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    Clinical Trial Results:
    A phase 2a study to explore treatment with Sodium Valproate in adults with McArdle Disease (Glycogen Storage Disorder Type V, GSDV)

    Summary
    EudraCT number
    		 2014-001637-88
    Trial protocol
    		 DK  
    Global end of trial date
    10 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Mar 2021
    First version publication date
    26 Mar 2021
    Other versions
    Summary report(s)
    		 Journal article
    Results file

    Trial information

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    Trial identification
    Sponsor protocol code
    2014-650
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03112889
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    John Vissing
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Neuromuscular research unit, Neuromuscular research unit, Rigshospitalet, 0045 35456135,
    Scientific contact
    Neuromuscular research unit, Neuromuscular research unit, Rigshospitalet, 0045 35456135,
    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
    10 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Investigate whether sodium valproate can improve muscle functioning in subjects with McArdle Disease (Glycogen storage disease type V)
    Protection of trial subjects
    Measures to protect patients included avoidance of pre-treatment muscle biopsy if the patient had previously had one performed. Regular trial monitoring was done on the part of the sponsor. Rapid notification of SAE. All subjects were given emergency contact details of the CI and investigators and regular telephone contact with the subjects was maintained during the trial between study visits.
    Background therapy
    		 No specific background therapy apart from study-drug
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 8
    Worldwide total number of subjects
    8
    EEA total number of subjects
    8
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    6
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 10 subjects were contacted to take part in this clinical trial. All patients were attending a highly specialized service for neuromuscular disorders including McArdle disease at Rigshospitalet, Copenhagen, Denmark. Recruitment started in October 2015 and last subject was recruited in June 2016.

    Pre-assignment
    Screening details
    		 8 patients were screened, 0 were not eligible. 6 subjects completed the study, 4 male and 2 females. Mean age of included subjects was 45 years (range 21-66, SD 18).

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    Not applicable (open-label study)

    Arms
    Arm title
    		 Overall study arm
    Arm description
    		 Open-label study of one study arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sodium Valproate
    Investigational medicinal product code
    VPA
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Modified release VPA was prescribed at a treatment dose of 20 mg/kg/day. The dose was rounded up or down to the nearest value dependent on weight. VPA dose was titrated over 4 weeks from a starting dose of 5 ml/kg/day to the treatment dose of 20mg/kg/day in order to minimise side effects. At the end of the study VPA was titrated down over 4 weeks.

    Number of subjects in period 1
    		Overall study arm
    Started
    8
    Completed
    6
    Not completed
    2
         Adverse event, non-fatal
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall period
    Reporting group description
    		 -

    Reporting group values
    		 Overall period Total
    Number of subjects
    		 8 8
    Age categorical
    All patients included in this open-label study
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 6 6
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45 ( 18 ) -
    Gender categorical
    All patients included in this open-label study
    Units: Subjects
        Female
    		 2 2
        Male
    		 6 6

    End points

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    End points reporting groups
    Reporting group title
    Overall study arm
    Reporting group description
    		 Open-label study of one study arm.

    Primary: Peak oxygen uptake (VO2peak)

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    End point title
    		 Peak oxygen uptake (VO2peak) [1]
    End point description
    Subjects performed exercise on a bike ergometer. Oxygen consumption was assessed by a face mask attached to a cardiopulmonary exercise training gas exchange analyser (Cosmed, Milan, Italy). An incremental exercise test was performed during the screening visit (20 watts baseline workload, with 5W increments every 2 minutes) to determine peak oxygen uptake (VO2peak). Heart rate was monitored during exercise by using a 3-lead cardiac monitor and rating of perceived exertion (RPE) were recorded every minute. Maximal workload was the highest attained workload at end of exercise (if held for at least 60 seconds).
    End point type
    Primary
    End point timeframe
    Change from baseline to post 28 weeks treatment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses for this end-point. Trial is a descriptive open-label feasibility trial. The aim of the trial is to provide information on whether a larger-scale trial is possible and if so data from this trial will be used to estimate parameters for making a well-informed power-calculation in a future randomized clinical trial.
    End point values
    		 Overall study arm
    Number of subjects analysed
    6
    Units: Millilitres of oxygen per minute
        arithmetic mean (standard deviation)
    0 ( 3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE documented at week 16 and 28. SAE reported within 24 hours.
    Adverse event reporting additional description
    AE were assessed as either not IMP-related, possibly IMP-related or probably IMP-related
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 All included patients, since this was an open label trial.

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    Nervous system disorders
    Tremor
    Additional description: Tremor of hands
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Cognitive disorder
    Additional description: Problems remembering
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
    Additional description: General tiredness
         subjects affected / exposed
    5 / 8 (62.50%)
         occurrences all number
    6
    Dry mouth
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Eye disorders
    Eye symptom
    Additional description: Twitching eye-muscles
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
    Additional description: Upset stomach
         subjects affected / exposed
    2 / 8 (25.00%)
         occurrences all number
    2
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Pain
    Additional description: Pain in muscles or joints
         subjects affected / exposed
    4 / 8 (50.00%)
         occurrences all number
    5
    Arthritis
    Additional description: None
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Inflammation
    Additional description: Ankle inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    fracture
    Additional description: High energy foot fracture
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Infections and infestations
    Viral infection
    Additional description: Common cold
         subjects affected / exposed
    3 / 8 (37.50%)
         occurrences all number
    3
    Gum infections
    Additional description: None
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1
    Erysipelas
         subjects affected / exposed
    1 / 8 (12.50%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    This study was a small open-label study, statistical analysis was descriptive in scope.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/32811700
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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