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    Clinical Trial Results:
    A Multicenter, Randomized, Double-Blind, Vehicle-Controlled Study Of The Safety And Efficacy Of AN2728 Topical Ointment, 2% In children, Adolescents, And Adults (Ages 2 Years And Older) With Atopic Dermatitis

    Summary
    EudraCT number
    		 2018-000731-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    29 Apr 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jun 2018
    First version publication date
    01 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AN2728-AD-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02118766
    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 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrial.gov Call Centers, Pfizer, Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002065-PIP01-16
    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
    23 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Apr 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and efficacy of AN2728 topical ointment, 2% in children, adolescents, and adults (ages 2 years and older) with atopic dermatitis (AD).
    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 Council for 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
    26 Mar 2014
    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
    United States: 763
    Worldwide total number of subjects
    763
    EEA total number of subjects
    0
    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)
    472
    Adolescents (12-17 years)
    188
    Adults (18-64 years)
    101
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 48 centers in United States between 26 March 2014 and 29 April 2015.

    Pre-assignment
    Screening details
    		 This was a multi center, randomized, double-blind, vehicle-controlled study where a total of 763 subjects with mild to moderate AD were randomized to receive either AN2728 ointment, 2 percent or AN2728 ointment matching vehicle, from Day 1 to Day 28.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AN2728 Topical Ointment, 2 Percent
    Arm description
    		 Subjects with mild to moderate AD applied AN2728 ointment, 2 percent to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crisaborole Topical Ointment, 2%
    Investigational medicinal product code
    Other name
    Crisaborole
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    AN2728 topical ointment, 2 percent to treatment targeted lesions, twice daily from Day 1 to Day 28.

    Arm title
    		 AN2728 Topical Ointment, Vehicle
    Arm description
    		 Subjects with mild to moderate AD applied AN2728 ointment matching vehicle to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crisaborole Topical Ointment, Vehicle
    Investigational medicinal product code
    Other name
    Crisaborole
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    AN2728 topical ointment, Vehicle to treatment targeted lesions, twice daily from Day 1 to Day 28.

    Number of subjects in period 1
    		AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Started
    507
    256
    Treated
    503
    256
    Completed
    477
    225
    Not completed
    30
    31
         Consent withdrawn by subject
    3
    6
         Unspecified
    3
    1
         Adverse Events
    7
    2
         Lost to follow-up
    5
    4
         Withdrawal by parent/guardian
    12
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AN2728 Topical Ointment, 2 Percent
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment, 2 percent to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Reporting group title
    AN2728 Topical Ointment, Vehicle
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment matching vehicle to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Reporting group values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle Total
    Number of subjects
    		 507 256 763
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    		 321 151 472
        Adolescents (12-17 years)
    		 121 67 188
        Adults (18-64 years)
    		 63 38 101
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 12.03 ( 11.64 ) 12.36 ( 10.70 ) -
    Gender Categorical
    Units: Subjects
        Female
    		 285 143 428
        Male
    		 222 113 335

    End points

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    End points reporting groups
    Reporting group title
    AN2728 Topical Ointment, 2 Percent
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment, 2 percent to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Reporting group title
    AN2728 Topical Ointment, Vehicle
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment matching vehicle to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Primary: Percentage of Subjects Who Achieved Treatment Success Based on Investigator’s Static Global Assessment (ISGA) at Day 29

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    End point title
    		 Percentage of Subjects Who Achieved Treatment Success Based on Investigator’s Static Global Assessment (ISGA) at Day 29
    End point description
    ISGA assessed the severity of AD (except scalp and venous access area) on a 5-point scale ranged from 0 (clear) to 4 (maximum severe), where higher scores indicate higher degree of AD. Grades for classification of severity: 0= clear (minor residual hypo/hyper pigmentation, no erythema or induration or papulation, no oozing or crusting), 1= almost clear (trace faint pink erythema, with barely perceptible induration or papulation and no oozing or crusting), 2= mild (faint pink erythema with mild induration or papulation and no oozing or crusting), 3= moderate (pink-red erythema with moderate induration or papulation with or without oozing or crusting) and 4= severe (deep or bright red erythema with severe induration or papulation and with oozing or crusting). Treatment success was defined as an ISGA score of Clear (0) or Almost Clear (1) with at least a 2-grade improvement from baseline. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Primary
    End point timeframe
    Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    503
    256
    Units: percentage of subjects
        number (not applicable)
    32.8
    25.4
    Statistical analysis title
    		 AN2728 Topical Ointment 2 percent Vs. Vehicle
    Comparison groups
    AN2728 Topical Ointment, 2 Percent v AN2728 Topical Ointment, Vehicle
    Number of subjects included in analysis
    759
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.038
    Method
    		 Regression, Logistic
    Confidence interval

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

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (AEs) And Serious Adverse Events (SAEs) [1]
    End point description
    An AE was any untoward medical occurrence attributed to 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 were events between first dose of study drug and up to end of study that were absent before treatment or that worsened relative to pre-treatment state. Safety population included all randomized subjects who received at least 1 confirmed dose of study drug, and had at least 1 post-baseline assessment.
    End point type
    Primary
    End point timeframe
    AEs: Baseline (Day 1) up to Day 29, SAEs: Baseline (Day 1) up to Day 36
    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 analyzed for this endpoint.
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    502
    252
    Units: subjects
        AEs
    147
    50
        SAEs
    5
    1
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change From Baseline in Vital Signs at Day 29

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    End point title
    		 Number of Subjects With Clinically Significant Change From Baseline in Vital Signs at Day 29 [2]
    End point description
    Following parameters were analyzed for examination of vital signs: systolic and diastolic blood pressure, respiratory rate and body temperature. Vital sign measurements were performed with the subject in the seated or supine position. Clinical significance of change from baseline value was determined by investigator. Safety population included all randomized subjects who received at least 1 confirmed dose of study drug, and had at least 1 post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Day 29
    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 analyzed for this endpoint.
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    502
    252
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Primary: Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values at Day 29

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    End point title
    		 Number of Subjects With Clinically Significant Change From Baseline in Laboratory Values at Day 29 [3]
    End point description
    Laboratory values included: Alkaline Phosphatase, Alanine Aminotransferase, Aspartate Aminotransferase, Albumin, Blood Urea Nitrogen, Creatinine, Hematocrit, Hemoglobin, Lymphocytes, Monocytes, Neutrophils, Platelets, Basophils, Eosinophils, Red blood cell count, White blood cell count, Total bilirubin and Glucose (nonfasting), Potassium, Total Protein, and Sodium. Clinical significance of change from baseline value was determined by investigator. Safety population included all randomized subjects who received at least 1 confirmed dose of study drug, and had at least 1 post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline, Day 29
    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 analyzed for this endpoint.
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    502
    252
    Units: subjects
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With an Investigator's Static Global Assessment (ISGA) Score of Clear (0) or Almost Clear (1) at Day 29

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    End point title
    		 Percentage of Subjects With an Investigator's Static Global Assessment (ISGA) Score of Clear (0) or Almost Clear (1) at Day 29
    End point description
    ISGA assessed the severity of AD (except scalp and venous access area) on a 5-point scale ranged from 0 (clear) to 4 (maximum severe), where higher scores indicate higher degree of AD. Grades for classification of severity: 0= clear (minor residual discoloration, no erythema or induration or papulation, no oozing or crusting), 1= almost clear (trace faint pink erythema, with barely perceptible induration or papulation and no oozing or crusting), 2= mild (faint pink erythema with mild induration or papulation and no oozing or crusting), 3= moderate (pink-red erythema with moderate induration or papulation with or without oozing or crusting) and 4= severe (deep or bright red erythema with severe induration or papulation and with oozing or crusting). Percentage of subjects with an ISGA score of 0 or 1 were reported. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Secondary
    End point timeframe
    Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    503
    256
    Units: percentage of subjects
        number (not applicable)
    51.7
    40.6
    No statistical analyses for this end point

    Secondary: Time to Achieve Treatment Success Based on Investigator’s Static Global Assessment (ISGA)

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    End point title
    		 Time to Achieve Treatment Success Based on Investigator’s Static Global Assessment (ISGA)
    End point description
    Time to achieve treatment success based on ISGA was defined as the time interval between the administrations of first dose of study drug until first documentation of success in ISGA. Success in ISGA was defined as an ISGA score of clear (0) or almost clear (1) with at least 2-grade improvement from baseline. It was analyzed using Kaplan-Meier method. The median time to achieve success in ISGA and its 95% confidence interval (CI) were not estimable, as fewer subjects (less than 50 percent) reached success in ISGA and has been denoted as 99999. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    503
    256
    Units: days
        median (confidence interval 95%)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Signs of Atopic Dermatitis (AD) at Day 29

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    End point title
    		 Change From Baseline in Signs of Atopic Dermatitis (AD) at Day 29
    End point description
    Signs of AD included erythema, induration/papulation, exudation, excoriation and lichenification. Each sign was assessed on a 4- point scale ranges from 0 to 3, where 0= none, 1= mild, 2= moderate to 3= severe. Higher score indicates severe signs and symptoms of AD. Here ‘n’ signifies those subjects who were evaluable at specified time point for each arm, respectively. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    503
    256
    Units: units on a scale
    arithmetic mean (standard deviation)
        Erythema: Baseline (n= 503, 256)
    1.7 ( 0.59 )
    1.6 ( 0.57 )
        Erythema: Change at Day 29 (n=478,228)
    -0.7 ( 0.79 )
    -0.4 ( 0.77 )
        Induration/Papulation: Baseline (n= 503, 256)
    1.8 ( 0.59 )
    1.9 ( 0.56 )
        Induration/Papulation:Change at Day 29 (n=478,228)
    -0.7 ( 0.85 )
    -0.7 ( 0.73 )
        Exudation: Baseline (n= 503, 256)
    0.8 ( 0.82 )
    0.8 ( 0.86 )
        Exudation: Change at Day 29 (n=478, 228)
    -0.5 ( 0.78 )
    -0.3 ( 0.80 )
        Excoriation: Baseline (n= 503, 256)
    1.4 ( 0.70 )
    1.5 ( 0.71 )
        Excoriation: Change at Day 29 (n=478, 228)
    -0.8 ( 0.81 )
    -0.7 ( 0.89 )
        Lichenification: Baseline (n= 503, 256)
    1.5 ( 0.73 )
    1.5 ( 0.67 )
        Lichenification: Change at Day 29 (n=478, 228)
    -0.7 ( 0.81 )
    -0.5 ( 0.77 )
    No statistical analyses for this end point

    Other pre-specified: Time to Improvement in Pruritus

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    End point title
    		 Time to Improvement in Pruritus
    End point description
    Time to improvement in pruritus was defined as the time interval between the administration of first dose of study drug till the first documentation of improvement in pruritus. Improvement in pruritus was defined as achieving none (0) or mild (1) score with at least a 1- grade improvement from baseline. Severity of pruritus was assessed on 4-point numeric scale ranges from 0 to 3, where 0= none (no itching), 1= mild (occasional, slight itching/scratching), 2= moderate (constant or intermittent itching/scratching which is not disturbing sleep) and 3= severe (bothersome itching/scratching which is disturbing sleep). Higher scores indicated more severe condition. It was analyzed using Kaplan-Meier method. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    428
    210
    Units: days
        median (confidence interval 95%)
    1.32 (1.19 to 1.60)
    1.87 (1.45 to 2.64)
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Dermatology Life Quality Index (DLQI) Score at Day 29

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    End point title
    		 Change From Baseline in Dermatology Life Quality Index (DLQI) Score at Day 29
    End point description
    The DLQI was a 10-item questionnaire that measures the impact of skin disease on subject’s quality of life. Each question was evaluated on a 4-point scale ranging from 0 (not at all) to 3 (very much); where higher scores indicate more impact on quality of life. The DLQI total score ranges from 0 (not at all) to 30 (very much): 0-1 = no effect at all on the subject’s life; 2-6 = small effect on the subject’s life; 7-12 = moderate effect on the subject's life; 13-18 = very large effect on the subject’s life; 19-30 = extremely large effect on the subjects’s life. Higher scores indicate more impact on quality of life of subjects. Here, ‘n’ signifies those subjects who were evaluable at specified time point for each arm, respectively. Intent to treat population included all randomized subjects who received the study drug.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Day 29
    End point values
    		 AN2728 Topical Ointment, 2 Percent AN2728 Topical Ointment, Vehicle
    Number of subjects analysed
    503
    256
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline (n =95, 52)
    9.6 ( 6.37 )
    9.5 ( 6.52 )
        Change at Day 29 (n =87, 44)
    -5.5 ( 5.45 )
    -3.6 ( 4.60 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to end of study (Day 36)
    Adverse event reporting additional description
    Same event may appear as both an AE and Serious AE. However, what is presented are distinct events. An event may be categorized as serious in one subject and as non-serious in another, or a subject may have experienced both a serious and non-serious event.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Crisaborole (AN2728) Ointment, 2 percent
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment, 2 percent to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Reporting group title
    Crisaborole (AN2728) Ointment Vehicle
    Reporting group description
    		 Subjects with mild to moderate AD applied AN2728 ointment matching vehicle to treatment-targeted lesions, twice daily from Day 1 to Day 28. Target lesions were identified at Baseline (Day 1) by investigator.

    Serious adverse events
    		 Crisaborole (AN2728) Ointment, 2 percent Crisaborole (AN2728) Ointment Vehicle
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 502 (1.00%)
    1 / 252 (0.40%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Kawasaki's disease
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Crisaborole (AN2728) Ointment, 2 percent Crisaborole (AN2728) Ointment Vehicle
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    145 / 502 (28.88%)
    50 / 252 (19.84%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Application site acne
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Application site discolouration
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Application site erosion
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Application site erythema
         subjects affected / exposed
    2 / 502 (0.40%)
    1 / 252 (0.40%)
         occurrences all number
    2
    1
    Application site irritation
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Application site pain
         subjects affected / exposed
    31 / 502 (6.18%)
    3 / 252 (1.19%)
         occurrences all number
    34
    3
    Application site pruritus
         subjects affected / exposed
    4 / 502 (0.80%)
    3 / 252 (1.19%)
         occurrences all number
    4
    3
    Application site rash
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Application site urticaria
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Application site vesicles
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    2
    Influenza like illness
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Medical device pain
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Pyrexia
         subjects affected / exposed
    12 / 502 (2.39%)
    3 / 252 (1.19%)
         occurrences all number
    14
    3
    Immune system disorders
    Food allergy
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    3 / 502 (0.60%)
    0 / 252 (0.00%)
         occurrences all number
    4
    0
    Cough
         subjects affected / exposed
    5 / 502 (1.00%)
    1 / 252 (0.40%)
         occurrences all number
    5
    1
    Dyspnoea
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    7 / 502 (1.39%)
    0 / 252 (0.00%)
         occurrences all number
    7
    0
    Nasal polyps
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 502 (0.80%)
    0 / 252 (0.00%)
         occurrences all number
    4
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Wheezing
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Depression
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Listless
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Blood pressure systolic increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Eosinophil count increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Monocyte count increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Staphylococcus test positive
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Blood urea increased
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Burns first degree
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Scratch
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    5 / 502 (1.00%)
    0 / 252 (0.00%)
         occurrences all number
    5
    0
    Presyncope
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphocytosis
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 502 (0.20%)
    2 / 252 (0.79%)
         occurrences all number
    1
    2
    Neutropenia
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    4 / 502 (0.80%)
    1 / 252 (0.40%)
         occurrences all number
    4
    1
    Myopia
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Xerophthalmia
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Anal fissure
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Dental discomfort
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 502 (0.60%)
    0 / 252 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    4 / 502 (0.80%)
    0 / 252 (0.00%)
         occurrences all number
    4
    0
    Tooth disorder
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    8 / 502 (1.59%)
    3 / 252 (1.19%)
         occurrences all number
    9
    3
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Dermatitis atopic
         subjects affected / exposed
    3 / 502 (0.60%)
    2 / 252 (0.79%)
         occurrences all number
    3
    2
    Eczema
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Erythema
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Ingrowing nail
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Pain of skin
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Pruritus generalised
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Rash papular
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Skin erosion
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    3
    0
    Miliaria
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Back pain
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Scoliosis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Growing pains
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Acarodermatitis
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Application site folliculitis
         subjects affected / exposed
    2 / 502 (0.40%)
    2 / 252 (0.79%)
         occurrences all number
    2
    2
    Application site infection
         subjects affected / exposed
    0 / 502 (0.00%)
    2 / 252 (0.79%)
         occurrences all number
    0
    2
    Bronchitis
         subjects affected / exposed
    3 / 502 (0.60%)
    0 / 252 (0.00%)
         occurrences all number
    3
    0
    Cellulitis
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Croup infectious
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Eczema infected
         subjects affected / exposed
    4 / 502 (0.80%)
    0 / 252 (0.00%)
         occurrences all number
    4
    0
    Folliculitis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Hand-foot-and-mouth disease
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Impetigo
         subjects affected / exposed
    5 / 502 (1.00%)
    0 / 252 (0.00%)
         occurrences all number
    5
    0
    Influenza
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Molluscum contagiosum
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    9 / 502 (1.79%)
    0 / 252 (0.00%)
         occurrences all number
    9
    0
    Oral herpes
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Otitis externa
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    2 / 502 (0.40%)
    2 / 252 (0.79%)
         occurrences all number
    2
    2
    Otitis media acute
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    3 / 502 (0.60%)
    0 / 252 (0.00%)
         occurrences all number
    3
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    1 / 502 (0.20%)
    2 / 252 (0.79%)
         occurrences all number
    1
    2
    Prostate infection
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Pyoderma
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Rash pustular
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    3 / 502 (0.60%)
    0 / 252 (0.00%)
         occurrences all number
    3
    0
    Skin infection
         subjects affected / exposed
    2 / 502 (0.40%)
    1 / 252 (0.40%)
         occurrences all number
    2
    1
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    14 / 502 (2.79%)
    10 / 252 (3.97%)
         occurrences all number
    15
    11
    Urinary tract infection
         subjects affected / exposed
    0 / 502 (0.00%)
    1 / 252 (0.40%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 502 (0.20%)
    1 / 252 (0.40%)
         occurrences all number
    1
    1
    Viral rash
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 502 (0.40%)
    0 / 252 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Iron deficiency
         subjects affected / exposed
    1 / 502 (0.20%)
    0 / 252 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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