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    Clinical Trial Results:
    A Phase 1 Open-Label Study of the Pharmacokinetics of Tacrolimus Cream B 0.1% after Twice Daily Topical Administration in Adolescents (more than or equal to 12 to less than or equal to 17 years of age) with Psoriasis

    Summary
    EudraCT number
    2006-002738-39
    Trial protocol
    LV  
    Global end of trial date
    03 May 2007

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    13 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    04-7-011
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma US, Inc.
    Sponsor organisation address
    1 Astellas Way, Northbrook, IL, United States, 60062
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., Astellas.resultsdisclosure@astellas.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 May 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 May 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    03 May 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the pharmacokinetics and safety of tacrolimus cream 0.1% in adolescents (≥ 12 to ≤ 17 years of age) with plaque psoriasis affecting ≥ 10% body surface area (BSA) (excluding the scalp) who were treated topically for 29 days (4 weeks).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Dec 2006
    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
    Latvia: 12
    Country: Number of subjects enrolled
    Bulgaria: 10
    Worldwide total number of subjects
    22
    EEA total number of subjects
    22
    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)
    22
    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
    Participants aged 12 to 17 years with a diagnosis of plaque psoriasis affecting ≥ 10% BSA and a Physician’s Static Global Assessment (PSGA) ≥ 3 were enrolled.

    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
    Tacrolimus cream 0.1%
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Tacrolimus cream 0.1%
    Investigational medicinal product code
    FK506
    Other name
    Tacrolimus cream B-0.1%
    Pharmaceutical forms
    Cream
    Routes of administration
    Topical use
    Dosage and administration details
    The investigator defined the areas for treatment at baseline (day 1) and each study visit. Tacrolimus cream 0.1% was applied topically as a thin coating on the specified treatment area twice daily for 28 days and once in the morning of day 29 (end of treatment/EOT). Applications were to occur at consistent times, approximately 12 hours apart. Participants were to wait at least 2 hours after application of study drug before bathing, showering, or heavy exercise. Any new non-scalp plaque lesions appearing after day 1 or existing plaques that increased in size were to be treated by the participant until clear plus an additional 7 days or until day 29, whichever came first. If the affected area decreased in size, the participant was to continue treatment of the area until day 29 or until the area was clear plus an additional 7 days, whichever came first.

    Number of subjects in period 1
    Tacrolimus cream 0.1%
    Started
    22
    Completed
    21
    Not completed
    1
         Consent withdrawn by subject
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus cream 0.1%
    Reporting group description
    -

    Reporting group values
    Tacrolimus cream 0.1% Total
    Number of subjects
    22 22
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    15.3 ± 1.52 -
    Gender categorical
    Units: Subjects
        Female
    13 13
        Male
    9 9
    BSA affected
    Units: percentage of BSA
        arithmetic mean (standard deviation)
    26 ± 14.42 -

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus cream 0.1%
    Reporting group description
    -

    Primary: Pharmacokinetic whole blood tacrolimus concentrations

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    End point title
    Pharmacokinetic whole blood tacrolimus concentrations [1]
    End point description
    The analysis population is the pharmacokinetic set, which consisted of all participants from the Safety Set whose profile data were adequate for the calculation of the primary pharmacokinetic parameters.
    End point type
    Primary
    End point timeframe
    Day 29 (predose, hours 1, 2, 4, 6, 8, 12, 14 postdose) to Day 35 (postdose)
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Predose (Day 29)
    0.2443 ± 0.30465
        Hour 1 (Day 29)
    0.3367 ± 0.35458
        Hour 2 (Day 29)
    0.2444 ± 0.28315
        Hour 4 (Day 29)
    0.2529 ± 0.27985
        Hour 6 (Day 29)
    0.2434 ± 0.28806
        Hour 8 (Day 29)
    0.254 ± 0.27366
        Hour 12 (Day 29)
    0.237 ± 0.25764
        Hour 14 (Day 29)
    0.2546 ± 0.28267
        Hour 24 (Day 30)
    0.2479 ± 0.27247
        Hour 48 (Day 31)
    0.1942 ± 0.22829
        Hour 72 (Day 32)
    0.1518 ± 0.16487
        Hour 96 (Day 33)
    0.1159 ± 0.14319
        Hour 120 (Day 34)
    0.0744 ± 0.11124
        Hour 144 (Day 25)
    0.048 ± 0.08668
    No statistical analyses for this end point

    Primary: Maximum observed whole blood tacrolimus concentration (Cmax)

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    End point title
    Maximum observed whole blood tacrolimus concentration (Cmax) [2]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.383 ± 0.3653
    No statistical analyses for this end point

    Primary: Maximum observed whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cmax0-tau)

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    End point title
    Maximum observed whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cmax0-tau) [3]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.375 ± 0.3632
    No statistical analyses for this end point

    Primary: Minimum observed whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cmin0-tau)

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    End point title
    Minimum observed whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cmin0-tau) [4]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.205 ± 0.2452
    No statistical analyses for this end point

    Primary: Time of the maximum whole blood tacrolimus concentration (tmax)

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    End point title
    Time of the maximum whole blood tacrolimus concentration (tmax) [5]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: hours
        median (full range (min-max))
    3.5 (0 to 24)
    No statistical analyses for this end point

    Primary: Average whole blood tacrolimus concentration over the morning dosing interval, i.e. from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cavg0-tau)

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    End point title
    Average whole blood tacrolimus concentration over the morning dosing interval, i.e. from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (Cavg0-tau) [6]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.334 ± 0.2664
    No statistical analyses for this end point

    Primary: Area under the whole blood tacrolimus concentration-time curve over the morning dosing interval; i.e., from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (AUC0-tau)

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    End point title
    Area under the whole blood tacrolimus concentration-time curve over the morning dosing interval; i.e., from t=0 hour (time of morning dosing) through 12 hours post dose (t=12 hour) (AUC0-tau) [7]
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Primary
    End point timeframe
    Days 29-35
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: hr x ng/mL
        arithmetic mean (standard deviation)
    4.01 ± 3.197
    No statistical analyses for this end point

    Primary: Safety as assessed by adverse events (AEs), clinical laboratory tests, vital signs, and physical examination

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    End point title
    Safety as assessed by adverse events (AEs), clinical laboratory tests, vital signs, and physical examination [8]
    End point description
    Safety is monitored by collecting AEs, which include abnormal laboratory tests, vital signs or physical examination data that were defined as an AE if the abnormality induced clinical signs or symptoms, required diagnostic evaluation, therapeutic intervention, interruption or discontinuation of study medication or was clinically significant in the investigator's opinion. A treatment-emergent adverse event (TEAE) was defined as an AE occurring from the first dose day of study drug to the last dose day of study drug with onset or worsening after the first study drug application. The analysis population is the Safety Set, which consisted of all participants who were administered any amount of tacrolimus cream 0.1%.
    End point type
    Primary
    End point timeframe
    From first dose of study drug up to 7 days after last dose of study drug
    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: This study was written with no planned statistical analyses (statistical hypothesis testing) to be performed for any endpoints due to the simple design (i.e., one treatment group) and purpose of the study.
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    22
    Units: participants
        Any adverse event
    5
        General disorders & administration site conditions
    2
        Blood & lymphatic system disorders
    1
        Infections & infestations
    1
        Injury, poisoning & procedural complications
    1
        Respiratory, thoracic & mediastinal disorders
    1
    No statistical analyses for this end point

    Secondary: Tacrolimus predose concentration at the end of the previous dosing interval (Ctrough)

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    End point title
    Tacrolimus predose concentration at the end of the previous dosing interval (Ctrough)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 1, 8, 15, 22 and 29
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1
    0 ± 0
        Day 8
    0.2317 ± 0.26139
        Day 15
    0.3179 ± 0.33797
        Day 22
    0.274 ± 0.33075
        Day 29
    0.2443 ± 0.30465
    No statistical analyses for this end point

    Secondary: Average whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 24 hours post dose (t=24 hour) (Cavg0-24)

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    End point title
    Average whole blood tacrolimus concentration from t=0 hour (time of morning dosing) through 24 hours post dose (t=24 hour) (Cavg0-24)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.331 ± 0.2672
    No statistical analyses for this end point

    Secondary: Time to last measurable concentration of the study drug (tlast)

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    End point title
    Time to last measurable concentration of the study drug (tlast)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: hours
        median (full range (min-max))
    108 (1 to 144)
    No statistical analyses for this end point

    Secondary: Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) through 24 hours post dose (t=24 hour) (AUC0-24)

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    End point title
    Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) through 24 hours post dose (t=24 hour) (AUC0-24)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: hr x ng/mL
        arithmetic mean (standard deviation)
    7.95 ± 6.412
    No statistical analyses for this end point

    Secondary: Peak-to-trough ratio over the 12 hours after the dose (PTRtau)

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    End point title
    Peak-to-trough ratio over the 12 hours after the dose (PTRtau)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    11
    Units: ratio
        arithmetic mean (standard deviation)
    1.51 ± 0.333
    No statistical analyses for this end point

    Secondary: Difference in extreme concentrations (Cmax0-tau, Cmin0-tau) relative to the average concentration (Cavg0-tau) over the morning dosing interval (FLCTN0-tau)

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    End point title
    Difference in extreme concentrations (Cmax0-tau, Cmin0-tau) relative to the average concentration (Cavg0-tau) over the morning dosing interval (FLCTN0-tau)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    16
    Units: ng/mL
        arithmetic mean (standard deviation)
    1.79 ± 3.101
    No statistical analyses for this end point

    Secondary: Elimination rate constant (Kel)

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    End point title
    Elimination rate constant (Kel)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    12
    Units: 1/hour
        arithmetic mean (standard deviation)
    0.0096 ± 0.00444
    No statistical analyses for this end point

    Secondary: Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) through time of last measurable concentration of tacrolimus (AUClast)

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    End point title
    Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) through time of last measurable concentration of tacrolimus (AUClast)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    21
    Units: hr x ng/mL
        arithmetic mean (standard deviation)
    21.95 ± 25.859
    No statistical analyses for this end point

    Secondary: Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) extrapolated to infinity (AUC0-inf)

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    End point title
    Area under the whole blood tacrolimus concentration-time curve from t=0 hour (time of morning dosing) extrapolated to infinity (AUC0-inf)
    End point description
    The analysis population is the pharmacokinetic set. Due to an insufficient number of measurable samples, AUC0-inf was assumed to be unreliable; hence, the value was not calculated.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    0 [9]
    Units: hr x ng/mL
        arithmetic mean (standard deviation)
    ±
    Notes
    [9] - Insufficient number of measurable samples.
    No statistical analyses for this end point

    Secondary: Terminal half life (t1/2)

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    End point title
    Terminal half life (t1/2)
    End point description
    The analysis population is the pharmacokinetic set.
    End point type
    Secondary
    End point timeframe
    Days 29-35
    End point values
    Tacrolimus cream 0.1%
    Number of subjects analysed
    12
    Units: hours
        arithmetic mean (standard deviation)
    95.61 ± 61.048
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 7 days after last dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    8.1
    Reporting groups
    Reporting group title
    Tacrolimus cream 0.1%
    Reporting group description
    -

    Serious adverse events
    Tacrolimus cream 0.1%
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tacrolimus cream 0.1%
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 22 (18.18%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    General disorders and administration site conditions
    Application site irritation
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Application site pruritus
         subjects affected / exposed
    1 / 22 (4.55%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 22 (9.09%)
         occurrences all number
    2
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 22 (4.55%)
         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
    14 Jun 2006
    The original study protocol dated February 2, 2006 was amended once on June 14, 2006 (Latvia-specific) in order to provide required text per European Regulatory guidelines with respect to concomitant medication administration, adverse event reporting, study timelines and drug supplies, administrative and regulatory considerations.

    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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