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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study of the Efficacy and Safety of Pregabalin as Adjunctive Therapy in Children 1 Month Through <4 Years of Age With Partial Onset Seizures

    Summary
    EudraCT number
    		 2013-003420-37
    Trial protocol
    		 BE   HU   NL   ES   DE   PL   SK   GR   PT   BG  
    Global end of trial date
    13 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2018
    First version publication date
    23 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A0081042
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02072824
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Jul 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 2 dose levels of Pregabalin compared to placebo as an adjunctive treatment in reducing the frequency of POS in pediatric subjects 1 month to <4 years of age.
    Protection of trial subjects
    The study was conducted in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Subjects were on a stable dose of 1 to 3 antiepileptic drugs concomitant to double-blind study medication throughout the duration of the study.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Sep 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
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    China: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Belarus: 4
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Lebanon: 6
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Philippines: 41
    Country: Number of subjects enrolled
    Romania: 2
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    Serbia: 4
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Thailand: 2
    Country: Number of subjects enrolled
    Turkey: 4
    Country: Number of subjects enrolled
    Ukraine: 57
    Country: Number of subjects enrolled
    United States: 6
    Worldwide total number of subjects
    175
    EEA total number of subjects
    25
    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)
    65
    Children (2-11 years)
    110
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects received treatment in double-blind treatment phase (total duration: 21 days) which included dose escalation (5 days), fixed-dose (9 days) and taper (7 days).

    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, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day
    Arm description
    		 Subjects aged greater than (>) 3 months to less than (<) 4 years, received Pregabalin 3.5 milligrams per kilogram per day (mg/kg/day) (3.0 mg/kg/day for subjects 1 to 3 months of age), orally three times daily (TID) in equally divided doses for first 5 days; followed by 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    NO3AX16
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Pregabalin was administered as oral solution, TID, up to 21 days.

    Arm title
    		 Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Arm description
    		 Subjects aged >3 months to <4 years, received Pregabalin 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for first 2 days and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days; followed by 14 mg/kg/day (12 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days; and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 4 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    NO3AX16
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Pregabalin was administered as oral solution, TID, up to 21 days.

    Arm title
    		 Placebo
    Arm description
    		 Subjects aged >3 months to <4 years received placebo matched to Pregabalin, orally TID for 21 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to Pregabalin was administered as oral solution, TID, up to 21 days.

    Number of subjects in period 1
    		Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Started
    71
    34
    70
    Completed
    69
    33
    67
    Not completed
    2
    1
    3
         Medication error
    -
    1
    -
         No longer willing to participate
    1
    -
    1
         Adverse Events
    -
    -
    1
         Insufficient clinical response
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pregabalin 7 mg/kg/day or 6 mg/kg/day
    Reporting group description
    		 Subjects aged greater than (>) 3 months to less than (<) 4 years, received Pregabalin 3.5 milligrams per kilogram per day (mg/kg/day) (3.0 mg/kg/day for subjects 1 to 3 months of age), orally three times daily (TID) in equally divided doses for first 5 days; followed by 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 7 days.

    Reporting group title
    Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Reporting group description
    		 Subjects aged >3 months to <4 years, received Pregabalin 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for first 2 days and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days; followed by 14 mg/kg/day (12 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days; and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 4 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects aged >3 months to <4 years received placebo matched to Pregabalin, orally TID for 21 days.

    Reporting group values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo Total
    Number of subjects
    		 71 34 70 175
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 27 12 26 65
        Children (2-11 years)
    		 44 22 44 110
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age Continuous
    Safety population included all randomized subjects who received at least 1 dose of study drug.
    Units: months
        arithmetic mean (standard deviation)
    		 27.5 ± 12.7 28.5 ± 12.5 28.8 ± 12.6 -
    Sex: Female, Male
    Safety population included all randomized subjects who received at least 1 dose of study drug.
    Units: Subjects
        Female
    		 26 14 32 72
        Male
    		 45 20 38 103
    Race (NIH/OMB)
    Safety population included all randomized subjects who received at least 1 dose of study drug.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 23 10 19 52
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 0 0
        White
    		 47 24 49 120
        More than one race
    		 0 0 0 0
        Other
    		 1 0 2 3
    Weight
    Safety population included all randomized subjects who received at least 1 dose of study drug.
    Units: kilogram
        arithmetic mean (standard deviation)
    		 11.7 ± 3.5 11.4 ± 3.4 11.4 ± 3.1 -

    End points

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    End points reporting groups
    Reporting group title
    Pregabalin 7 mg/kg/day or 6 mg/kg/day
    Reporting group description
    		 Subjects aged greater than (>) 3 months to less than (<) 4 years, received Pregabalin 3.5 milligrams per kilogram per day (mg/kg/day) (3.0 mg/kg/day for subjects 1 to 3 months of age), orally three times daily (TID) in equally divided doses for first 5 days; followed by 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 7 days.

    Reporting group title
    Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Reporting group description
    		 Subjects aged >3 months to <4 years, received Pregabalin 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for first 2 days and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days; followed by 14 mg/kg/day (12 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days; and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 4 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects aged >3 months to <4 years received placebo matched to Pregabalin, orally TID for 21 days.

    Primary: Log Transformed 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase

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    End point title
    		 Log Transformed 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase
    End point description
    All partial onset seizures experienced during treatment phase were recorded by central reader during the 48 to 72 hour video-electroencephalogram (EEG). Double Blind 24 hour EEG seizure rate for all partial onset seizures = ([Number of seizures in double blind 48 to 72 hour EEG assessment] divided by [number of hours of video-EEG monitoring])*24. The EEG assessment was done at the end of the fixed dose treatment. For log-transformation, the quantity 1 was added to the double blind 24 hour EEG seizure rate for all subjects to account for any possible "0" seizure incidence. This resulted in final calculation as: log transformed (double-blind 24-hour EEG seizure rate + 1). Modified intent-to-treat (mITT) population included all randomized subjects who took at least one dose of study drug during the double-blind treatment phase, had a baseline with at least one partial onset seizure identified by video-EEG (at least 24 hours of evaluable monitoring) and a treatment phase video-EEG.
    End point type
    Primary
    End point timeframe
    Day 1 up to Day 14
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    59
    28
    53
    Units: seizures per 24 hours
        least squares mean (standard error)
    1.69 ± 0.115
    1.15 ± 0.163
    1.58 ± 0.129
    Statistical analysis title
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day vs. Placebo
    Statistical analysis description
    Linear model with log transformed baseline seizure rate as continuous covariate and treatment, age stratum, and geographical region as fixed factor effects.
    Comparison groups
    Pregabalin 7 mg/kg/day or 6 mg/kg/day v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4606
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.42
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.153
    Statistical analysis title
    		 Pregabalin 14 mg/kg/day or 12 mg/kg/day vs.Placebo
    Statistical analysis description
    Linear model with log transformed baseline seizure rate as continuous covariate and treatment, age stratum, and geographical region as fixed factor effects.
    Comparison groups
    Pregabalin 14 mg/kg/day or 12 mg/kg/day v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0223
    Method
    		 ANCOVA
    Parameter type
    		 Least Square Mean Difference
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 -0.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.185

    Secondary: Responder Rate: Percentage of Subjects With at Least 50 Percent (%) or Greater Reduction From Baseline in 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase

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    End point title
    		 Responder Rate: Percentage of Subjects With at Least 50 Percent (%) or Greater Reduction From Baseline in 24-Hour Seizure Rate for All Partial Onset Seizures During the Double-Blind Treatment Phase
    End point description
    Responder Rate was defined as percentage of subjects who had a 50% or greater reduction from baseline in 24-hour seizure rate during the double-blind treatment phase. Double Blind 24 hour EEG seizure rate for all partial onset seizures = ([Number of seizures in double blind 48 to 72 hour EEG assessment] divided by [number of hours of video-EEG monitoring])*24. The EEG assessment was done at the end of the fixed dose treatment. mITT population included all randomized subjects who took at least one dose of study drug during the double-blind treatment phase, had a baseline with at least one partial onset seizure identified by video-EEG (at least 24 hours of evaluable monitoring) and a treatment phase video-EEG.
    End point type
    Secondary
    End point timeframe
    Day 1 up to Day 14
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    59
    28
    53
    Units: percentage of subjects
        number (not applicable)
    30.51
    53.57
    41.51
    Statistical analysis title
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day vs.Placebo
    Statistical analysis description
    The dichotomized responder variable was analyzed using a logistic regression model via maximum likelihood estimation with treatment group, age stratum, and geographical region as a fixed effect covariates.
    Comparison groups
    Pregabalin 7 mg/kg/day or 6 mg/kg/day v Placebo
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2418
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.625
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.284
         upper limit
    		 1.373
    Statistical analysis title
    		 Pregabalin 14 mg/kg/day or 12 mg/kg/day vs.Placebo
    Statistical analysis description
    The dichotomized responder variable was analyzed using a logistic regression model via maximum likelihood estimation with treatment group, age stratum, and geographical region as a fixed effect covariates.
    Comparison groups
    Pregabalin 14 mg/kg/day or 12 mg/kg/day v Placebo
    Number of subjects included in analysis
    81
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.305
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.622
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.644
         upper limit
    		 4.086

    Other pre-specified: Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events which occurred between first dose of study drug and up to end of study (up to Day 25) that were absent before treatment or that worsened relative to pre-treatment state. AEs included both serious and non-serious adverse events. Safety population included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 up to End of study (EOS) (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: subjects
        AEs
    32
    17
    38
        SAEs
    0
    1
    4
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-Related Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    Treatment-related AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent AEs were events which occurred between first dose of study drug and up to end of study (up to Day 25) that were absent before treatment or that worsened relative to pre-treatment state. Relatedness to drug was assessed by the investigator. AEs included both serious and non-serious adverse events. Safety population included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 up to EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: subjects
        AEs
    15
    8
    13
        SAEs
    0
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Number of Adverse Events by Severity

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    End point title
    		 Number of Adverse Events by Severity
    End point description
    An AE was any untoward medical occurrence attributed to study drug in a subject who received study drug. AEs were classified according to the severity in 3 categories a) mild: AEs does not interfere with subject’s usual function b) moderate: AEs interferes to some extent with subject’s usual function c) severe: AEs interferes significantly with subject’s usual function. Safety population included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    Day 1 up to EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: events
        Mild|
    60
    23
    67
        Moderate|
    3
    13
    19
        Severe|
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Test Abnormalities

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    End point title
    		 Number of Subjects With Laboratory Test Abnormalities
    End point description
    Abnormality Criteria: hemoglobin,hematocrit,red blood cells(RBC)count:<0.8*lower limit of normal[LLN],platelets:<0.5*LLN/>1.75*upper limit of normal[ULN]; leukocytes:<0.6*LLN/>1.5*ULN; lymphocytes,neutrophils, total protein,albumin, tetraiodothyronine,thyroid stimulating hormone:<0.8*LLN/>1.2*ULN; basophils,eosinophils,monocytes:>1.2*ULN; prothrombin [PT],PT international ratio:>1.1*ULN; aspartate aminotransferase,alanine aminotransferase,alkaline phosphatase,gamma glutamyl transferase:>0.3*ULN; bilirubin:>1.5*ULN; blood urea nitrogen,creatinine, cholesterol,triglycerides:>1.3*ULN; sodium: <0.95*LLN/>1.05*ULN; potassium,chloride,calcium,bicarbonate:<0.9*LLN/>1.1*ULN; glucose fasting:<0.6*LLN/>1.5*ULN; creatine kinase:>2*ULN;urine glucose,ketone,protein:>=1;urine WBC,RBC:>= 20/High Power Field[HPF]; urine casts,hyaline casts:>1/Low Power Field; urine bacteria:>20/HPF. Analysis was performed on safety population.Here,number of subject analyzed=subjects evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline up to EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    69
    Units: subjects
    65
    29
    61
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Vital Signs Abnormalities

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    End point title
    		 Number of Subjects With Vital Signs Abnormalities
    End point description
    Criteria for abnormalities in vital signs included: sitting/supine systolic blood pressure (SBP) values: maximum increase and decrease of greater than or equal to (>=) 30 millimeter of mercury (mmHg) from baseline; sitting/supine diastolic blood pressure (DBP) value: maximum increase and decrease of >=20 mmHg from baseline. Safety population included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    From Baseline (BL) up to EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: subjects
        Maximum Increase from BL(>=30):sitting/supine SBP
    2
    0
    1
        Maximum Increase from BL(>=20):sitting/supine DBP
    7
    1
    3
        Maximum Decrease from BL(>=30):sitting/supine SBP
    1
    0
    1
        Maximum Decrease from BL(>=20):sitting/supine DBP
    2
    2
    1
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Abnormal Physical Examination Findings at Screening and End of Study

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    End point title
    		 Percentage of Subjects With Abnormal Physical Examination Findings at Screening and End of Study
    End point description
    Physical examinations evaluated the following body systems/organs: abdomen; ears; extremities; eyes; general appearance; head; heart; lungs; lymph nodes; mouth; musculoskeletal; nose; skin and throat. Abnormalities in physical examination were based on investigator's discretion. Safety population included all randomized subjects who received at least 1 dose of study drug. Here, "n" signifies number of subjects who were evaluable for the specified category for each arm respectively.
    End point type
    Other pre-specified
    End point timeframe
    Screening and EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: percentage of subjects
    number (not applicable)
        Abdomen: Screening (n=71,34,70)
    4.2
    5.9
    2.9
        Abdomen: EOS (n=71,34,69)
    4.2
    5.9
    1.4
        Ears: Screening (n=71,34,70)
    1.4
    0
    1.4
        Ears: EOS (n=70,34,69)
    1.4
    0
    1.4
        Extremities: Screening (n=71,34,70)
    14.1
    26.5
    15.7
        Extremities: EOS (n=71,34,69)
    14.1
    26.5
    18.8
        Eyes: Screening (n=71,34,70)
    9.9
    20.6
    17.1
        Eyes: EOS (n=71,34,69)
    9.9
    20.6
    18.8
        General appearance: Screening (n=71,34,70)
    15.5
    26.5
    15.7
        General appearance: EOS (n=71,34,69)
    15.5
    23.5
    15.9
        Head: Screening (n=71,34,70)
    31.0
    47.1
    31.4
        Head: EOS (n=71,34,69)
    33.8
    47.1
    31.9
        Heart: Screening (n=71,34,70)
    1.4
    8.8
    4.3
        Heart: EOS (n=71,34,69)
    1.4
    5.9
    4.3
        Lungs: Screening (n=71,34,70)
    2.8
    8.8
    4.3
        Lungs: EOS (n=71,34,69)
    2.8
    8.8
    5.8
        Lymph nodes: Screening (n=71,34,70)
    0
    8.8
    0
        Lymph nodes: EOS (n=70,34,69)
    0
    2.9
    0
        Mouth: Screening (n=71,34,70)
    9.9
    2.9
    5.7
        Mouth: EOS (n=70,34,69)
    7.1
    2.9
    5.8
        Musculoskeletal: Screening (n=71,34,70)
    31.0
    38.2
    35.7
        Musculoskeletal: EOS (n=71,34,69)
    33.8
    38.2
    37.7
        Nose: Screening (n=71,34,70)
    0
    2.9
    0
        Nose: EOS (n=70,34,69)
    0
    0
    5.8
        Skin: Screening (n=71,34,70)
    9.9
    14.7
    21.4
        Skin: EOS (n=71,34,69)
    8.5
    14.7
    21.7
        Throat: Screening (n=71,34,70)
    1.4
    2.9
    0
        Throat: EOS (n=70,34,68)
    0
    5.9
    2.9
    No statistical analyses for this end point

    Other pre-specified: Percentage of Subjects With Abnormal Neurological Examination Findings at Baseline and End of Study

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    End point title
    		 Percentage of Subjects With Abnormal Neurological Examination Findings at Baseline and End of Study
    End point description
    Neurological examinations included: coordination; cranial nerve function (CNF); gait and station; level of consciousness (LOC); lower and upper extremity sensation; muscle strength (str.); muscle tone; nystagmus; reflexes and speech. Abnormalities in neurological examination were based on investigator's discretion and also, some components of the neurological examination were not done for certain subjects due to subject age or significant developmental impairment. Only those categories of neurological examination in which at least 10% of subjects had an abnormality in any treatment group at any time point were reported in this endpoint. Safety population included all randomized subjects who received at least 1 dose of study drug. Here, "n" signifies number of subjects who were evaluable for the specified category for each arm respectively.
    End point type
    Other pre-specified
    End point timeframe
    Baseline (BL) and EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: percentage of subjects
    number (not applicable)
        Coordination-left hand movement(BL)(n=71,34,70)
    1.4
    11.8
    8.6
        Coordination-left hand movement(EOS)(n=71,34,69)
    1.4
    8.8
    10.1
        Coordination-right hand movement(EOS)(n=71,34,69)
    2.8
    5.9
    10.1
        Coordination romberg test (BL)(n=71,34,70)
    2.8
    8.8
    10.0
        Coordination-romberg test (EOS)(n=71,34,69)
    2.8
    5.9
    11.6
        CNF-left eye visual field(BL)(n=71,34,70)
    12.7
    8.8
    10.0
        CNF-left eye visual field(EOS)(n=71,34,69)
    12.7
    8.8
    10.1
        CNF-right eye visual field (BL)(n=71,34,70)
    12.7
    5.9
    10.0
        CNF- right eye visual field (EOS)(n=71,34,69)
    12.7
    5.9
    10.1
        CNF-left fundoscopic exam(BL)(n=71,34,70)
    12.7
    26.5
    12.9
        CNF-left fundoscopic exam(EOS)(n=71,34,69)
    12.7
    23.5
    14.5
        CNF-right fundoscopic exam(BL)(n=71,34,70)
    11.3
    20.6
    14.3
        CNF-right fundoscopic exam(EOS)(n=71,34,69)
    11.3
    17.6
    14.5
        CNF-left visual acuity(BL)(n=71,34,70)
    11.3
    11.8
    12.9
        CNF-left visual acuity(EOS)(n=71,34,69)
    11.3
    11.8
    13.0
        CNF-right visual acuity(BL)(n=71,34,70)
    11.3
    11.8
    11.4
        CNF-right visual acuity(EOS)(n=71,34,69)
    11.3
    11.8
    11.6
        CNF-finger tracking(BL)(n=71,34,70)
    22.5
    26.5
    24.3
        CNF-finger tracking (EOS)(n=71,34,69)
    21.1
    23.5
    26.1
        CNF-swallowing(BL)(n=71,34,70)
    14.1
    14.7
    14.3
        CNF-swallowing (EOS)(n=71,34,69)
    14.1
    14.7
    14.5
        CNF-Leftshoulder,headturn str.(BL)(n=71,34,70)
    11.3
    2.9
    7.1
        CNF-Leftshoulder,headturn str.(EOS)(n=71,34,69)
    11.3
    2.9
    10.1
        Gait and station–gait (BL)(n=71,34,70)
    52.1
    50.0
    45.7
        Gait and station–gait (EOS)(n=71,34,69)
    52.1
    52.9
    46.4
        Level of consciousness(BL)(n=71,34,70)
    5.6
    20.6
    5.7
        Level of consciousness(EOS)(n=71,34,69)
    7.0
    20.6
    2.9
        Muscle str.-lower extremities (BL)(n=71,34,70)
    49.3
    58.8
    51.4
        Muscle str.-lower extremities(EOS)(n=71,34,69)
    49.3
    58.8
    53.6
        Muscle strength-upper extremities (BL)(n=71,34,70)
    47.9
    58.8
    50.0
        Muscle strength-upper extremities(EOS)n=71,34,69
    49.3
    58.8
    52.2
        Muscle strength-trunk(BL)(n=71,34,70)
    43.7
    38.2
    44.3
        Muscle strength-trunk(EOS)(n=71,34,69)
    39.4
    38.2
    42.0
        Muscle tone-lower extremities(BL)(n=70,34,69)
    64.3
    73.5
    63.8
        Muscle tone-lower extremities(EOS)(n=71,34,68)
    64.8
    73.5
    66.2
        Muscle tone-upper extremities(BL)(n=71,34,69)
    64.8
    73.5
    63.8
        Muscle tone-upper extremities (EOS)(n=71,34,68)
    64.8
    73.5
    66.2
        Nystagmus-horizontal(BL)(n=71,34,70)
    9.9
    11.8
    7.1
        Nystagmus-horizontal(EOS)(n=71,34,69)
    8.5
    11.8
    5.8
        Reflexes-left ankle(BL)(n=71,34,70)
    46.5
    52.9
    47.1
        Reflexes-left ankle(EOS)(n=71,34,69)
    46.5
    52.9
    46.4
        Reflexes-right ankle(BL)(n=71,34,70)
    46.5
    58.8
    47.1
        Reflexes-right ankle (EOS)(n=71,34,69)
    45.1
    58.8
    46.4
        Reflexes-left babinski(BL)(n=71,34,70)
    42.3
    47.1
    47.1
        Reflexes-left babinski(EOS)(n=71,34,69)
    40.8
    47.1
    47.8
        Reflexes-right babinski(BL)(n=71,34,70)
    42.3
    55.9
    50.0
        Reflexes-right babinski(EOS)(n=71,34,69)
    40.8
    55.9
    50.7
        Reflexes-left biceps(BL)(n=71,34,70)
    47.9
    52.9
    50.0
        Reflexes-left biceps(EOS)(n=71,34,69)
    47.9
    52.9
    49.3
        Reflexes-right biceps(BL)(n=71,34,70)
    46.5
    58.8
    52.9
        Reflexes-right biceps(EOS)(n=71,34,69)
    46.5
    58.8
    52.2
        Reflexes-left brachioradialis(BL)(n=71,34,70)
    45.1
    52.9
    48.6
        Reflexes-left brachioradialis(EOS)(n=71,34,69)
    45.1
    52.9
    47.8
        Reflexes-right brachioradialis(BL)(n=71,34,70)
    43.7
    58.8
    50.0
        Reflexes-right brachioradialis(EOS)(n=71,34,69)
    43.7
    58.8
    50.7
        Reflexes-left knee(BL)(n=71,34,70)
    53.5
    55.9
    57.1
        Reflexes-left knee(EOS)(n=71,34,69)
    52.1
    58.8
    56.5
        Reflexes-right knee(BL)(n=71,34,70)
    52.1
    61.8
    61.4
        Reflexes-right knee (EOS)(n=71,34,69)
    50.7
    64.7
    59.4
        Reflexes-left triceps(BL)(n=71,34,70)
    46.5
    52.9
    45.7
        Reflexes-left triceps(EOS)(n=71,34,69)
    46.5
    52.9
    44.9
        Reflexes-right triceps(BL)(n=71,34,70)
    45.1
    58.8
    48.6
        Reflexes-right triceps(EOS)(n=71,34,69)
    45.1
    58.8
    47.8
        Speech-articulation(BL)(n=71,34,70)
    53.5
    47.1
    45.7
        Speech-articulation(EOS)(n=71,34,69)
    54.9
    44.1
    47.8
        Speech-language(BL)(n=71,34,70)
    69.0
    76.5
    65.7
        Speech-language(EOS)(n=71,34,68)
    69.0
    73.5
    66.7
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Subjects With Electrocardiogram (ECG) Abnormalities
    End point description
    Criteria for abnormalities in ECG findings: 1) Time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization (QRS complex): >=140 milliseconds (msec); 2) The interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization (PR interval): >=200 msec; 3) Time from ECG Q wave to the end of the T wave corresponding to electrical systole corrected for heart rate using Fridericia’s formula (QTCF interval): absolute value 450 to <480 msec, 480 to <500 msec, >=500 msec; 4) Maximum QT interval: >=500 msec; 5) Maximum QTCB interval (Bazett’s correction): 450 to< 480 msec, 480 to <500 msec, >=500 msec. Only those categories of ECG abnormalities in which subjects were found abnormal (maximum QTCB interval 450-<480 msec), were reported in this endpoint. Safety population included all randomized subjects who received at least 1 dose of study drug.
    End point type
    Other pre-specified
    End point timeframe
    From screening up to EOS (maximum Day 25)
    End point values
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Pregabalin 14 mg/kg/day or 12 mg/kg/day Placebo
    Number of subjects analysed
    71
    34
    70
    Units: subjects
    0
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 up to End of Study (maximum Day 25)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    v20.1
    Reporting groups
    Reporting group title
    Pregabalin 7 mg/kg/day or 6 mg/kg/day
    Reporting group description
    		 Subjects aged > 3 months to < 4 years, received Pregabalin 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for first 5 days; followed by 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 7 days.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects aged >3 months to <4 years received placebo matched to Pregabalin, orally TID for 21 days.

    Reporting group title
    Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Reporting group description
    		 Subjects aged >3 months to <4 years, received Pregabalin 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for first 2 days and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days; followed by 14 mg/kg/day (12 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for 9 days; and 7 mg/kg/day (6 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 4 days and 3.5 mg/kg/day (3.0 mg/kg/day for subjects 1 to 3 months of age), orally TID in equally divided doses for next 3 days.

    Serious adverse events
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Placebo Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 71 (0.00%)
    4 / 70 (5.71%)
    1 / 34 (2.94%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Choking
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Pregabalin 7 mg/kg/day or 6 mg/kg/day Placebo Pregabalin 14 mg/kg/day or 12 mg/kg/day
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 71 (45.07%)
    37 / 70 (52.86%)
    16 / 34 (47.06%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 70 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    1
    2
    0
    General disorders and administration site conditions
    Application site irritation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    Asthenia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperthermia
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    4 / 71 (5.63%)
    4 / 70 (5.71%)
    2 / 34 (5.88%)
         occurrences all number
    4
    5
    2
    Sluggishness
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Feeling hot
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Bronchial hyperreactivity
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Cough
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 70 (4.29%)
    0 / 34 (0.00%)
         occurrences all number
    1
    3
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    3
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Enuresis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Irritability
         subjects affected / exposed
    3 / 71 (4.23%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    3
    2
    0
    Sleep disorder
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Electrocardiogram repolarisation abnormality
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte morphology abnormal
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lymphocyte percentage increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil percentage decreased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Platelet count increased
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Fall
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    2
    1
    0
    Skin abrasion
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 70 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Cardiac disorders
    Bradyarrhythmia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Tachycardia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Dysarthria
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Epilepsy
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hypersomnia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Lethargy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Myoclonic epilepsy
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Psychomotor hyperactivity
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Seizure
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 70 (4.29%)
    2 / 34 (5.88%)
         occurrences all number
    1
    3
    2
    Somnolence
         subjects affected / exposed
    8 / 71 (11.27%)
    4 / 70 (5.71%)
    6 / 34 (17.65%)
         occurrences all number
    9
    4
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 70 (2.86%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Eye disorders
    Chalazion
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Mydriasis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    2
    Diarrhoea
         subjects affected / exposed
    3 / 71 (4.23%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    4
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Gingival bleeding
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Oral contusion
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Regurgitation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 71 (1.41%)
    6 / 70 (8.57%)
    0 / 34 (0.00%)
         occurrences all number
    1
    6
    0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Dermatitis diaper
         subjects affected / exposed
    0 / 71 (0.00%)
    3 / 70 (4.29%)
    0 / 34 (0.00%)
         occurrences all number
    0
    3
    0
    Eczema
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Erythema
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 70 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Rash
         subjects affected / exposed
    0 / 71 (0.00%)
    3 / 70 (4.29%)
    0 / 34 (0.00%)
         occurrences all number
    0
    3
    0
    Skin irritation
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Vesicoureteric reflux
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Bronchitis viral
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Fungal infection
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Impetigo
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lice infestation
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 70 (4.29%)
    2 / 34 (5.88%)
         occurrences all number
    1
    3
    2
    Otitis media
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 70 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Respiratory tract infection viral
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 70 (1.43%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    1
    Rhinitis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 71 (7.04%)
    8 / 70 (11.43%)
    4 / 34 (11.76%)
         occurrences all number
    5
    8
    5
    Urinary tract infection
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 70 (2.86%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Viral infection
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 70 (2.86%)
    2 / 34 (5.88%)
         occurrences all number
    3
    2
    2
    Viral rash
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 71 (0.00%)
    3 / 70 (4.29%)
    0 / 34 (0.00%)
         occurrences all number
    0
    3
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Increased appetite
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 70 (1.43%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    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.
    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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