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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double Blind, Vehicle Controlled Study of the Efficacy and Safety of Crisaborole Ointment, 2% in Chinese and Japanese Pediatric and Adult Subjects (Ages 2 Years and Older) With Mild to Moderate Atopic Dermatitis

    Summary
    EudraCT number
    		 2021-006538-38
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    08 Sep 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Mar 2022
    First version publication date
    01 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C3291032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04360187
    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., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Sep 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of crisaborole ointment, 2% in Chinese and Japanese pediatric and adult subjects (ages 2 years and older) with mild to moderate atopic dermatitis involving at least 5% treatable body surface area (BSA).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed. The external data monitoring committee (E-DMC) was responsible for ongoing monitoring of the safety of subjects in the study according to the charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jul 2020
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    China: 237
    Country: Number of subjects enrolled
    Japan: 154
    Worldwide total number of subjects
    391
    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)
    192
    Adolescents (12-17 years)
    40
    Adults (18-64 years)
    154
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 418 subjects were screened, 391 of whom were randomized and treated.

    Period 1
    Period 1 title
    Double-Blind Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vehicle Twice a Day (BID)
    Arm description
    		 Vehicle was applied BID for 28 days to the Treatable body surface area (BSA) identified at Baseline/Day 1 and new atopic dermatitis (AD) lesions that appear after the Baseline/Day 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle was applied BID to all treatable AD involved areas (excluding the scalp) identified at Baseline/Day 1 through Day 28

    Arm title
    		 Crisaborole 2% Twice a Day (BID)
    Arm description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crisaborole 2%
    Investigational medicinal product code
    PF-06930164
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Crisaborole 2% was applied BID to all treatable AD involved areas (excluding the scalp) identified at Baseline/Day 1 through Day 28

    Number of subjects in period 1
    		Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Started
    131
    260
    Completed
    108
    245
    Not completed
    23
    15
         Physician decision
    1
    -
         Consent withdrawn by subject
    4
    2
         Adverse event, non-fatal
    9
    11
         Withdrawal By Parent/Guardian
    2
    -
         Lack of efficacy
    7
    2
    Period 2
    Period 2 title
    Follow-Up
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vehicle Twice a Day (BID)
    Arm description
    		 Vehicle was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Vehicle was applied BID to all treatable AD involved areas (excluding the scalp) identified at Baseline/Day 1 through Day 28

    Arm title
    		 Crisaborole 2% Twice a Day (BID)
    Arm description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crisaborole 2%
    Investigational medicinal product code
    PF-06930164
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Crisaborole 2% was applied BID to all treatable AD involved areas (excluding the scalp) identified at Baseline/Day 1 through Day 28

    Number of subjects in period 2 [1]
    		Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Started
    114
    232
    Completed
    113
    232
    Not completed
    1
    0
         Lost to follow-up
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: All subjects from double-blind treatment period did not enter into follow-up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vehicle Twice a Day (BID)
    Reporting group description
    		 Vehicle was applied BID for 28 days to the Treatable body surface area (BSA) identified at Baseline/Day 1 and new atopic dermatitis (AD) lesions that appear after the Baseline/Day 1.

    Reporting group title
    Crisaborole 2% Twice a Day (BID)
    Reporting group description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.

    Reporting group values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID) Total
    Number of subjects
    		 131 260 391
    Age Categorical
    Units: Subjects
        2-11 Years
    		 69 123 192
        12-17 Years
    		 15 25 40
        >=18 Years
    		 47 112 159
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 16.0 ± 13.58 19.4 ± 15.80 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 64 122 186
        Male
    		 67 138 205
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 131 260 391
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 0 0 0
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 0 0 0
        Not Hispanic or Latino
    		 131 260 391
        Unknown or Not Reported
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Vehicle Twice a Day (BID)
    Reporting group description
    		 Vehicle was applied BID for 28 days to the Treatable body surface area (BSA) identified at Baseline/Day 1 and new atopic dermatitis (AD) lesions that appear after the Baseline/Day 1.

    Reporting group title
    Crisaborole 2% Twice a Day (BID)
    Reporting group description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.
    Reporting group title
    Vehicle Twice a Day (BID)
    Reporting group description
    		 Vehicle was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.

    Reporting group title
    Crisaborole 2% Twice a Day (BID)
    Reporting group description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.

    Primary: Percent Change From Baseline in Eczema Area and Severity Index (EASI) Total Score at Day 29

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    End point title
    		 Percent Change From Baseline in Eczema Area and Severity Index (EASI) Total Score at Day 29
    End point description
    The EASI quantifies the severity of a subject's atopic dermatitis (AD) based on both severity of lesion clinical signs and the percent of body surface area (BSA) affected. EASI is a composite scoring of the degree of erythema, induration/papulation, excoriation, and lichenification (each scored separately) for each of four body regions, with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Primary
    End point timeframe
    Baseline, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    124
    256
    Units: Percent Change
        least squares mean (confidence interval 95%)
    -42.79 (-50.14 to -35.44)
    -59.92 (-64.86 to -54.98)
    Statistical analysis title
    		 Crisaborole versus Vehicle
    Comparison groups
    Crisaborole 2% Twice a Day (BID) v Vehicle Twice a Day (BID)
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0002
    Method
    		 Mixed effect Model for Repeated Measures
    Parameter type
    		 LS mean of difference
    Point estimate
    -17.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.98
         upper limit
    		 -8.27

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

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    End point title
    		 Percentage of Subjects With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [1]
    End point description
    An adverse event was considered as a treatment-emergent adverse event (TEAE) if the event started after the first dose of treatment regardless of whether a similar event of equal or greater severity existed in the baseline period. 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. AEs are classified according to the severity in 3 categories a) mild – AEs does not interfere with subject’s usual function b) moderate – AEs interferes to some extent with subject’s usual function c) severe – AEs interferes significantly with subject’s usual function. Overall number of subjects analyzed included all subjects who were randomized and received at least 1 confirmed dose of investigational product.
    End point type
    Primary
    End point timeframe
    Baseline up to Day 60
    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
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
    number (not applicable)
        With Adverse Events (AEs)
    44.3
    46.2
        With Serious AEs
    0.8
    0.4
        With Severe AEs
    1.5
    0
        Discontinued (D/C) From Study due to AEs
    0.8
    0
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Clinically Significant Changes From Baseline in Clinical Laboratory Parameters

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    End point title
    		 Percentage of Subjects With Clinically Significant Changes From Baseline in Clinical Laboratory Parameters [2]
    End point description
    Laboratory parameters included: hematology and chemistry. Clinically significant laboratory abnormalities are defined as abnormal values that have clinical manifestations or require medical intervention. Clinically significant laboratory criteria included Hemoglobin <0.8 x lower limit of normal (LLN), Leukocytes >1.5 x upper limit of normal (ULN), Lymphocytes <0.8 x LLN, Lymphocytes/Leukocytes >1.2 x ULN, Neutrophils <0.8 x LLN, Neutrophils >1.2x ULN, Neutrophils/Leukocytes <0.8 x LLN, Basophils/Leukocytes >1.2 x ULN, Eosinophils >1.2 x ULN, Eosinophils/Leukocytes >1.2 x ULN, Monocytes >1.2 x ULN, Monocytes/Leukocytes (%) >1.2 x ULN, Bicarbonate <0.9 x LLN, and Glucose >1.5x ULN. Overall number of subjects analyzed included all subjects who were randomized and received at least 1 confirmed dose of investigational product.
    End point type
    Primary
    End point timeframe
    Baseline up to 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
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    126
    258
    Units: Percentage of Subjects
    number (not applicable)
        Hemoglobin <0.8 x lower limit of normal (LLN)
    1.6
    0
        Leukocytes >1.5 x upper limit of normal (ULN)
    0
    0.4
        Lymphocytes <0.8 x LLN
    0.8
    0
        Lymphocytes/Leukocytes >1.2 x ULN
    3.2
    1.9
        Neutrophils <0.8 x LLN
    0
    0.4
        Neutrophils >1.2 x ULN
    0
    0.4
        Neutrophils/Leukocytes <0.8 x LLN
    3.2
    2.7
        Basophils/Leukocytes >1.2 x ULN
    4.8
    3.1
        Eosinophils >1.2 x ULN
    33.1
    31.1
        Eosinophils/Leukocytes >1.2 x ULN
    29.8
    33.1
        Monocytes >1.2 x ULN
    0
    0.4
        Monocytes/Leukocytes >1.2 x ULN
    1.6
    1.6
        Bicarbonate <0.9 x LLN
    0.8
    0.8
        Glucose >1.5 x ULN
    0
    0.8
    No statistical analyses for this end point

    Primary: Percentage of Subjects With Clinically Significant Changes From Baseline in Vital Signs

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    End point title
    		 Percentage of Subjects With Clinically Significant Changes From Baseline in Vital Signs [3]
    End point description
    Vital signs (temperature, respiratory rate, pulse, systolic and diastolic blood pressure) were obtained with subjects in the seated position, after having sat/lied calmly for at least 5 minutes. Clinically significant vital signs criteria included Diastolic Blood Pressure (DBP) Value <50 mmHg, DBP Change ≥20 mmHg increase, DBP Change ≥20 mmHg decrease, Pulse Rate Value >120 beats per minute (bpm), Systolic Blood Pressure (SBP) Value <90 mmHg, SBP Change ≥30 mmHg increase, SBP Change ≥30mmHg decrease. Overall number of subjects analyzed included all subjects who were randomized and received at least 1 confirmed dose of investigational product.
    End point type
    Primary
    End point timeframe
    Baseline up to 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
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    129
    259
    Units: Percentage of Subjects
    number (not applicable)
        Diastolic Blood Pressure (DBP) Value <50 mmHg
    7.8
    7.3
        DBP Change ≥20mmHg increase
    2.3
    3.5
        DBP Change ≥20mmHg decrease
    3.9
    3.1
        Pulse Rate Value >120 beats per minute (bpm)
    2.3
    1.9
        Systolic Blood Pressure (SBP) Value <90mmHg
    23.3
    26.3
        SBP Change ≥30mmHg increase
    0
    2.3
        SBP Change ≥30mmHg decrease
    3.1
    0.8
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Improvement in Investigator's Static Global Assessment (ISGA) at Day 29

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    End point title
    		 Percentage of Subjects Achieving Improvement in Investigator's Static Global Assessment (ISGA) at Day 29
    End point description
    ISGA assessed the severity of AD 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, 1 = almost clear, 2 = mild, 3 = moderate, and 4 = severe. Improvement in ISGA is defined as ISGA score of 0 or 1. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
        number (confidence interval 95%)
    28.5 (20.4 to 36.6)
    41.4 (35.4 to 47.5)
    Statistical analysis title
    		 Crisaborole versus Vehicle
    Comparison groups
    Vehicle Twice a Day (BID) v Crisaborole 2% Twice a Day (BID)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0124
    Method
    		 normal approximation to response rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    12.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.8
         upper limit
    		 23.1

    Secondary: Percentage of Subjects Achieving Success in ISGA at Day 29

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    End point title
    		 Percentage of Subjects Achieving Success in ISGA at Day 29
    End point description
    ISGA assessed the severity of AD 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, 1 = almost clear, 2 = mild, 3 = moderate, and 4 = severe. Success in ISGA is defined as an ISGA score of Clear (0) or Almost Clear (1) with at least a 2 grade improvement from Baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
        number (confidence interval 95%)
    15.9 (9.4 to 22.5)
    27.6 (22.1 to 33.1)
    Statistical analysis title
    		 Crisaborole versus Vehicle
    Comparison groups
    Vehicle Twice a Day (BID) v Crisaborole 2% Twice a Day (BID)
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0078
    Method
    		 normal approximation to response rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    11.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.1
         upper limit
    		 20.3

    Secondary: Change From Baseline in Peak Pruritus Numeric Rating Scale (NRS) at Week 4-for Subjects ≥12 years

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    End point title
    		 Change From Baseline in Peak Pruritus Numeric Rating Scale (NRS) at Week 4-for Subjects ≥12 years
    End point description
    Subject-rated pruritus score of lesions rated the severity of pruritus suffered in the past 24 hours on an 11-point NRS where 0 is no pruritus and 10 is worst itch imaginable. Change: score at Week 4 minus score at baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    60
    131
    Units: Units on a Scale
        least squares mean (confidence interval 95%)
    -0.79 (-1.18 to -0.40)
    -1.58 (-1.84 to -1.33)
    Statistical analysis title
    		 Crisaborole versus Vehicle
    Comparison groups
    Vehicle Twice a Day (BID) v Crisaborole 2% Twice a Day (BID)
    Number of subjects included in analysis
    191
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0009
    Method
    		 Mixed effect Model for Repeated Measures
    Parameter type
    		 LS mean of difference
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.26
         upper limit
    		 -0.33

    Secondary: Percentage of Subjects Achieving Success in ISGA Over Time

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    End point title
    		 Percentage of Subjects Achieving Success in ISGA Over Time
    End point description
    ISGA assessed the severity of AD 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, 1 = almost clear, 2 = mild, 3 = moderate, and 4 = severe. Success in ISGA is defined as an ISGA score of Clear (0) or Almost Clear (1) with at least a 2 grade improvement from Baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 8
    0.0 (-0.2 to 0.2)
    4.8 (2.2 to 7.4)
        Day 15
    4.9 (1.1 to 8.7)
    11.6 (7.6 to 15.6)
        Day 22
    10.8 (5.2 to 16.3)
    18.1 (13.4 to 22.8)
        Day 29
    15.9 (9.4 to 22.5)
    27.6 (22.1 to 33.1)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Improvement in ISGA Over Time

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    End point title
    		 Percentage of Subjects Achieving Improvement in ISGA Over Time
    End point description
    ISGA assessed the severity of AD on a 5-point scale ranged from 0 (clear) to 4 (maximum severe), where higher scores indicate higher degree of AD. Improvement in ISGA is defined as an ISGA score of Clear (0) or Almost Clear (1). Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 8
    7.8 (3.2 to 12.4)
    16.8 (12.3 to 21.4)
        Day 15
    18.3 (11.6 to 25.1)
    25.6 (20.2 to 31.0)
        Day 22
    25.1 (17.4 to 32.7)
    32.3 (26.6 to 38.1)
        Day 29
    28.5 (20.4 to 36.6)
    41.4 (35.4 to 47.5)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in EASI Total Score Over Time

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    End point title
    		 Percent Change From Baseline in EASI Total Score Over Time
    End point description
    The EASI quantifies the severity of a subject's AD based on both severity of lesion clinical signs and the percent of BSA affected. EASI is a composite scoring of the degree of erythema, induration/papulation, excoriation, and lichenification (each scored separately) for each of four body regions, with adjustment for the percent of BSA involved for each body region and for the proportion of the body region to the whole body. Total EASI score ranged from 0.0 to 72.0, higher scores = greater severity of AD. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    124
    256
    Units: Percent Change
    least squares mean (confidence interval 95%)
        Day 8
    -21.43 (-28.43 to -14.44)
    -36.65 (-41.52 to -31.78)
        Day 15
    -37.15 (-44.24 to -30.05)
    -49.65 (-54.53 to -44.76)
        Day 22
    -42.92 (-50.16 to -35.69)
    -55.05 (-59.96 to -50.13)
        Day 29
    -42.79 (-50.14 to -35.44)
    -59.92 (-64.86 to -54.98)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Percent Body Surface Area (%BSA) Over Time

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    End point title
    		 Change from Baseline in Percent Body Surface Area (%BSA) Over Time
    End point description
    4 body regions were evaluated: head and neck, upper limbs, trunk (including axillae and groin) and lower limbs (including buttocks). Scalp was excluded. BSA was calculated using handprint method. Number of handprints (size of subject's hand with fingers in a closed position) fitting in the affected area of a body region was estimated. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    129
    259
    Units: Percentage BSA
    least squares mean (confidence interval 95%)
        Day 8
    -1.75 (-3.37 to -0.13)
    -5.12 (-6.26 to -3.98)
        Day 15
    -3.31 (-4.94 to -1.68)
    -7.60 (-8.75 to -6.46)
        Day 22
    -4.38 (-6.04 to -2.71)
    -8.72 (-9.87 to -7.57)
        Day 29
    -4.81 (-6.50 to -3.11)
    -9.89 (-11.05 to -8.73)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving EASI-50 Over Time

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    End point title
    		 Percentage of Subjects Achieving EASI-50 Over Time
    End point description
    The EASI quantifies the severity of a subject's AD based on both severity of lesion clinical signs and the percent of BSA affected. The EASI score can vary in increments of range from 0.0 to 72.0, with higher scores representing greater severity of atopic dermatitis. EASI-50 is defined as EASI score has ≥50% improvement from baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 8
    18.5 (11.8 to 25.1)
    37.1 (31.2 to 43.0)
        Day 15
    32.7 (24.5 to 40.8)
    58.9 (52.9 to 65.0)
        Day 22
    42.2 (33.5 to 50.9)
    66.4 (60.7 to 72.2)
        Day 29
    49.4 (40.5 to 58.2)
    72.7 (67.3 to 78.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving EASI-75 Over Time

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    End point title
    		 Percentage of Subjects Achieving EASI-75 Over Time
    End point description
    The EASI quantifies the severity of a subject's AD based on both severity of lesion clinical signs and the percent of BSA affected. The EASI score can vary in increments of range from 0.0 to 72.0, with higher scores representing greater severity of atopic dermatitis. EASI-75 is defined as EASI score has ≥75% improvement from baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    131
    260
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Day 8
    6.1 (2.0 to 10.2)
    11.2 (7.4 to 15.0)
        Day 15
    15.4 (9.2 to 21.6)
    26.3 (20.9 to 31.7)
        Day 22
    26.3 (18.6 to 34.0)
    38.2 (32.2 to 44.1)
        Day 29
    27.6 (19.8 to 35.4)
    46.4 (40.3 to 52.5)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Peak Pruritus NRS Over Time-for Subjects ≥12 Years

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    End point title
    		 Change From Baseline in Peak Pruritus NRS Over Time-for Subjects ≥12 Years
    End point description
    Peak Pruritus NRS is subjects-rated pruritus score of lesions rated the severity of pruritus suffered in the past 24 hours on an 11-point NRS where 0 is no pruritus and 10 is worst itch imaginable. Change: score at observation minus score at baseline. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    60
    131
    Units: Units on a Scale
    least squares mean (confidence interval 95%)
        Week 1
    -0.38 (-0.75 to -0.01)
    -0.94 (-1.19 to -0.69)
        Week 2
    -0.53 (-0.90 to -0.15)
    -1.26 (-1.52 to -1.01)
        Week 3
    -0.64 (-1.02 to -0.26)
    -1.41 (-1.66 to -1.16)
        Week 4
    -0.79 (-1.18 to -0.40)
    -1.58 (-1.84 to -1.33)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Reported Itch Severity Scale Over Time-for Subjects ≥6 Years and <12 Years

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    End point title
    		 Change From Baseline in Patient Reported Itch Severity Scale Over Time-for Subjects ≥6 Years and <12 Years
    End point description
    Patient Reported Itch Severity Scale is a 5-point scale indicating no itchy to very itchy (ranged from 0 to 4, where 0=no itch to 4=worst itch imaginable) for subjects ≥6 and <12 years of age. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    36
    76
    Units: Units on a Scale
    least squares mean (confidence interval 95%)
        Week 1
    -0.26 (-0.47 to -0.05)
    -0.51 (-0.66 to -0.36)
        Week 2
    -0.22 (-0.43 to -0.01)
    -0.70 (-0.85 to -0.55)
        Week 3
    -0.37 (-0.59 to -0.16)
    -0.78 (-0.92 to -0.63)
        Week 4
    -0.52 (-0.74 to -0.30)
    -0.86 (-1.00 to -0.71)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Observer Reported Itch Severity Scale Over Time-for Subjects <6 Years

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    End point title
    		 Change From Baseline in Observer Reported Itch Severity Scale Over Time-for Subjects <6 Years
    End point description
    Observer Reported Itch Severity Scale is an 11-point (ranged from 0 to 10, where 0=no itch to 10=worst itch imaginable) scale and must be completed by the observer (caregivers of subjects) for subjects <6 years of age. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    30
    41
    Units: Units on a Scale
    least squares mean (confidence interval 95%)
        Week 1
    -0.31 (-0.80 to 0.17)
    -1.03 (-1.44 to -0.62)
        Week 2
    -0.73 (-1.22 to -0.24)
    -1.68 (-2.10 to -1.27)
        Week 3
    -0.96 (-1.46 to -0.47)
    -1.79 (-2.21 to -1.38)
        Week 4
    -1.25 (-1.75 to -0.75)
    -1.95 (-2.37 to -1.53)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score Over Time

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    End point title
    		 Change From Baseline in Dermatology Life Quality Index (DLQI) Total Score Over Time
    End point description
    The DLQI was a 10-item questionnaire that measures the impact of skin disease on subject's quality of life. The questionnaire will be completed by all subjects aged 16 years and older, based on the age at Screening Visit/time of informed consent/assent. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    49
    117
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -1.1 ± 4.02
    -1.7 ± 3.57
        Day 29
    -1.5 ± 4.67
    -1.8 ± 4.11
    No statistical analyses for this end point

    Secondary: Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) Score Over Time

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    End point title
    		 Change From Baseline in Children's Dermatology Life Quality Index (CDLQI) Score Over Time
    End point description
    The CDLQI was a 10-item questionnaire that measures the impact of skin disease on children's (aged 4-15 years) quality of life. The CDLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    67
    127
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -1.3 ± 5.18
    -3.6 ± 4.64
        Day 29
    -1.8 ± 6.00
    -3.9 ± 5.37
    No statistical analyses for this end point

    Secondary: Change From Infants' Dermatitis Quality of Life Index (IDQOL) Total Score Over Time

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    End point title
    		 Change From Infants' Dermatitis Quality of Life Index (IDQOL) Total Score Over Time
    End point description
    The IDQOL was completed by observer for subjects aged 2-3 years, based on the age at the Screening Visit/time of informed consent/assent. The IDQOL is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score the more quality of life is impaired. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    15
    16
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -1.3 ± 3.34
    -3.0 ± 3.30
        Day 29
    -0.7 ± 3.86
    -4.3 ± 4.44
    No statistical analyses for this end point

    Secondary: Change From Baseline in Dermatitis Family Impact Questionnaire (DFI) Score Over Time

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    End point title
    		 Change From Baseline in Dermatitis Family Impact Questionnaire (DFI) Score Over Time
    End point description
    The DFI was completed by all observer for subjects aged 2-17 years, based on the age at Screening Visit/time of informed consent/assent. The minimum DFI score is 0; the maximum DFI score is 30. The higher score means worse outcome. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    84
    148
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -0.5 ± 3.87
    -2.4 ± 4.66
        Day 29
    -2.1 ± 4.86
    -3.0 ± 5.22
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient-Oriented Eczema Measure (POEM) Over Time in Subjects ≥12 Years

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    End point title
    		 Change From Baseline in Patient-Oriented Eczema Measure (POEM) Over Time in Subjects ≥12 Years
    End point description
    The POEM is a validated 7-item measure used to assess the impact of AD over the past week. The POEM contains 7 symptom based questions with responses rating number of days each symptom is experienced over the past week, from 0 (no days) to 4 (every day), with a maximum score of 28. Higher score means worse outcome. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    62
    137
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -1.8 ± 5.25
    -5.4 ± 5.19
        Day 29
    -3.3 ± 5.38
    -5.7 ± 6.32
    No statistical analyses for this end point

    Secondary: Change From Baseline in POEM Over Time in Subjects ≥2 Years and <12 Years

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    End point title
    		 Change From Baseline in POEM Over Time in Subjects ≥2 Years and <12 Years
    End point description
    The POEM is a validated 7-item measure used to assess the impact of AD over the past week. The POEM contains 7 symptom based questions with responses rating number of days each symptom is experienced over the past week, from 0 (no days) to 4 (every day), with a maximum score of 28. Higher score means worse outcome. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 15, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    69
    123
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 15
    -2.5 ± 5.17
    -6.7 ± 6.09
        Day 29
    -3.8 ± 5.33
    -7.7 ± 5.41
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Average of Patient Global Impression of Severity (PGIS) Score

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    End point title
    		 Change From Baseline in Weekly Average of Patient Global Impression of Severity (PGIS) Score
    End point description
    The PGIS (for subjects 12 years and older) is a single item patient-rated measure of the subject's AD condition severity at a given point in time. This single item instrument uses a 7-point rating scale, which range from 1 to 7, where 1=Not present to 7=Extremely severe. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    61
    133
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Week 1
    -0.24 ± 0.511
    -0.43 ± 0.649
        Week 2
    -0.26 ± 0.692
    -0.60 ± 0.836
        Week 3
    -0.38 ± 0.871
    -0.66 ± 0.913
        Week 4
    -0.44 ± 0.965
    -0.71 ± 1.028
    No statistical analyses for this end point

    Secondary: Patient Global Impression of Change (PGIC) Score

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    End point title
    		 Patient Global Impression of Change (PGIC) Score
    End point description
    The PGIC (for subjects 12 years and older) was used to determine global improvement as assessed by the patient. It was used as an anchor to define a responder definition for the peak pruritus scales for ‘clinically important responder’ and as a sensitivity analysis for defining a ‘clinical important difference’ on the peak pruritus scales. This single item instrument is a 7-point rating scale, anchored by (1) ‘very much improved’ to (7) ‘very much worse’. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    62
    137
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 8
    3.3 ± 1.05
    2.6 ± 1.10
        Day 15
    3.2 ± 1.10
    2.6 ± 1.07
        Day 22
    3.0 ± 1.19
    2.6 ± 1.04
        Day 29
    2.9 ± 1.21
    2.5 ± 1.12
    No statistical analyses for this end point

    Secondary: Change From Baseline in Weekly Average of Observer Reported Global Impression of Severity (OGIS) Score

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    End point title
    		 Change From Baseline in Weekly Average of Observer Reported Global Impression of Severity (OGIS) Score
    End point description
    The OGIS (for subjects ≥2 and <12 years) is a single item observer-rated measure of the subject's AD condition severity at a given point in time. This single item instrument uses a 7-point rating scale, which ranged from 1 to 7, where 1=Not present to 7=Extremely severe. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 1, Week 2, Week 3, Week 4
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    67
    119
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Week 1
    -0.12 ± 0.593
    -0.62 ± 0.667
        Week 2
    -0.27 ± 0.617
    -0.93 ± 0.794
        Week 3
    -0.41 ± 0.770
    -1.03 ± 0.822
        Week 4
    -0.54 ± 0.854
    -1.14 ± 0.893
    No statistical analyses for this end point

    Secondary: Observer Reported Global Impression of Change (OGIC) Score

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    End point title
    		 Observer Reported Global Impression of Change (OGIC) Score
    End point description
    The OGIC (for subjects ≥2 and <12 years) was used to determine global improvement as assessed by the observer. It was used as an anchor to define a responder definition for the peak pruritus scales for ‘clinically important responder’ and as a sensitivity analysis for defining a ‘clinical important difference’ on the peak pruritus scales. This single item instrument is a 7-point rating scale, anchored by (1) ‘very much improved’ to (7) ‘very much worse’. Overall number of subjects analyzed included all subjects randomized and dispensed study drug. Subjects were assigned to the randomized treatment regardless of what treatment was received.
    End point type
    Secondary
    End point timeframe
    Day 8, Day 15, Day 22, Day 29
    End point values
    		 Vehicle Twice a Day (BID) Crisaborole 2% Twice a Day (BID)
    Number of subjects analysed
    69
    123
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        Day 8
    3.0 ± 1.08
    2.3 ± 0.81
        Day 15
    3.0 ± 1.10
    2.3 ± 0.92
        Day 22
    2.9 ± 1.16
    2.4 ± 0.99
        Day 29
    2.8 ± 1.07
    2.2 ± 1.05
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to Day 60
    Adverse event reporting additional description
    Same event may appear as AE and serious AE, what is presented are distinct events. Event may be categorized as serious in 1 subject and as non-serious in another subject or 1 subject may have experienced both serious and non-serious event during study. Safety analysis set analyzed.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Crisaborole 2% Twice a Day (BID)
    Reporting group description
    		 Crisaborole 2% was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.

    Reporting group title
    Vehicle Twice a Day (BID)
    Reporting group description
    		 Vehicle was applied BID for 28 days to the Treatable BSA identified at Baseline/Day 1 and new AD lesions that appear after the Baseline/Day 1.

    Serious adverse events
    		 Crisaborole 2% Twice a Day (BID) Vehicle Twice a Day (BID)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 260 (0.38%)
    1 / 131 (0.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Myocardial necrosis marker increased
         subjects affected / exposed
    0 / 260 (0.00%)
    1 / 131 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 260 (0.38%)
    0 / 131 (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: 1%
    Non-serious adverse events
    		 Crisaborole 2% Twice a Day (BID) Vehicle Twice a Day (BID)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    101 / 260 (38.85%)
    43 / 131 (32.82%)
    General disorders and administration site conditions
    Application site discolouration
         subjects affected / exposed
    9 / 260 (3.46%)
    1 / 131 (0.76%)
         occurrences all number
    9
    1
    Application site pain
         subjects affected / exposed
    34 / 260 (13.08%)
    5 / 131 (3.82%)
         occurrences all number
    41
    6
    Application site paraesthesia
         subjects affected / exposed
    7 / 260 (2.69%)
    1 / 131 (0.76%)
         occurrences all number
    8
    1
    Application site irritation
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 131 (0.76%)
         occurrences all number
    3
    1
    Application site urticaria
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 131 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    6 / 260 (2.31%)
    1 / 131 (0.76%)
         occurrences all number
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 131 (0.00%)
         occurrences all number
    5
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    4 / 260 (1.54%)
    3 / 131 (2.29%)
         occurrences all number
    5
    4
    Dermatitis atopic
         subjects affected / exposed
    20 / 260 (7.69%)
    15 / 131 (11.45%)
         occurrences all number
    22
    15
    Pruritus
         subjects affected / exposed
    0 / 260 (0.00%)
    3 / 131 (2.29%)
         occurrences all number
    0
    3
    Miliaria
         subjects affected / exposed
    0 / 260 (0.00%)
    2 / 131 (1.53%)
         occurrences all number
    0
    3
    Dermatitis contact
         subjects affected / exposed
    6 / 260 (2.31%)
    1 / 131 (0.76%)
         occurrences all number
    6
    1
    Urticaria
         subjects affected / exposed
    3 / 260 (1.15%)
    1 / 131 (0.76%)
         occurrences all number
    3
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 131 (1.53%)
         occurrences all number
    3
    2
    Folliculitis
         subjects affected / exposed
    8 / 260 (3.08%)
    6 / 131 (4.58%)
         occurrences all number
    8
    6
    Gastroenteritis
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 131 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    9 / 260 (3.46%)
    4 / 131 (3.05%)
         occurrences all number
    9
    6
    Otitis media acute
         subjects affected / exposed
    1 / 260 (0.38%)
    2 / 131 (1.53%)
         occurrences all number
    1
    2
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 260 (3.46%)
    4 / 131 (3.05%)
         occurrences all number
    10
    4
    Tonsillitis
         subjects affected / exposed
    3 / 260 (1.15%)
    0 / 131 (0.00%)
         occurrences all number
    3
    0
    Pharyngitis
         subjects affected / exposed
    3 / 260 (1.15%)
    2 / 131 (1.53%)
         occurrences all number
    3
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2019
    Updated the primary and key secondary efficacy endpoints to align with global clinical development program, including: Change of primary endpoint from ISGA (Investigator’s Static Global Assessment) to EASI (Eczema Area and Severity Index). Addition of ISGA as a key secondary endpoint. Addition of age specification for Pruritus assessments. Addition of tertiary endpoints pertaining to pruritus assessment.
    28 Aug 2020
    (1) Only for Japan: Japan subjects who completed the study intervention period in Study C3291032 were offered participation in the long-term safety extension study C3291027 if eligibility criteria were met. The subjects who rolled over into study C3291027 without a Post Treatment Follow Up period were considered completers in this study. (2) All female subjects who were of childbearing potential as applicable to the study who were, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must have agreed to use an appropriate method of contraception consistently and correctly for the screening period, the duration of the active treatment period and for at least 28 days after the last dose of investigational product.
    18 Dec 2020
    Updated the sample size and power: The total sample size of 384 subjects in this study with a 2:1 randomization ratio (256:128) provided approximately 90% power to detect a 12% difference of percent change from baseline in EASI total score at Day 29 between crisaborole arm and vehicle arm at the 0.05 (2-sided) significance level, assuming the common standard deviation of percent change from baseline in EASI total score at Day 29 is 34%.

    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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