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    Clinical Trial Results:
    The effect of lacosamide in peripheral neuropathic pain: a randomized, double-blind, placebo-controlled, phenotype-stratified study

    Summary
    EudraCT number
    		 2018-003110-40
    Trial protocol
    		 DK  
    Global end of trial date
    03 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jul 2023
    First version publication date
    18 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LACOSAMIDE-2018
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03777956
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University
    Sponsor organisation address
    Palle Juul-Jensens Boulevard, Aarhus N, Denmark, 8200
    Public contact
    Danish Pain Research Center, Aarhus University, 45 93508575, finnerup@clin.au.dk
    Scientific contact
    Danish Pain Research Center, Aarhus University, 45 78464230, finnerup@clin.au.dk
    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
    01 Dec 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the change in pain intensity during treatment with a sodium-channel blocker (lacosamide) in patients with peripheral neuropathic pain with and without the irritable nociceptor phenotype
    Protection of trial subjects
    Written informed consent was obtained from patient. The information interview was conducted in an office without disturbances and interruptions, and there was enough time to give information and discuss possible questions. After the interview, the patients were given the possibility of at least 24 hours to decide whether they wanted to participate in the project or not before they signed the informed consent form. The patients were informed that their participation is voluntary, and that they can withdraw from the project at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Feb 2019
    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
    Denmark: 63
    Worldwide total number of subjects
    63
    EEA total number of subjects
    63
    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)
    43
    From 65 to 84 years
    19
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was performed from February 2019 to July 2022 at 2 centers in Denmark. The study was terminated prematurely due to COVID-19 lockdowns and recruitment problems.

    Pre-assignment
    Screening details
    		 We screened 422 patients and based on a clinical evaluation of in- and exclusioncriteria, 93 patients were included and randomized.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lacosamide
    Arm description
    		 Lacosamide 50 mg tablets, starting at 2 x 50 mg and increased by 50 mg each week until optimal symptom relief (with minimum acceptable level of side effects), not lower than 2 x 100 mg or to maximal dose 2 x 200 mg (400 mg daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lacosamide
    Investigational medicinal product code
    PR1
    Other name
    Vimpat, N03AX18
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lacosamide treatment BID. Gradually increasing dose starting at 2 x 50 mg daily up to a maximum tolerated dose between 200-400 mg daily and then kept in a stable dose for 6 weeks, with a total treatment period of 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 Inert placebo, matched to lacosamide. Orally BID for up to 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    PR1
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to investigational product, administered BID orally for 12 weeks.

    Number of subjects in period 1
    		Lacosamide Placebo
    Started
    41
    22
    Completed
    35
    14
    Not completed
    6
    8
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    2
    3
         Lack of efficacy
    3
    1
         Protocol deviation
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    		 Lacosamide 50 mg tablets, starting at 2 x 50 mg and increased by 50 mg each week until optimal symptom relief (with minimum acceptable level of side effects), not lower than 2 x 100 mg or to maximal dose 2 x 200 mg (400 mg daily)

    Reporting group title
    Placebo
    Reporting group description
    		 Inert placebo, matched to lacosamide. Orally BID for up to 12 weeks

    Reporting group values
    		 Lacosamide Placebo Total
    Number of subjects
    		 41 22 63
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 30 13 43
        From 65-84 years
    		 11 8 19
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.9 ± 15.7 59.8 ± 12.8 -
    Gender categorical
    Units: Subjects
        Female
    		 23 6 29
        Male
    		 18 16 34

    End points

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    End points reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    		 Lacosamide 50 mg tablets, starting at 2 x 50 mg and increased by 50 mg each week until optimal symptom relief (with minimum acceptable level of side effects), not lower than 2 x 100 mg or to maximal dose 2 x 200 mg (400 mg daily)

    Reporting group title
    Placebo
    Reporting group description
    		 Inert placebo, matched to lacosamide. Orally BID for up to 12 weeks

    Primary: Change from baseline to end of week 12 in weekly average neuropathic pain intensity

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    End point title
    		 Change from baseline to end of week 12 in weekly average neuropathic pain intensity
    End point description
    The patients rated their average neuropathic pain intensity over the past 24 hours using the numerical rating scale (NRS 0-10). A negative change from baseline indicates an improvement. The primary analysis is based on the intent-to-treat (ITT) population which includes all randomised subjects who took at least one dose of randomised study treatment.
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 Lacosamide Placebo
    Number of subjects analysed
    41
    22
    Units: NRS (0-10)
        arithmetic mean (standard deviation)
    -1.3 ± 2.1
    0.6 ± 1.2
    Statistical analysis title
    		 Lacosamide vs placebo
    Comparison groups
    Lacosamide v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.7
         upper limit
    		 0.3

    Secondary: Pain relief

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    End point title
    		 Pain relief
    End point description
    End point type
    Secondary
    End point timeframe
    Last week of treatment (week 12)
    End point values
    		 Lacosamide Placebo
    Number of subjects analysed
    41
    22
    Units: Number
        Complete
    2
    0
        Good
    8
    1
        Moderate
    1
    5
        Mild
    3
    1
        None
    19
    13
        Worse
    7
    1
    Statistical analysis title
    		 Lacosamide vs placebo
    Comparison groups
    Lacosamide v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.91
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Use of escape medication (tablets paracetamol 500 mg)

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    End point title
    		 Use of escape medication (tablets paracetamol 500 mg)
    End point description
    Change in average weekly number of paracetamol tablets from baseline
    End point type
    Secondary
    End point timeframe
    During the 12 week treatment
    End point values
    		 Lacosamide Placebo
    Number of subjects analysed
    41
    22
    Units: Tablets
        arithmetic mean (standard deviation)
    -1.0 ± 7.5
    -0.6 ± 7.7
    Statistical analysis title
    		 Lacosamide vs placebo
    Comparison groups
    Lacosamide v Placebo
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.5
         upper limit
    		 3.8

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Week 1-12 of treatment periods
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    		 Lacosamide 50 mg tablets, starting at 2 x 50 mg and increased by 50 mg each week until optimal symptom relief (with minimum acceptable level of side effects), not lower than 2 x 100 mg or to maximal dose 2 x 200 mg (400 mg daily)

    Reporting group title
    Placebo
    Reporting group description
    		 Inert placebo

    Serious adverse events
    		 Lacosamide Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 41 (2.44%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Lacosamide Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 41 (73.17%)
    14 / 22 (63.64%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 41 (26.83%)
    1 / 22 (4.55%)
         occurrences all number
    11
    1
    Tiredness
         subjects affected / exposed
    6 / 41 (14.63%)
    4 / 22 (18.18%)
         occurrences all number
    6
    4
    Headache
         subjects affected / exposed
    4 / 41 (9.76%)
    1 / 22 (4.55%)
         occurrences all number
    4
    1
    Tremor
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    Cognitive impairment
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Gastrointestinal disturbance
         subjects affected / exposed
    3 / 41 (7.32%)
    2 / 22 (9.09%)
         occurrences all number
    3
    2
    Nausea
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Mucous membrane disorder
         subjects affected / exposed
    0 / 41 (0.00%)
    3 / 22 (13.64%)
         occurrences all number
    0
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    itch
         subjects affected / exposed
    3 / 41 (7.32%)
    0 / 22 (0.00%)
         occurrences all number
    3
    0
    perspiration excessive
         subjects affected / exposed
    2 / 41 (4.88%)
    1 / 22 (4.55%)
         occurrences all number
    2
    1
    Psychiatric disorders
    Mood change
         subjects affected / exposed
    2 / 41 (4.88%)
    4 / 22 (18.18%)
         occurrences all number
    2
    4
    sleep disturbance
         subjects affected / exposed
    1 / 41 (2.44%)
    1 / 22 (4.55%)
         occurrences all number
    1
    1
    Renal and urinary disorders
    Involuntary urination
         subjects affected / exposed
    2 / 41 (4.88%)
    0 / 22 (0.00%)
         occurrences all number
    2
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 41 (0.00%)
    2 / 22 (9.09%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    swollen joints
         subjects affected / exposed
    3 / 41 (7.32%)
    1 / 22 (4.55%)
         occurrences all number
    3
    1
    Restless legs syndrome
         subjects affected / exposed
    2 / 41 (4.88%)
    2 / 22 (9.09%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Weight gain
         subjects affected / exposed
    4 / 41 (9.76%)
    0 / 22 (0.00%)
         occurrences all number
    4
    0

    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.
    The study was terminated prematurely due to COVID-19 lockdowns and recruitment problems. The results presented here are for lacosamide vs placebo. For the primary objective, there was no statistically significant differences between IN and NIN grps
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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