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    Clinical Trial Results:
    A randomized, double blind, double-dummy placebo controlled, 3-way cross-over study to determine the test-retest reliability of, and the effect of oral retigabine and riluzole on, peripheral motor nerve excitability measurements in patients with ALS.

    Summary
    EudraCT number
    		 2015-001431-20
    Trial protocol
    		 NL  
    Global end of trial date
    10 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Mar 2022
    First version publication date
    12 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CHDR1417
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Centre for Human Drug Research
    Sponsor organisation address
    Zernikedreef 8, Leiden, Netherlands, 2333CL
    Public contact
    Research Director, CHDR, GGroeneveld@chdr.nl
    Scientific contact
    Research Director, CHDR, GGroeneveld@chdr.nl
    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
    11 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Apr 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the test-retest reliability of nerve excitability threshold tracking in patients with ALS.
    Protection of trial subjects
    A total of 18 patients with ALS will be enrolled in the study. In order to determine test-retest reliability of the threshold tracking technique and use it as a proof-of-biology and proof-of-efficacy marker, the study has to be performed in patients with ALS. There is significant difference in parameters of excitability threshold tracking between healthy volunteers and patients with ALS. Safety will be assessed by: vital signs at each clinical visit and collection of procedure related adverse events (AEs) or serious adverse events (SAEs) throughout the study. Retigabine and riluzole are registered drugs. The safety profiles of these compounds are known. However, side effects might occur. Therefore, study drug administrations will be done in the clinic under medical supervision. Subjects will be closely monitored and will only be discharged from the unit if their medical condition allows this. As subjects will receive single doses of the two registered drugs, the risk is small and therefore acceptable compared to the (scientific) benefit.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2015
    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
    Netherlands: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    13
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Start 01JUN2015 in the Netherlands. . Subjects will be recruited via media advertisement or from the patientdatabase of the University Medical Centre Utrecht (UMCU), Utrecht, the Netherlands.

    Pre-assignment
    Screening details
    		 A total of 18 subjects who are patients with ALS will be enrolled into the study following satisfactory completion of a screening visit where eligibility for the study will be checked. Each subject must stop riluzole 24hrs before each occasion.

    Period 1
    Period 1 title
    Studyperiod (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The investigational drugs and their matching placebo will be indistinguishable and will be packaged in the same way.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Retigabine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Retigabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 300mg. Two over-encapsulated capsule of resp. 200 and 100 mg will be administered orally.

    Arm title
    		 Riluzole
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Riluzole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 100mg. Two over-encapsulated capsules of each 50 mg will be administered orally.

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of two over-encapsulated placebo capsules will be administered orally.

    Number of subjects in period 1
    		Retigabine Riluzole Placebo
    Started
    18
    18
    18
    Completed
    18
    17
    18
    Not completed
    0
    1
    0
         Adverse event, non-fatal
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Retigabine
    Reporting group description
    		 -

    Reporting group title
    Riluzole
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Retigabine Riluzole Placebo Total
    Number of subjects
    		 18 18 18 18
    Age categorical
    Units: Subjects
        Age 18-80 years
    		 18 18 18 18
    Gender categorical
    Units: Subjects
        Female
    		 1 1 1 1
        Male
    		 17 17 17 17

    End points

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    End points reporting groups
    Reporting group title
    Retigabine
    Reporting group description
    		 -

    Reporting group title
    Riluzole
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: SDTC (Stength Duration Time Constant)

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    End point title
    		 SDTC (Stength Duration Time Constant) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Pre dose till 6h post dose
    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: See attached article for endpoints and analyses.
    End point values
    		 Retigabine Riluzole Placebo
    Number of subjects analysed
    18
    18
    18
    Units: milliseconds
        arithmetic mean (standard deviation)
    0.416 ± 0.064
    0.455 ± 0.058
    0.458 ± 0.080
    Attachments
    		 Kovalchuk&Heuberger_et_al-2018-Clinical_Pharmacolo
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Retigabine
    Reporting group description
    		 -

    Reporting group title
    Riluzole
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Retigabine Riluzole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Retigabine Riluzole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 18 (61.11%)
    7 / 18 (38.89%)
    6 / 18 (33.33%)
    Injury, poisoning and procedural complications
    Excoriation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Head injury
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Limb injury
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    0
    Headache
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Somnolence
         subjects affected / exposed
    5 / 18 (27.78%)
    2 / 18 (11.11%)
    3 / 18 (16.67%)
         occurrences all number
    7
    2
    3
    General disorders and administration site conditions
    Feeling abnormal
         subjects affected / exposed
    0 / 18 (0.00%)
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Amblyopia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Eye symptom
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Nov 2015
    Addition of a measurement during the study, called the POWERjar
    17 Feb 2016
    Change of location of fasciculations in arm in inclusion criterion, as hyperexcitability of the nerves is expected if they occur in the arms in general. Change of alcohol/drug dependence and alcohol breath test exclusion criterion, as this is not expected to impact the study validity.

    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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    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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