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    Clinical Trial Results:
    A Multiple Dose Pharmacokinetic Open-Label Study of Pregabalin (Lyrica) in Healthy Lactating Women

    Summary
    EudraCT number
    2012-003197-57
    Trial protocol
    BE  
    Global end of trial date
    16 Aug 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    30 May 2016
    First version publication date
    11 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    A0081181
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01727791
    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 Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 800-718-1021, 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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    03 Mar 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine pregabalin drug concentrations in human breast milk and estimate the infant daily dose that would result from pregabalin secretion in breast milk.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Dec 2012
    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: 10
    Worldwide total number of subjects
    10
    EEA total number of subjects
    10
    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)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    The study was conducted in Belgium from 13 Dec 2012 to 16 Aug 2013.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Pregabalin
    Arm description
    Subjects received pregabalin immediate release (IR) capsules over 12 hour dosing intervals on Day 1, Day 2 and Day 3.
    Arm type
    Experimental

    Investigational medicinal product name
    Pregabalin
    Investigational medicinal product code
    Other name
    Lyrica
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received pregabalin 150 milligram (mg) capsules every 12 hour beginning on Day 1 (evening), Day 2 (morning and evening) and Day 3 (morning).

    Number of subjects in period 1
    Pregabalin
    Started
    10
    Completed
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    Subjects received pregabalin immediate release (IR) capsules at 12 hours dosing interval on Day 1, Day 2 and Day 3.

    Reporting group values
    Overall Study Total
    Number of subjects
    10 10
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    31.7 ± 4.5 -
    Gender categorical
    Units: Subjects
        Female
    10 10
        Male
    0 0

    End points

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    End points reporting groups
    Reporting group title
    Pregabalin
    Reporting group description
    Subjects received pregabalin immediate release (IR) capsules over 12 hour dosing intervals on Day 1, Day 2 and Day 3.

    Primary: Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau)

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    End point title
    Area Under the Curve from Time Zero to End of Dosing Interval (AUCtau) [1]
    End point description
    Area under concentration-time profile from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours. The pharmacokinetic (PK) parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: microgram*hour per milliliter(mcg*hr/mL)
        geometric mean (geometric coefficient of variation)
    32.5 ± 24
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    Maximum Observed Plasma Concentration (Cmax) [2]
    End point description
    Cmax was the peak concentration in plasma post Day 3 dose. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    4.67 ± 18
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Plasma Concentration (Tmax)

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    End point title
    Time to Reach Maximum Observed Plasma Concentration (Tmax) [3]
    End point description
    Tmax was the time to peak concentration in plasma post Day 3 dose. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: hr
        median (full range (min-max))
    2.01 (1 to 3)
    No statistical analyses for this end point

    Primary: Plasma Half-Life (t1/2)

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    End point title
    Plasma Half-Life (t1/2) [4]
    End point description
    Plasma decay half-life (t1/2) was the time for the plasma concentration to decrease by one-half. The t1/2 is based on the terminal elimination phase time points from this timeframe. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: hr
        arithmetic mean (standard deviation)
    5.624 ± 0.65656
    No statistical analyses for this end point

    Primary: Average Plasma Concentration During the Dosing Interval (Cav)

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    End point title
    Average Plasma Concentration During the Dosing Interval (Cav) [5]
    End point description
    Average plasma concentration during the dosing interval (Cav) was calculated by dividing AUCtau (plasma) with tau, where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    2.709 ± 24
    No statistical analyses for this end point

    Primary: Minimum Observed Plasma Trough Concentration (Cmin)

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    End point title
    Minimum Observed Plasma Trough Concentration (Cmin) [6]
    End point description
    Cmin was the minimum observed plasma concentration of a drug after post Day 3 dose. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post-dose on Day 3
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    1.246 ± 36
    No statistical analyses for this end point

    Primary: Apparent Oral Clearance (CL/F)

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    End point title
    Apparent Oral Clearance (CL/F) [7]
    End point description
    Apparent oral clearance (CL/F) was calculated by dividing dose by the AUCtau, where tau was the dosing interval of 12 hours. Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. Clearance obtained after oral dose (apparent oral clearance) is influenced by the fraction of the dose absorbed. Drug clearance is a quantitative measure of the rate at which a drug substance is removed from the blood. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6,10, 12 hours post-dose on Day 3
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: milliliter/minute (mL/min)
        geometric mean (geometric coefficient of variation)
    76.9 ± 24
    No statistical analyses for this end point

    Primary: Area Under the Curve from Time Zero to End of Dosing Interval for Breast Milk (AUCtau [breast milk])

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    End point title
    Area Under the Curve from Time Zero to End of Dosing Interval for Breast Milk (AUCtau [breast milk]) [8]
    End point description
    AUCtau (breast milk) was the area under the curve for breast milk, from time 0 to tau (AUCtau), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg*hr/mL
        geometric mean (geometric coefficient of variation)
    24.64 ± 27
    No statistical analyses for this end point

    Primary: Maximum Observed Concentration in Breast Milk (Cmax [breast milk])

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    End point title
    Maximum Observed Concentration in Breast Milk (Cmax [breast milk]) [9]
    End point description
    Cmax (breast milk) was the maximum observed concentration in breast milk post Day 3 dose. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/mL
        geometric mean (geometric coefficient of variation)
    2.474 ± 30
    No statistical analyses for this end point

    Primary: Time to Reach Maximum Observed Breast Milk Concentration (Tmax [breast milk])

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    End point title
    Time to Reach Maximum Observed Breast Milk Concentration (Tmax [breast milk]) [10]
    End point description
    Tmax (breast milk) was time of the maximum observed breast milk concentration Day 3 post dose. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: hr
        median (full range (min-max))
    4.63 (3.08 to 6.16)
    No statistical analyses for this end point

    Primary: Terminal Half-Life for Breast Milk (t1/2 [breast milk])

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    End point title
    Terminal Half-Life for Breast Milk (t1/2 [breast milk]) [11]
    End point description
    The terminal half-life for breast milk (t1/2 [breast milk]) was the time measured for breast milk concentration to decrease by one-half. For the first 5 subjects enrolled under protocol amendment dated: 18 Sep 2012, breast milk was collected up to 24 hours after Day 3 dosing over the following time intervals: 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24 hours. Terminal half-life was determined over those points characterizing the elimination phase. For the remaining 5 subjects, there were 3 additional collection intervals (24 to 32, 32 to 40, 40 to 48 hours) for characterizing the terminal elimination phase. The t1/2 (breast milk) is based on the terminal elimination phase time points from this timeframe. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post-dose on Day 3
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: hr
        arithmetic mean (standard deviation)
    8.117 ± 3.0871
    No statistical analyses for this end point

    Primary: Amount Excreted in Breast Milk Over the Dosing Interval tau (Aetaubm)

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    End point title
    Amount Excreted in Breast Milk Over the Dosing Interval tau (Aetaubm) [12]
    End point description
    Aetaubm was the amount excreted in breast milk over the dosing interval tau (12 hours). It was calculated as the sum of (breast milk concentration * sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Sample volume was based on ratio of volume weight and density. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg
        geometric mean (geometric coefficient of variation)
    286.9 ± 60
    No statistical analyses for this end point

    Primary: Percentage of Dose Excreted in Breast Milk During the Dosing Interval tau (Aetaubm percent)

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    End point title
    Percentage of Dose Excreted in Breast Milk During the Dosing Interval tau (Aetaubm percent) [13]
    End point description
    Percentage of dose excreted in breast milk during the dosing interval tau (Aetaubm percent) was calculated by using the formula: 100*(Aetaubm [sum of {breast milk concentration * sample volume} for each collection interval from 0 to 12 hours post­dose] divided by dose), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: percentage of dose
        geometric mean (geometric coefficient of variation)
    0.1913 ± 60
    No statistical analyses for this end point

    Primary: Breast Milk Clearance (CLbm)

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    End point title
    Breast Milk Clearance (CLbm) [14]
    End point description
    Breast milk clearance (CLbm) was calculated by dividing Aetaubm (sum of [breast milk concentration * sample volume] for each collection interval from 0 to 12 hours post-­dose) by plasma AUCtau, where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Plasma: Pre-​dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post​-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mL/min
        geometric mean (geometric coefficient of variation)
    0.1473 ± 60
    No statistical analyses for this end point

    Primary: Amount Recovered in Urine During the Dosing Interval tau (Aetauurine)

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    End point title
    Amount Recovered in Urine During the Dosing Interval tau (Aetauurine) [15]
    End point description
    Aetauurine was the amount excreted in urine over the dosing interval tau (12 hours). It was calculated as the sum of (urine concentration * sample volume) for each collection interval from 0 to 12 hours post-dose, where tau was the dosing interval of 12 hours. Here, sample volume was based on the ratio of volume weight and density. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8 and 8 to 12 hours post-dose on Day 3
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mg
        geometric mean (geometric coefficient of variation)
    133.1 ± 12
    No statistical analyses for this end point

    Primary: Percent of Dose Recovered in Urine During the Dosing Interval tau (Aetauurine percent)

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    End point title
    Percent of Dose Recovered in Urine During the Dosing Interval tau (Aetauurine percent) [16]
    End point description
    Percent of dose recovered in urine during the dosing interval tau (Aetauurine percent) was calculated as 100*(Aetau [sum of {urine concentration * sample volume} for each collection interval from 0 to 12 hours post-dose] divided by the dose), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8 and 8 to 12 hours post-dose on Day 3
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: percentage of dose
        geometric mean (geometric coefficient of variation)
    88.6 ± 12
    No statistical analyses for this end point

    Primary: Renal Clearance (CLr)

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    End point title
    Renal Clearance (CLr) [17]
    End point description
    Renal clearance (CLr) was the volume of plasma from which the drug was completely removed by the kidney in a given amount of time. It was calculated by dividing Aetauurine (sum of [urine concentration * sample volume] for each collection interval from 0 to 12 hours post-dose) with the plasma AUCtau, where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Urine: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8 and 8 to 12 hours post-dose on Day 3
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mL/min
        geometric mean (geometric coefficient of variation)
    68.16 ± 24
    No statistical analyses for this end point

    Primary: Daily Amount of Pregabalin Excreted in Breast Milk (Ae24bm)

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    End point title
    Daily Amount of Pregabalin Excreted in Breast Milk (Ae24bm) [18]
    End point description
    Ae24bm was the daily amount of pregabalin excreted in breast milk. It was calculated by the formula: 2 * Aetaubm (sum of [breast milk concentration * sample volume] for each collection interval from 0 to 12 hours post-­dose), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-­dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg
        arithmetic mean (full range (min-max))
    664.6 (270 to 1720)
    No statistical analyses for this end point

    Primary: Milk to Plasma Ratio for AUCtau (MPAUCtau)

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    End point title
    Milk to Plasma Ratio for AUCtau (MPAUCtau) [19]
    End point description
    MPAUCtau was the ratio of AUCtau (breast milk) to AUCtau (plasma), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre­-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: ratio
        arithmetic mean (full range (min-max))
    0.769 (0.493 to 0.956)
    No statistical analyses for this end point

    Primary: Milk to Plasma Ratio for Maximum Observed Concentration (MPCmax)

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    End point title
    Milk to Plasma Ratio for Maximum Observed Concentration (MPCmax) [20]
    End point description
    Milk to plasma ratio for maximum observed concentration (MPCmax) was calculated as the ratio of Cmax (breast milk) to Cmax (plasma). The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Plasma: Pre-­dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12, 18, 24 hours post­-dose on Day 3. Breast milk: Pre-dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12, 12 to 24, 24 to 32, 32 to 40 and 40 to 48 hours post­-dose on Day 3.
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: ratio
        arithmetic mean (full range (min-max))
    0.5413 (0.335 to 0.755)
    No statistical analyses for this end point

    Primary: Body Weight Normalized Infant Dose (BWNID)

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    End point title
    Body Weight Normalized Infant Dose (BWNID) [21]
    End point description
    Body weight normalized infant dose (BWNID) of pregabalin was the dose that an infant received from breast-feeding and was calculated from the milk to plasma AUCtau ratio multiplied by the average maternal plasma pregabalin concentration (Cav) multiplied by the standardized milk consumption for an infant (150 milliliter/kilogram/day [mL/kg/day]), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Plasma: Pre-dose on Day 3; 0.5, 1, 2, 3, 4, 6, 10, 12 hours post-dose on Day 3. Breast milk: Pre-­dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post-dose on Day 3
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/kg/day
        arithmetic mean (full range (min-max))
    317.3 (202 to 458)
    No statistical analyses for this end point

    Primary: Body Weight Normalized Maternal Dose (BWNMD)

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    End point title
    Body Weight Normalized Maternal Dose (BWNMD) [22]
    End point description
    Body weight normalized maternal dose (BWNMD) was calculated as the maternal dose in microgram per day (mcg/day) divided by maternal weight in kilogram (kg) at screening. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose to 24 hours post-dose on Day 3
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/kg/day
        arithmetic mean (full range (min-max))
    4343.6 (3444 to 5676)
    No statistical analyses for this end point

    Primary: Infant Dose Expressed as Percentage of Body Weight Normalized Maternal Dose (BWNIDPCM)

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    End point title
    Infant Dose Expressed as Percentage of Body Weight Normalized Maternal Dose (BWNIDPCM) [23]
    End point description
    Infant dose expressed as percentage of body weight normalized maternal dose (BWNIDPCM) was the relative infant dose (relative to maternal dose) calculated by the formula: 100 * BWNID (Body Weight Normalized Infant Dose) / Body Weight Normalized Maternal Dose (BWNMD), where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-dose to 24 hours post-dose on Day 3
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: percentage of dose
        arithmetic mean (full range (min-max))
    7.341 (4.43 to 9.78)
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment ­Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs)

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    End point title
    Number of Subjects With Treatment ­Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [24]
    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 are events between first dose of study drug and up to 28 days after last dose that were absent before treatment or that worsened relative to pretreatment state. Safety analysis included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days after last dose of study drug
    Notes
    [24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: subjects
        AE
    8
        SAE
    0
    No statistical analyses for this end point

    Primary: Number of Subjects with Laboratory Abnormalities

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    End point title
    Number of Subjects with Laboratory Abnormalities [25]
    End point description
    Following parameters were analyzed for laboratory examination: hematology: (hemoglobin, hematocrit, red blood cell count, mean corpuscular volume [MCV], mean corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], platelets, white blood cell count, lymphocytes, total neutrophils, basophils, eosinophils, monocytes); liver function (bilirubin, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total protein, albumin); renal function (blood urea nitrogen, creatinine, uric acid); electrolytes (sodium, potassium, chloride, calcium, bicarbonate); clinical chemistry (glucose); urinalysis (urine pH, glucose, ketones, protein, urine blood/hemoglobin, nitrite). Safety analysis included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days after last dose of study drug
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: subjects
    4
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs

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    End point title
    Number of Subjects With Clinically Significant Change From Baseline in Vital Signs [26]
    End point description
    Following parameters were analyzed for examination of vital signs: electrocardiogram (ECG), systolic and diastolic blood pressure, temperature, pulse rate, respiratory rate, radial pulse and body temperature. Safety analysis included all subjects who received at least 1 dose of study medication.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days after last dose of study drug
    Notes
    [26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: subjects
    0
    No statistical analyses for this end point

    Primary: Average Breast Milk Concentration During the Dosing Interval (Cav)

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    End point title
    Average Breast Milk Concentration During the Dosing Interval (Cav) [27]
    End point description
    Average breast milk concentration during the dosing interval (Cav) was calculated by dividing AUCtau (breast milk) with tau, where tau was the dosing interval of 12 hours. The PK parameter analysis population included subjects who received study medication and had at least 1 of the PK parameters of primary interest.
    End point type
    Primary
    End point timeframe
    Pre-­dose on Day 3; 0 to 2, 2 to 4, 4 to 8, 8 to 12 hours post­-dose on Day 3
    Notes
    [27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint.
    End point values
    Pregabalin
    Number of subjects analysed
    10
    Units: mcg/mL
        arithmetic mean (full range (min-max))
    2.116 (1.34 to 3.06)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 28 days after last dose of study drug
    Adverse event reporting additional description
    The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Pregabalin
    Reporting group description
    Subjects received pregabalin immediate release (IR) capsules at 12 hours dosing interval on Day 1, Day 2 and Day 3.

    Serious adverse events
    Pregabalin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Pregabalin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 10 (60.00%)
         occurrences all number
    9
    Headache
         subjects affected / exposed
    2 / 10 (20.00%)
         occurrences all number
    2
    Restless legs syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Somnolence
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Dry mouth
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 10 (10.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2012
    1. Added breast milk expression tests, Columbia Suicidality Severity Rating Scale (C-SSRS) and the Nursing Mother Questionnaire at both pre and post dosing. 2. Updated the urine analysis section which reflected the 12 hour intervals (0-2, 2-4, 4-8 and 8-12 hours post Day 3) on which urine samples were assayed. 3. Subject were observed for a minimum of 3 hours by the qualified Clinic personnel, in case they took doses at home.
    22 Feb 2013
    1. Adverse events and concomitant medications were monitored up to 48 hours post-dose Day 3 (on Day 4 and Day 5). 2. Post-amendment dated: 18 Sep 2012, breast milk was collected up to 48 hours after Day 3 dosing.

    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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