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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, cross-over, multi-center trial in healthy subjects to investigate the effects of lacosamide, pregabalin and tapentadol on biomarkers of pain processing observed by electro-encephalography (EEG)

    Summary
    EudraCT number
    		 2019-001204-37
    Trial protocol
    		 BE   IT  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Mar 2024
    First version publication date
    06 Mar 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IMI2-PainCare-BioPain-RCT3
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCLouvain
    Sponsor organisation address
    Place de l'Université 1, Louvain-la-Neuve, Belgium, 1348
    Public contact
    Clinical Trials Information, Institute of Neuroscience (IoNS), Université catholique de Louvain, 0032 027645447, andre.mouraux@uclouvain.be
    Scientific contact
    Clinical Trials Information, Institute of Neuroscience (IoNS), Université catholique de Louvain, 0032 027645447, andre.mouraux@uclouvain.be
    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
    30 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Apr 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1. To test if the percentage reduction of LEP amplitude 60 minutes post-drug administration differs in the tapentadol period as compared to the placebo period, at the non-sensitized forearm. 2. To test if the percentage reduction of PEP amplitude 60 minutes post-drug administration differs in the tapentadol period as compared to the placebo period, at the sensitized forearm.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the ICH Good Clinical Practice (GCP) guidelines. Local regulatory requirements were followed. Written informed consent was obtained from all subjects. The information interview was conducted in an office without disturbances and interruptions, and there was enough time to give information and discuss possible questions. The subjects 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
    07 Sep 2020
    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
    Belgium: 16
    Country: Number of subjects enrolled
    Italy: 4
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was performed from 07.09.2020 to 01.04.2022 at 4 centers in Belgium, Germany, Italy and the UK. No subjects were recruited in the UK and Germany, and the trial had to be terminated early due operational impact of the Covid-19 pandemic during the past 2 years and as the overall timelines of the project did not allow any further extension o

    Pre-assignment
    Screening details
    		 We screened 23 subjects, of which 18 were screened in Belgium, 1 in Germany and 4 in Italy. In total, 20 subjects were enrolled/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, Data analyst, Assessor
    Blinding implementation details
    Lacosamide, pregabalin, tapentadol or placebo were assigned to each subject by a double-blind randomization schedule. The investigator/trial personnel and subjects were blinded to the assignment of pregabalin, tapentadol, lacosamide and placebo (double-blind procedure).

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Lacosamide
    Arm description
    		 Lacosamide 200 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lacosamide
    Investigational medicinal product code
    Other name
    N03AX18, vimpat
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2x 100 mg lacosamide tablets, single dose

    Arm title
    		 Pregabalin
    Arm description
    		 Pregabalin 150 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    Other name
    Lyrica
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2x 75 mg pregabalin capsule , single dose

    Arm title
    		 Tapentadol
    Arm description
    		 Tapentadol 100 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    oTapentadol
    Investigational medicinal product code
    Other name
    N02AX06
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2x 50 mg tapentadol immediate release tablet, single dose

    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
    2 x hard gelatine capsules filled with mannitol and colloidal silicon dioxide (DAC - Deutscher Arzneimittel Codex). Single dose

    Number of subjects in period 1
    		Lacosamide Pregabalin Tapentadol Placebo
    Started
    20
    20
    20
    20
    Completed
    20
    20
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall study
    Reporting group description
    		 -

    Reporting group values
    		 overall study Total
    Number of subjects
    		 20 20
    Age categorical
    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)
    		 20 20
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.7 ( 4.43 ) -
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 9 9
    Subject analysis sets

    Subject analysis set title
    Full analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    subjects in the ‘all enrolled set’ that have been randomized

    Subject analysis sets values
    		 Full analysis Set
    Number of subjects
    20
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    20
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25.7 ( 4.43 )
    Gender categorical
    Units: Subjects
        Female
    11
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    Lacosamide
    Reporting group description
    		 Lacosamide 200 mg

    Reporting group title
    Pregabalin
    Reporting group description
    		 Pregabalin 150 mg

    Reporting group title
    Tapentadol
    Reporting group description
    		 Tapentadol 100 mg

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    subjects in the ‘all enrolled set’ that have been randomized

    Primary: First co-primary endpoint (LEP Tapentadol vs Placebo)

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    End point title
    		 First co-primary endpoint (LEP Tapentadol vs Placebo) [1]
    End point description
    Comparison of the tapentadol vs placebo effects on the percentage of change in amplitude of the N2-P2 complex of laser-evoked potentials (LEPs), at the non-sensitized forearm.
    End point type
    Primary
    End point timeframe
    The first measurement post dosing (around 1 hour after drug administration) relative to the pre-dose measurement (i.e. change relative to period-specific baseline).
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Different arms are present in order to validate different endpoints. So, all endpoints are not concerning all arms.
    End point values
    		 Tapentadol Placebo
    Number of subjects analysed
    20
    19
    Units: %
        arithmetic mean (standard deviation)
    -11.18 ( 29.94 )
    1.83 ( 31.81 )
    Statistical analysis title
    		 First co-primary outcome
    Statistical analysis description
    percentage of change in amplitude of the N2-P2 complex of laser-evoked potentials (LEPs) in tapentadol treatment arm vs the placebo treatment arm, at the non-sensitized forearm.
    Comparison groups
    Tapentadol v Placebo
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.025 [2]
    Method
    		 Mixed Models for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.59
         upper limit
    		 -3.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.1
    Notes
    [2] - The two co-primary endpoints are tested for their differences between the arms Tapentadol versus Placebo. This is conducted in parallel, splitting the overall α equally between the endpoint tests: each test has a Type I error of α/2 (0.05/2=0.025)

    Primary: Second co-primary endpoint (PEP Tapentadol vs Placebo)

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    End point title
    		 Second co-primary endpoint (PEP Tapentadol vs Placebo) [3]
    End point description
    Comparison of the tapentadol vs placebo effects on the percentage of change in amplitude of the N2-P2 complex of pinprick-evoked potentials (PEPs), at the sensitized forearm.
    End point type
    Primary
    End point timeframe
    The first measurement post dosing (around 1 hour after drug administration) relative to the pre-dose measurement (i.e. change relative to period-specific baseline).
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Different arms are present in order to validate different endpoints. So, all endpoints are not concerning all arms.
    End point values
    		 Tapentadol Placebo
    Number of subjects analysed
    20
    20
    Units: %
        arithmetic mean (standard deviation)
    -5.83 ( 24.15 )
    0.04 ( 45.32 )
    Statistical analysis title
    		 Second co-primary outcome
    Statistical analysis description
    percentage of change in amplitude of the N2-P2 complex of pinprick-evoked potentials (PEPs) in the tapentadol treatment arm vs the placebo treatment arm, at the sensitized forearm.
    Comparison groups
    Tapentadol v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.025 [4]
    Method
    		 Mixed Models for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.41
         upper limit
    		 10.45
    Variability estimate
    Standard error of the mean
    Dispersion value
    8.04
    Notes
    [4] - The two co-primary endpoints are tested for their differences between the arms Tapentadol versus Placebo. This is conducted in parallel, splitting the overall α equally between the endpoint tests: each test has a Type I error of α/2 (0.05/2=0.025)

    Secondary: First key secondary analysis of primary endpoints (LEP)

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    End point title
    		 First key secondary analysis of primary endpoints (LEP) [5]
    End point description
    Comparison of the mean effects of lacosamide & pregabalin vs placebo on the percentage of change in amplitude of the N2-P2 complex of laser-evoked potentials (LEPs), at the non-sensitized forearm.
    End point type
    Secondary
    End point timeframe
    The first measurement post dosing (around 1 hour after drug administration) relative to the pre-dose measurement (i.e. change relative to period-specific baseline).
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Different arms are present in order to validate different endpoints. So, all endpoints are not concerning all arms.
    End point values
    		 Lacosamide Placebo
    Number of subjects analysed
    20
    19
    Units: %
        arithmetic mean (standard deviation)
    -15.53 ( 17.02 )
    1.83 ( 31.81 )
    Statistical analysis title
    		 First key secondary analysis of primary endpoints
    Statistical analysis description
    Mean percentage of change in amplitude of the N2-P2 complex of laser-evoked potentials (LEPs) in the lacosamide & pregabalin treatment arms vs the placebo treatment arm, at the non-sensitized forearm.
    Comparison groups
    Placebo v Lacosamide
    Number of subjects included in analysis
    39
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.02 [6]
    Method
    		 Mixed Models for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.7
         upper limit
    		 1.88
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.96
    Notes
    [6] - If any of these two co-primary endpoint tests showed significant differences, key secondary analyses were pre-specified using the α-levels as detailed in Mouraux et al (2021). Trials, 22(1), 404. https://doi.org/10.1186/s13063-021-05272-y

    Secondary: Second key secondary analysis of primary endpoints (PEP)

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    End point title
    		 Second key secondary analysis of primary endpoints (PEP) [7]
    End point description
    Comparison of the mean effects of lacosamide & pregabalin vs placebo on the percentage of change in amplitude of the N2-P2 complex of pinprick-evoked potentials (PEPs), at the sensitized forearm.
    End point type
    Secondary
    End point timeframe
    The first measurement post dosing (around 1 hour after drug administration) relative to the pre-dose measurement (i.e. change relative to period-specific baseline).
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Different arms are present in order to validate different endpoints. So, all endpoints are not concerning all arms.
    End point values
    		 Lacosamide Placebo
    Number of subjects analysed
    20
    20
    Units: %
        arithmetic mean (standard deviation)
    -5.20 ( 17.21 )
    0.04 ( 45.32 )
    Statistical analysis title
    		 Second key secondary analysis of primary endpoints
    Statistical analysis description
    Mean percentage of change in amplitude of the N2-P2 complex of pinprick-evoked potentials (PEPs) in the lacosamide & pregabalin treatment arms vs the placebo treatment arm, at the sensitized forearm.
    Comparison groups
    Lacosamide v Placebo
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.004 [8]
    Method
    		 Mixed Models for repeated measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.55
         upper limit
    		 12.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    7
    Notes
    [8] - If any of these two co-primary endpoint tests showed significant differences, key secondary analyses were pre-specified using the α-levels as detailed in Mouraux et al (2021). Trials, 22(1), 404. https://doi.org/10.1186/s13063-021-05272-y

    Secondary: Secondary endpoint (EEG)

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    End point title
    		 Secondary endpoint (EEG)
    End point description
    Differences across all treatment arms (lacosamide, pregabalin, tapentadol and placebo) on the percentage of change in amplitude of theta band oscillations in the resting EEG (eyes open).
    End point type
    Secondary
    End point timeframe
    The first measurement post dosing (around 1 hour after drug administration) relative to the pre-dose measurement (i.e. change relative to period-specific baseline).
    End point values
    		 Lacosamide Pregabalin Tapentadol Placebo
    Number of subjects analysed
    20
    19
    20
    20
    Units: %
        arithmetic mean (standard deviation)
    21.69 ( 21.22 )
    6.73 ( 8.45 )
    2.55 ( 9.87 )
    6.45 ( 10.51 )
    Statistical analysis title
    		 Key secondary endpoint analysis (theta)
    Statistical analysis description
    Mean percentage of change in amplitude of theta oscillations (resting EEG eyes open) compared across all treatment arms (lacosamide, pregabalin, tapentadol and placebo).
    Comparison groups
    Lacosamide v Pregabalin v Tapentadol v Placebo
    Number of subjects included in analysis
    79
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0083 [9]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [9] - If any of these two co-primary endpoint tests showed significant differences, key secondary analyses were pre-specified using the α-levels as detailed in Mouraux et al (2021). Trials, 22(1), 404. https://doi.org/10.1186/s13063-021-05272-y

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study period 1 to 7-14 days after last study period
    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
    		 -

    Reporting group title
    Pregabaline
    Reporting group description
    		 -

    Reporting group title
    Tapentadol
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Lacosamide Pregabaline Tapentadol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Lacosamide Pregabaline Tapentadol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
    3 / 20 (15.00%)
    3 / 20 (15.00%)
    1 / 20 (5.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 20 (0.00%)
    2 / 20 (10.00%)
    1 / 20 (5.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    1
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    1 / 20 (5.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 20 (0.00%)
    0 / 20 (0.00%)
    2 / 20 (10.00%)
    0 / 20 (0.00%)
         occurrences all number
    0
    0
    2
    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.
    Intermittent interruptions due to COVID-19 lockdown and regulations
    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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