRI right side for VM

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    End point title
    		 Muscle MRI right side for VM
    End point description
    Change from baseline in MRI assessment for Vastus Medialis (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    6
    12
    Units: muscle fat fraction
        arithmetic mean (standard deviation)
    -1.5 ± 3.6
    -8.3 ± 16.9
    Statistical analysis title
    		 MRI right side (VM)(Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [11]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [11] - No statistically significant differences were detected (p=0.352)

    Secondary: Muscle MRI right side for Soleus

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    End point title
    		 Muscle MRI right side for Soleus
    End point description
    Change from baseline in MRI assessment for Soleus (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (Change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    6
    11
    Units: Muscle Fat Fraction
        arithmetic mean (standard deviation)
    -2.1 ± 5.1
    -20.8 ± 28.1
    Statistical analysis title
    		 MRI right side (Soleus) (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [12]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [12] - No statistically significant differences were detected (p=0.131)

    Secondary: Muscle MRI right side for Tibialis Ant

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    End point title
    		 Muscle MRI right side for Tibialis Ant
    End point description
    Change from baseline in MRI assessment for Tibialis Ant (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (Change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    6
    11
    Units: Muscle Fat Fraction
        arithmetic mean (standard deviation)
    -1.45 ± 3.53
    -8.59 ± 15.50
    Statistical analysis title
    		 MRI right side (Tibialis Ant) (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [13]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [13] - No statistically significant differences were detected (p=0.29)

    Secondary: Muscle MRI right side for Lateral GM

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    End point title
    		 Muscle MRI right side for Lateral GM
    End point description
    Change from baseline in MRI assessment for Lateral Gluteus Medius
    End point type
    Secondary
    End point timeframe
    W52 (Change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    6
    11
    Units: Muscle Fat Fraction
        arithmetic mean (standard deviation)
    -1.3 ± 3.3
    -14.5 ± 24.3
    Statistical analysis title
    		 MRI right side (Lateral GM)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [14]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [14] - No statistically significant differences were detected (p=0.215)

    Secondary: DM1 assessments (original version)

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    End point title
    		 DM1 assessments (original version)
    End point description
    Dystrophy type 1 activity and social participation scale (DM1 scale) - original version (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    7
    8
    Units: Score
        arithmetic mean (standard deviation)
    0.8 ± 10.1
    6.8 ± 10.9
    Statistical analysis title
    		 DM1 original version (delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    15
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [15]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [15] - No statistically significant differences were detected (p=0.297)

    Secondary: DM1 scale - Active C version

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    End point title
    		 DM1 scale - Active C version
    End point description
    Dystrophy type 1 activity and social participation scale (DM1 scale) - Active C version (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    8
    11
    Units: score
        arithmetic mean (standard deviation)
    2.2 ± 3.2
    2.5 ± 5.7
    Statistical analysis title
    		 DM1 Active C version(Delta W52-W0)
    Comparison groups
    Placebo group v metformin group - Controlled phase
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [16]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [16] - No statistically significant differences were detected (p=0.906)

    Secondary: INQoL scores per dimension (Delta W52-W0)_(20 subjects)

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    End point title
    		 INQoL scores per dimension (Delta W52-W0)_(20 subjects)
    End point description
    INQoL scores per dimension (Delta W52-W0)_20 subjects : 9 in the metformin group and 11 in the placebo group
    End point type
    Secondary
    End point timeframe
    W52 (changes from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    9
    11
    Units: Score
    median (inter-quartile range (Q1-Q3))
        weakness
    5.3 (-5.3 to 26.3)
    5.3 (-21.1 to 10.5)
        pain
    0.0 (-10.5 to 0.0)
    0.0 (-15.8 to 5.3)
        activities
    0.0 (-3.7 to 8.3)
    -5.6 (-11.1 to 15.7)
        independence
    2.8 (0.0 to 11.1)
    -2.8 (-19.4 to 12.5)
        social relationships
    1.9 (0.0 to 12.0)
    -8.3 (-20.4 to 1.9)
        body image
    2.78 (0.0 to 16.7)
    -2.8 (-13.9 to 13.9)
        perceived treatment effects
    -25.0 (-41.7 to 0.0)
    0.0 (-16.7 to 25.0)
        expected treatment effects
    -16.7 (-25.0 to 0.0)
    16.7 (-16.7 to 25.0)
    Statistical analysis title
    		 INQoL questionnaire_Weakness (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 > 0.05
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [17] - No statistically significant differences were detected (p=0.175)
    Statistical analysis title
    		 INQoL questionnaire_Pain (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [18]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [18] - No statistically significant differences were detected (p=0.698)
    Statistical analysis title
    		 INQoL questionnaire_Activities (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [19]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [19] - No statistically significant differences were detected (p=0.333)
    Statistical analysis title
    		 INQoL questionnaire_Independence (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [20]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [20] - No statistically significant differences were detected (p=0.124)
    Statistical analysis title
    		 INQoL questionnaire_Social Relation (Delta W52-W0)
    Statistical analysis description
    INQoL: Social Relationships
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [21]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [21] - No statistically significant differences were detected (p=0.13)
    Statistical analysis title
    		 INQoL questionnaire_Body image (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [22]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [22] - No statistically significant differences were detected (p=0.393)
    Statistical analysis title
    		 INQoL questionnaire_Perceived treat (Delta W52-W0)
    Statistical analysis description
    INQoL: Perceived treatment effects
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [23]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [23] - Statistically significant differences were detected (p=0.034)
    Statistical analysis title
    		 INQoL questionnaire_Expected treat. (Delta W52-W0)
    Statistical analysis description
    INQoL questionnaire: Expected treatment effects
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [24]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [24] - Statistically significant differences were detected (p=0.043)

    Secondary: INQoL scores per dimension (Delta W52-W0)_(19 subjects)

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    End point title
    		 INQoL scores per dimension (Delta W52-W0)_(19 subjects)
    End point description
    INQoL scores per dimension (Delta W52-W0)_19 subjects : 8 in the metformin group and 11 in the placebo group
    End point type
    Secondary
    End point timeframe
    W52 (Change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    8
    11
    Units: score
    median (inter-quartile range (Q1-Q3))
        fatigue
    0.0 (-2.6 to 13.2)
    0.0 (-21.1 to 15.8)
        emotions
    2.31 (0.0 to 7.4)
    -13.9 (-26.9 to 1.9)
        NMD related QoL
    1.9 (0.3 to 4.2)
    -0.6 (-5.6 to 1.7)
    Statistical analysis title
    		 INQoL scores_Fatigue (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [25]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [25] - No statistically significant differences were detected (p=0.462)
    Statistical analysis title
    		 INQoL scores_Emotions (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [26]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [26] - No statistically significant differences were detected (p=0.112)
    Statistical analysis title
    		 INQoL scores_NMD-related QoL (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [27]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [27] - No statistically significant differences were detected (p=0.06)

    Secondary: INQoL scores per dimension (Delta W52-W0)_(18 subjects)

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    End point title
    		 INQoL scores per dimension (Delta W52-W0)_(18 subjects)
    End point description
    INQoL scores per dimension (Delta W52-W0)_19 subjects : 8 in the metformin group and 10 in the placebo group
    End point type
    Secondary
    End point timeframe
    W52 (change from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    8
    10
    Units: score
    median (inter-quartile range (Q1-Q3))
        Muscle lock
    2.6 (-2.6 to 10.5)
    -2.6 (-15.8 to 5.3)
    Statistical analysis title
    		 INQoL scores-muscle lock
    Statistical analysis description
    INQoL scores for muscle lock (Delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [28]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [28] - No statistically significant differences were detected (p=0.539)

    Secondary: ECG_results at W52

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    End point title
    		 ECG_results at W52
    End point description
    Cardiac 12-lead resting ECG: results at Week 52
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: Percentage
    number (not applicable)
        Normal
    66.7
    83.3
        Abnormal, not clinically significant
    33.3
    16.7
    Statistical analysis title
    		 ECG_results at Week 52
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [29]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [29] - No statistically significant differences were detected (p=0.29)

    Secondary: Biomarker evaluation_FAS exon 6

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    End point title
    		 Biomarker evaluation_FAS exon 6
    End point description
    Absolute changes from baseline in evaluation of biomarker FAS exon 6 (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: not applicable
    arithmetic mean (standard deviation)
        Standardization on a common calibrator
    0.01 ± 0.15
    0.04 ± 0.16
        Standardization on D1
    0.01 ± 0.12
    0.03 ± 0.13
    Statistical analysis title
    		 FAS exon 6_standardization on a common calibrator
    Statistical analysis description
    Absolute change from baseline (delta W52-W0)
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [30]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [30] - No statistically significant differences were detected (p=0.615)
    Statistical analysis title
    		 FAS exon 6_standardization on D1
    Statistical analysis description
    Delta W52-W0
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [31]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [31] - No statistically significant differences were detected (p=0.677)

    Secondary: Biomarker evaluation_LaminA/LaminC

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    End point title
    		 Biomarker evaluation_LaminA/LaminC
    End point description
    Absolute changes from baseline in evaluation of biomarker LaminA/LaminC (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    Week 52 (changes from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: not applicable
    arithmetic mean (standard deviation)
        Standardization on a common calibrator
    0.06 ± 0.49
    -0.22 ± 0.48
        Standardization on D1
    0.07 ± 0.22
    -0.05 ± 0.31
    Statistical analysis title
    		 LaminA/LaminC_Standardization on a common calibr.
    Comparison groups
    Placebo group v metformin group - Controlled phase
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [32]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [32] - no statistically significant differences were detected (p=0.126)
    Statistical analysis title
    		 LaminA/LaminC_Standardization on D1
    Statistical analysis description
    Delta W52-W0
    Comparison groups
    Placebo group v metformin group - Controlled phase
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [33]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [33] - No statistically significant differences were detected (p=0.238)

    Secondary: Biomarker evaluation_INSR exon 11 (irba)

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    End point title
    		 Biomarker evaluation_INSR exon 11 (irba)
    End point description
    Absolute changes from baseline in evaluation of biomarker INSR exon 11 (irba) (Delta W52-W0)
    End point type
    Secondary
    End point timeframe
    W52 (changes from baseline)
    End point values
    		 metformin group - Controlled phase Placebo group
    Number of subjects analysed
    12
    18
    Units: not applicable
    arithmetic mean (standard deviation)
        Standardization on a common calibrator
    -0.05 ± 0.06
    -0.03 ± 0.06
        Standardization on D1
    -0.08 ± 0.08
    -0.04 ± 0.08
    Statistical analysis title
    		 INSR exon 11_Standardization on a common calibrat.
    Statistical analysis description
    Delta W52-W0
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [34]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [34] - No statistically significant differences were detected (p=0.299)
    Statistical analysis title
    		 INSR exon 11_Standardization on D1
    Statistical analysis description
    Delta W52-W0
    Comparison groups
    metformin group - Controlled phase v Placebo group
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05 [35]
    Method
    		 t-test, 2-sided
    Confidence interval
    Notes
    [35] - No statistically significant differences were detected (p=0.263)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 18 February 2014 to 17 November 2017
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Metformin group, Safety population
    Reporting group description
    		 -

    Reporting group title
    Placebo group, Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Metformin group, Safety population Placebo group, Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (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: 0%
    Non-serious adverse events
    		 Metformin group, Safety population Placebo group, Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 20 (100.00%)
    18 / 18 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    2 / 20 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Lymphoedema
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 20 (40.00%)
    3 / 18 (16.67%)
         occurrences all number
    12
    3
    Chest pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Social circumstances
    Menopause
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Breast discharge
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Ejaculation disorder
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Ovarian cyst
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Ovarian prolapse
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Uterine prolapse
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Depression
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Libido decreased
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    5 / 20 (25.00%)
    0 / 18 (0.00%)
         occurrences all number
    10
    0
    Lipase increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Weight increased
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    3 / 20 (15.00%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    Fall
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Joint injury
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    3
    Head injury
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Spinal column injury
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Thermal burn
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Dysgeusia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    2
    3
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    2
    Dry eye
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    15 / 20 (75.00%)
    5 / 18 (27.78%)
         occurrences all number
    30
    10
    Abdominal pain
         subjects affected / exposed
    10 / 20 (50.00%)
    6 / 18 (33.33%)
         occurrences all number
    18
    10
    Nausea
         subjects affected / exposed
    7 / 20 (35.00%)
    3 / 18 (16.67%)
         occurrences all number
    8
    4
    Vomiting
         subjects affected / exposed
    4 / 20 (20.00%)
    3 / 18 (16.67%)
         occurrences all number
    4
    3
    Constipation
         subjects affected / exposed
    3 / 20 (15.00%)
    3 / 18 (16.67%)
         occurrences all number
    3
    3
    Dyspepsia
         subjects affected / exposed
    4 / 20 (20.00%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Dry mouth
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Dysphagia
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dermal cyst
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psoriasis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Arthralgia
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Neck pain
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    1 / 20 (5.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Bursitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 20 (10.00%)
    8 / 18 (44.44%)
         occurrences all number
    4
    12
    Pharyngitis
         subjects affected / exposed
    2 / 20 (10.00%)
    5 / 18 (27.78%)
         occurrences all number
    2
    6
    Nasopharyngitis
         subjects affected / exposed
    4 / 20 (20.00%)
    2 / 18 (11.11%)
         occurrences all number
    4
    3
    Gastroenteritis
         subjects affected / exposed
    2 / 20 (10.00%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Ear infection
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    3
    Influenza
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Rhinitis
         subjects affected / exposed
    1 / 20 (5.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Laryngitis
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    4
    Eye infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Sinusitis
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    2 / 20 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2014
    - Modification of inclusion and exclusion criteria - Modification of the blood sampling plan and volume - A urine pregnancy test was added to guarantee the safety of women who participated in the study - A fatigue evaluation scale was added at D1, W16, W28, W52 and end of visit to determine the impact of the 6-minute test on the state of fatigue of the patients - A time window for visits (from 1 to 7 days) was added to guarantee the comfort of the patients
    17 Oct 2014
    - To introduce editorials changes and modify the name and contact details of the Clinical Project Manager - To extend the study period to Q2 2016 instead of Q3 2015 - To amend the study design with an additional paragraph: “After the enrolment of the first 5 patients of each arm, a blinded assessment of the tolerance will be performed in order to check the patients’ compliance to the study treatment and take appropriate measures if required Additional blinded safety reviews may occur on a regular basis during the course of the study for the same purpose” - To add complementary information for the end of study visit as follows: “In addition any patient having successfully completed the dose escalation phase and reached the 3000 mg/day dose of treatment will be assessed at week 52 in case of withdrawal from the study for 6 MWT with Locometrix and Fatigue Visual Analogue Scale” - To amend the evaluation period of the study flow chart with an additional W8 visit, with AEs reporting, and a review of concomitant medications/treatments.
    12 Jun 2015
    - To add an open-label extension phase for patients who had completed their 52-week follow-up in the randomised phase of the study in order to not deprive these patients of potentially effective treatment. In order to take part to the open-label extension phase, the patients must have completed the 52 weeks study period, given their written informed consent for the open label extension study and a positive benefit/risk assessment according to the investigator’s opinion.
    18 Feb 2016
    - To introduce a list of biomarkers relevant to the assessment of the efficiency of a drug tested in the a clinical trial for DM1 - To add information regarding the end-of-study visit of the open extension phase. In addition, a biological analysis including the clearance of creatinine was added at the end of the participation of patients in the open extension phase to check the renal function of patients and ensure their good tolerance to metformin - To provide clarifications on the analysis and reporting issues for the randomised and open label phases of the study
    04 Aug 2016
    - Modification and clarification of exclusion criteria
    21 Nov 2016
    - To extend the open‐label extension phase of the MYOMET study for a period of 1 year until December 2017 in order to collect long term exposure data for an additional year

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

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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30169600
    http://www.ncbi.nlm.nih.gov/pubmed/26528939
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