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    Clinical Trial Results:
    Randomized, double-blind, cross-over efficacy and safety study based on the pharmacodynamic model of topical use of the new combination gel containing diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g versus placebo in the treatment of local skin inflammatory and allergic lesions induced by the provocative test with histamine in healthy subjects.

    Summary
    EudraCT number
    2018-004502-26
    Trial protocol
    PL  
    Global end of trial date
    26 Aug 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    16 May 2021
    First version publication date
    16 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DL/HL/09/18
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Przedsiębiorstwo Produkcji Farmaceutycznej (P.P.F.) HASCO-LEK S.A.
    Sponsor organisation address
    Żmigrodzka 242E , Wrocław, Poland, 51-131
    Public contact
    Clinical Trial Information Desk, Przedsiębiorstwo Produkcji Farmaceutycznej (P.P.F.) HASCO-LEK S.A., 48 71327 18 61 261, a.puchala@hasco-lek.pl
    Scientific contact
    Clinical Trial Information Desk, Przedsiębiorstwo Produkcji Farmaceutycznej (P.P.F.) HASCO-LEK S.A., 48 71327 18 61 261, a.puchala@hasco-lek.pl
    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
    26 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Aug 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate efficacy and safety of the new combination topical gel containing diphenhydramine hydrochloride 20 mg/g and lidocaine hydrochloride 10 mg/g versus placebo in the treatment of local skin inflammatory and allergic lesions induced in the provocative test with histamine (skin prick test)
    Protection of trial subjects
    Observation per subject from enrolment to the study (screening examination) until the end-of study evaluation. Medical surveillance at site. Safety procedures: physical examination, vital signs, laboratory tests, safety monitoring (AEs).
    Background therapy
    Not applicable
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Aug 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    44
    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 screening procedures applied. Volunteers who signed informed consent form (ICF), met all inclusion criteria and none of the exclusion criteria were enrolled into the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    The double-blind design was used for the study. The aim of this was to decrease the risk of systematic error. Especially, this ensured more results reliability at the point of asking subjects about symptoms intensity as well as during taking measurements by the Investigator. Blinding could have been only broken in emergency situations for reasons of subjects safety. IPs were packed and labelled in a way that prevented unblinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Sequence TP - Test product then Placebo
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Diphenhydramine hydrochloride and lidocaine hydrochloride, 20 mg/g and 10 mg/g, gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Dose: 0.16 mL of a product - single application Mode of administration: Topical administration

    Investigational medicinal product name
    Placebo, gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Dose: 0.16 mL of a product - single application Mode of administration: Topical administration

    Arm title
    Sequence PT - Placebo than Test product
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo, gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Dose: 0.16 mL of a product - single application Mode of administration: Topical administration

    Investigational medicinal product name
    Diphenhydramine hydrochloride and lidocaine hydrochloride, 20 mg/g and 10 mg/g, gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel
    Routes of administration
    Topical use
    Dosage and administration details
    Dose: 0.16 mL of a product - single application Mode of administration: Topical administration

    Number of subjects in period 1
    Sequence TP - Test product then Placebo Sequence PT - Placebo than Test product
    Started
    22
    22
    wash-out
    21
    22
    Completed
    21
    22
    Not completed
    1
    0
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    44 44
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    44 44
    Gender categorical
    Units: Subjects
        Female
    24 24
        Male
    20 20
    Subject analysis sets

    Subject analysis set title
    Test product
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Diphenhydramine hydrochloride and lidocaine hydrochloride, 20 mg/g and 10 mg/g, gel

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Placebo, gel

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    all subjects exposed to the study products were the part of the safety analysis

    Subject analysis sets values
    Test product Placebo Safety population
    Number of subjects
    43
    44
    44
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    43
    44
    44
    Age continuous
    Units:
        
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
    23
    24
    24
        Male
    20
    20
    20

    End points

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    End points reporting groups
    Reporting group title
    Sequence TP - Test product then Placebo
    Reporting group description
    -

    Reporting group title
    Sequence PT - Placebo than Test product
    Reporting group description
    -

    Subject analysis set title
    Test product
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Diphenhydramine hydrochloride and lidocaine hydrochloride, 20 mg/g and 10 mg/g, gel

    Subject analysis set title
    Placebo
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Placebo, gel

    Subject analysis set title
    Safety population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    all subjects exposed to the study products were the part of the safety analysis

    Primary: Difference in itching AUC

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    End point title
    Difference in itching AUC
    End point description
    End point type
    Primary
    End point timeframe
    Evaluation of itch using VAS scale was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: minute
        arithmetic mean (standard deviation)
    185.7 ± 289.3
    301.5 ± 504.4
    Statistical analysis title
    Comparison of itching AUC between products
    Statistical analysis description
    Wilcoxon test for paired data
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Comparison of logarithmically transformed itching
    Statistical analysis description
    t-test for paired data
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.024
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Change in diameter of the wheal

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    End point title
    Change in diameter of the wheal
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of the diameter of the wheal and the erythema was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: mm
    arithmetic mean (standard deviation)
        0min
    1.7 ± 1.1
    1.8 ± 1.1
        2min
    2.1 ± 0.9
    1.9 ± 0.9
        4min
    2.9 ± 0.9
    3.0 ± 0.9
        6min
    3.8 ± 0.7
    4.0 ± 0.8
        8min
    4.2 ± 0.8
    4.4 ± 0.9
        10min
    4.6 ± 0.9
    4.9 ± 1.1
        15min
    4.6 ± 1.1
    5.2 ± 1.4
        20min
    4.8 ± 1.1
    5.1 ± 1.4
        30min
    4.5 ± 1.6
    4.8 ± 1.5
        60min
    2.6 ± 2.1
    3.3 ± 2.0
        90min
    1.6 ± 1.7
    2.3 ± 2.2
    Statistical analysis title
    Change in diameter of the wheal
    Statistical analysis description
    Linear mixed effect model
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05 [1]
    Method
    Mixed models analysis
    Confidence interval
    Notes
    [1] - NA

    Secondary: Peak itching intensity

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    End point title
    Peak itching intensity
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of itch using VAS scale was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration.
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: number
        arithmetic mean (standard deviation)
    22.8 ± 16.6
    24.9 ± 17.0
    Statistical analysis title
    Comparison of peak itching intensity
    Statistical analysis description
    Wilcoxon signed rank test
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.311
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Rate of decrease in itching

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    End point title
    Rate of decrease in itching
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of itch using VAS scale was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration.
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: number
    arithmetic mean (standard deviation)
        0min
    20.8 ± 16.1
    21.0 ± 17.1
        2min
    14.9 ± 15.5
    18.4 ± 17.4
        4min
    11.5 ± 13.9
    15.0 ± 15.6
        6min
    7.4 ± 11.3
    11.7 ± 15.3
        8min
    5.7 ± 11.1
    8.4 ± 13.1
        10min
    4.2 ± 8.9
    6.2 ± 11.8
        15min
    3.1 ± 8.0
    4.8 ± 11.3
        20min
    2.1 ± 6.7
    4.2 ± 10.4
        30min
    1.2 ± 3.0
    3.1 ± 8.3
        60min
    0.4 ± 1.2
    0.9 ± 2.5
        90min
    0.2 ± 0.4
    0.4 ± 1.5
    Statistical analysis title
    Rate of decrease in itching intensity
    Statistical analysis description
    Linear mixed effect model
    Comparison groups
    Placebo v Test product
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Change in area of the wheal

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    End point title
    Change in area of the wheal
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of the diameter of the wheal and the erythema was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration.
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: mm2
    arithmetic mean (standard deviation)
        0min
    2.68 ± 2.33
    3.22 ± 3.00
        2min
    3.71 ± 2.38
    3.40 ± 2.24
        4min
    6.79 ± 3.42
    7.49 ± 3.46
        6min
    11.30 ± 3.92
    11.62 ± 3.72
        8min
    13.09 ± 4.51
    14.88 ± 5.06
        10min
    15.91 ± 5.54
    17.44 ± 6.89
        15min
    15.89 ± 6.69
    20.28 ± 10.07
        20min
    17.58 ± 7.61
    20.44 ± 11.63
        30min
    17.02 ± 10.15
    19.11 ± 11.05
        60min
    7.93 ± 7.86
    10.67 ± 9.45
        90min
    4.13 ± 5.62
    7.27 ± 8.86
    Statistical analysis title
    Change in area of the wheal
    Statistical analysis description
    Linear mixed effect model
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Change in diameter of the erythema

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    End point title
    Change in diameter of the erythema
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of the diameter of the wheal and the erythema was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration.
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: mm
    arithmetic mean (standard deviation)
        0min
    2.1 ± 1.3
    2.6 ± 2.0
        2min
    2.6 ± 1.0
    2.5 ± 1.3
        4min
    5.1 ± 5.0
    4.4 ± 3.5
        6min
    6.1 ± 4.8
    6.6 ± 5.3
        8min
    6.8 ± 4.1
    7.7 ± 6.1
        10min
    6.9 ± 3.6
    8.4 ± 6.5
        15min
    6.7 ± 3.6
    9.7 ± 7.7
        20min
    6.8 ± 3.7
    9.5 ± 7.3
        30min
    6.1 ± 3.5
    8.4 ± 6.7
        60min
    2.6 ± 2.1
    4.2 ± 4.6
        90min
    1.6 ± 1.7
    2.3 ± 2.2
    Statistical analysis title
    Change in diameter of the erythema
    Statistical analysis description
    Linear mixed effect model
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Change in area of the erythema

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    End point title
    Change in area of the erythema
    End point description
    End point type
    Secondary
    End point timeframe
    Evaluation of the diameter of the wheal and the erythema was performed after histamine administration (time “0”) and at: 2, 4, 6, 8, 10, 15, 20, 30, 60 and 90 minutes after test product/placebo administration.
    End point values
    Test product Placebo
    Number of subjects analysed
    39
    39
    Units: mm2
    arithmetic mean (standard deviation)
        0min
    4.01 ± 4.14
    7.83 ± 13.64
        2min
    5.46 ± 3.58
    5.80 ± 5.07
        4min
    36.33 ± 89.24
    21.69 ± 58.86
        6min
    41.34 ± 89.62
    49.42 ± 105.58
        8min
    44.30 ± 72.79
    63.96 ± 120.36
        10min
    41.89 ± 65.54
    69.26 ± 149.16
        15min
    41.75 ± 66.89
    102.67 ± 197.67
        20min
    42.89 ± 69.09
    90.52 ± 149.26
        30min
    36.55 ± 60.21
    73.20 ± 129.09
        60min
    8.26 ± 8.43
    25.60 ± 65.97
        90min
    4.23 ± 5.86
    7.79 ± 9.31
    Statistical analysis title
    Change in area of the erythema
    Statistical analysis description
    Linear mixed effect model
    Comparison groups
    Test product v Placebo
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Confidence interval

    Secondary: Occurance of AEs

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    End point title
    Occurance of AEs
    End point description
    End point type
    Secondary
    End point timeframe
    all subjects exposed to study product were included into the safety population
    End point values
    Test product Placebo Safety population
    Number of subjects analysed
    43
    44
    44
    Units: number
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    All subjects exposed to the study products were a part of the safety analysis. All Adverse Events (AE) reported during the study should be included in this analysis.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    -

    Reporting group title
    Test product
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    Safety population Test product Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    Safety population Test product Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 43 (0.00%)
    0 / 44 (0.00%)
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: During the study there were no adverse events (AEs) reported in the study subjects

    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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