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    Clinical Trial Results:
    A Multicenter, Open-Label Study of the Long-Term Safety of AN2728 Topical Ointment, 2% in the Treatment of Children, Adolescents, and Adults (Ages 2 Years and Older) With Atopic Dermatitis

    Summary
    EudraCT number
    		 2018-000904-40
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    27 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 May 2019
    First version publication date
    17 May 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    C3291005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 800-718-1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    24 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the long-term safety of open-label treatment with AN2728 Topical Ointment, 2% in children, adolescents, and adults (ages 2 years and older) with mild to moderate 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 trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Apr 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: 517
    Worldwide total number of subjects
    517
    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)
    308
    Adolescents (12-17 years)
    146
    Adults (18-64 years)
    61
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted at 41 investigational sites in the United States from 30 Apr 2014 to 27 Aug 2015. A total of 517 subjects were enrolled.

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

    Arms
    Arm title
    		 AN2728 Ointment, 2 percent
    Arm description
    		 AN2728 ointment 2 percent was applied topically to investigator-identified AD-involved areas of the skin (excluding scalp) in subjects with mild to moderate AD, twice daily in each treatment cycle for up to 48 weeks (each cycle 4 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AN2728 Topical Ointment, 2%
    Investigational medicinal product code
    Other name
    Crisaborole
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Subjects were applied AN2728 Topical Ointment, 2 percent twice daily for 48 weeks (each cycle 4 weeks).

    Number of subjects in period 1
    		AN2728 Ointment, 2 percent
    Started
    517
    Completed
    271
    Not completed
    246
         Consent withdrawn by subject
    23
         Adverse event
    9
         Withdrawal by Parent/Guardian
    63
         Unspecified
    115
         Lost to follow-up
    36

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AN2728 Ointment, 2 percent
    Reporting group description
    		 AN2728 ointment 2 percent was applied topically to investigator-identified AD-involved areas of the skin (excluding scalp) in subjects with mild to moderate AD, twice daily in each treatment cycle for up to 48 weeks (each cycle 4 weeks).

    Reporting group values
    		 AN2728 Ointment, 2 percent Total
    Number of subjects
    		 517 517
    Age Categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 308 308
        Adolescents (12-17 years)
    		 146 146
        Adults (18-64 years)
    		 61 61
        From 65-84 years
    		 2 2
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 11.71 ± 10.39 -
    Gender Categorical
    Units: Subjects
        Female
    		 306 306
        Male
    		 211 211
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 28 28
        Black or African American
    		 152 152
        Native Hawaiian or Other Pacific Islander
    		 1 1
        White
    		 315 315
        Other
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    AN2728 Ointment, 2 percent
    Reporting group description
    		 AN2728 ointment 2 percent was applied topically to investigator-identified AD-involved areas of the skin (excluding scalp) in subjects with mild to moderate AD, twice daily in each treatment cycle for up to 48 weeks (each cycle 4 weeks).

    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 in a subject who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug and up to end of study (up to 48 weeks) that were absent before treatment or that worsened relative to pretreatment state. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study (up to 48 weeks)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: subjects
        AEs
    336
        SAEs
    9
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Baseline

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Baseline [2]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: subjects
        None
    346
        Mild
    87
        Moderate
    56
        Severe
    28
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 4

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 4 [3]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 4
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    494
    Units: subjects
        None
    306
        Mild
    110
        Moderate
    52
        Severe
    26
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 8

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 8 [4]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 8
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    454
    Units: subjects
        None
    294
        Mild
    101
        Moderate
    47
        Severe
    12
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 12

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 12 [5]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 12
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    439
    Units: subjects
        None
    308
        Mild
    79
        Moderate
    39
        Severe
    13
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 16

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 16 [6]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 16
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    417
    Units: subjects
        None
    296
        Mild
    82
        Moderate
    33
        Severe
    6
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 20

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 20 [7]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 20
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    407
    Units: subjects
        None
    291
        Mild
    66
        Moderate
    40
        Severe
    10
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 24

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 24 [8]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 24
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    403
    Units: subjects
        None
    282
        Mild
    89
        Moderate
    28
        Severe
    4
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 28

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 28 [9]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 28
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    384
    Units: subjects
        None
    294
        Mild
    59
        Moderate
    23
        Severe
    3
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 32

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 32 [10]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 32
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    377
    Units: subjects
        None
    271
        Mild
    77
        Moderate
    23
        Severe
    6
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 36

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 36 [11]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 36
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    348
    Units: subjects
        None
    259
        Mild
    63
        Moderate
    19
        Severe
    7
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 40

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 40 [12]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 40
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    319
    Units: subjects
        None
    228
        Mild
    68
        Moderate
    14
        Severe
    9
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 44

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 44 [13]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 44
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    291
    Units: subjects
        None
    214
        Mild
    51
        Moderate
    21
        Severe
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Local Tolerability Symptoms at Week 48

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    End point title
    		 Number of Subjects With Local Tolerability Symptoms at Week 48 [14]
    End point description
    Local tolerability symptoms were assessed on 4-point scale ranging from 0 to 3, where 0 = none (no stinging/burning), 1 = mild (slight warm, tingling sensation, not really bothersome); 2= moderate (definite warm; tingling or stinging sensation that was somewhat bothersome and severe) and 3= severe (hot, tingling or stinging sensation that had caused definite discomfort). Higher scores indicated more severe symptoms. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Week 48
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    273
    Units: subjects
        None
    212
        Mild
    46
        Moderate
    12
        Severe
    3
    No statistical analyses for this end point

    Primary: Change From Baseline in Investigator's Static Global Assessment (ISGA) Score

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    End point title
    		 Change From Baseline in Investigator's Static Global Assessment (ISGA) Score [15]
    End point description
    Data not reported since disease severity assessments were not evaluated as primary endpoint because this was only to determine need for treatment.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study (up to 48 weeks)
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    0 [16]
    Units: subjects
    Notes
    [16] - Data not reported.
    No statistical analyses for this end point

    Primary: Number of Subjects With Concomitant use of Topical Corticosteroid (TCS)

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    End point title
    		 Number of Subjects With Concomitant use of Topical Corticosteroid (TCS) [17]
    End point description
    Concomitant medications administered prior to and during the study were reported across World Health Organization drug dictionary anatomical therapeutic chemical (ATC) categories and were typically indicated for use for pre-existing medical conditions (including AD, dryness of the skin, allergic rhinitis, asthma) or AEs. The most commonly reported medications by ATC Level 2 term were antihistamines for systemic use, drugs for obstructive airway diseases, antibacterials for systemic use, corticosteroids and dermatological preparations. Corticosteroids, dermatological preparations that were used by at least 1% of subjects by preferred name, were triamcinolone, hydrocortisone, desonide, triamcinolone acetonide, and mometasone furoate. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment.
    End point type
    Primary
    End point timeframe
    Baseline up to end of study (up to 48 weeks)
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: subjects
    121
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Body Temperature at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48

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    End point title
    		 Change From Baseline in Body Temperature at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point description
    Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment. Here, "n" signifies subjects evaluable for the specific categories at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: fahrenheit
    arithmetic mean (standard deviation)
        Temperature: At Baseline (n=517)
    98.00 ± 0.634
        Temperature: Change at Week 4 (n=495)
    0.04 ± 0.673
        Temperature: Change at Week 8 (n=460)
    0.01 ± 0.742
        Temperature: Change at Week 12 (n=446)
    -0.01 ± 0.711
        Temperature: Change at Week 16 (n=422)
    -0.06 ± 0.761
        Temperature: Change at Week 20 (n=407)
    -0.03 ± 0.734
        Temperature: Change at Week 24 (n=401)
    -0.07 ± 0.694
        Temperature: Change at Week 28 (n=383)
    -0.05 ± 0.745
        Temperature: Change at Week 32 (n=378)
    -0.05 ± 0.748
        Temperature: Change at Week 36 (n=349)
    -0.08 ± 0.735
        Temperature: Change at Week 40 (n=319)
    -0.06 ± 0.733
        Temperature: Change at Week 44 (n=291)
    -0.02 ± 0.729
        Temperature: Change at Week 48 (n=273)
    -0.01 ± 0.714
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48

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    End point title
    		 Change From Baseline in Systolic Blood Pressure (SBP) and Diastolic Blood Pressure (DBP) at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point description
    Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment. Here, "n" signifies subjects evaluable for the specific categories at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: millimeters of mercury
    arithmetic mean (standard deviation)
        SBP: At Baseline (n=517)
    105.3 ± 13.45
        SBP: Change at Week 4 (n=493)
    -0.3 ± 10.10
        SBP: Change at Week 8 (n=458)
    -0.4 ± 10.84
        SBP: Change at Week 12 (n=446)
    0.2 ± 11.17
        SBP: Change at Week 16 (n=421)
    0.4 ± 10.43
        SBP: Change at Week 20 (n=404)
    1.2 ± 11.38
        SBP: Change at Week 24 (n=401)
    0.6 ± 10.93
        SBP: Change at Week 28 (n=383)
    1.9 ± 11.04
        SBP: Change at Week 32 (n=377)
    1.2 ± 10.92
        SBP: Change at Week 36 (n=348)
    1.4 ± 11.11
        SBP: Change at Week 40 (n=318)
    0.7 ± 11.64
        SBP: Change at Week 44 (n=290)
    0.2 ± 11.91
        SBP: Change at Week 48 (n=272)
    2.0 ± 11.06
        DBP: At Baseline (n=517)
    66.1 ± 9.04
        DBP: At Week 4 (n=493)
    0.2 ± 8.98
        DBP: At Week 8 (n=457)
    -0.2 ± 9.00
        DBP: At Week 12 (n=446)
    0.2 ± 8.87
        DBP: At Week 16 (n=421)
    0.6 ± 8.85
        DBP: At Week 20 (n=404)
    0.7 ± 9.04
        DBP: At Week 24 (n=401)
    0.5 ± 9.63
        DBP: At Week 28 (n=383)
    0.6 ± 9.40
        DBP: At Week 32 (n=377)
    0.9 ± 9.89
        DBP: At Week 36 (n=348)
    0.9 ± 9.96
        DBP: At Week 40 (n=318)
    0.1 ± 9.60
        DBP: At Week 44 (n=290)
    0.4 ± 10.33
        DBP: At Week 48 (n=272)
    0.8 ± 9.71
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Pulse Rate at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48

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    End point title
    		 Change From Baseline in Pulse Rate at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point description
    Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment. Here, "n" signifies subjects evaluable for the specific categories at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: beats per minute
    arithmetic mean (standard deviation)
        Pulse Rate: At Baseline (n=517)
    85.3 ± 14.05
        Pulse Rate: Change at Week 4 (n=493)
    -0.4 ± 12.58
        Pulse Rate: Change at Week 8 (n=457)
    -1.3 ± 12.03
        Pulse Rate: Change at Week 12 (n=446)
    -0.4 ± 13.75
        Pulse Rate: Change at Week 16 (n=421)
    -0.5 ± 12.90
        Pulse Rate: Change at Week 20 (n=406)
    0.1 ± 13.11
        Pulse Rate: Change at Week 24 (n=401)
    0.0 ± 13.54
        Pulse Rate: Change at Week 28 (n=383)
    0.2 ± 13.65
        Pulse Rate: Change at Week 32 (n=377)
    0.4 ± 12.66
        Pulse Rate: Change at Week 36 (n=348)
    0.2 ± 12.34
        Pulse Rate: Change at Week 40 (n=318)
    0.1 ± 12.58
        Pulse Rate: Change at Week 44 (n=290)
    -1.4 ± 12.08
        Pulse Rate: Change at Week 48 (n=272)
    -0.7 ± 12.36
    No statistical analyses for this end point

    Other pre-specified: Change From Baseline in Respiratory Rate at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48

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    End point title
    		 Change From Baseline in Respiratory Rate at Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point description
    Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment. Here, "n" signifies subjects evaluable for the specific categories at specified time point.
    End point type
    Other pre-specified
    End point timeframe
    Baseline; Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44 and 48
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: breaths per minute
    arithmetic mean (standard deviation)
        Respiratory Rate: At Baseline (n=517)
    18.9 ± 3.33
        Respiratory Rate: Change at Week 4 (n=494)
    0.2 ± 2.74
        Respiratory Rate: Change at Week 8 (n=459)
    0.1 ± 2.85
        Respiratory Rate: Change at Week 12 (n=445)
    0.1 ± 2.91
        Respiratory Rate: Change at Week 16 (n=421)
    0.1 ± 2.91
        Respiratory Rate: Change at Week 20 (n=407)
    0.3 ± 3.13
        Respiratory Rate: Change at Week 24 (n=401)
    0.3 ± 2.71
        Respiratory Rate: Change at Week 28 (n=384)
    0.2 ± 2.96
        Respiratory Rate: Change at Week 32 (n=378)
    0.1 ± 2.94
        Respiratory Rate: Change at Week 36 (n=349)
    0.2 ± 2.73
        Respiratory Rate: Change at Week 40 (n=318)
    0.4 ± 2.88
        Respiratory Rate: Change at Week 44 (n=291)
    0.1 ± 3.06
        Respiratory Rate: Change at Week 48 (n=273)
    0.2 ± 2.78
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Laboratory Abnormalities

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    End point title
    		 Number of Subjects With Laboratory Abnormalities
    End point description
    Laboratory parameters included: hematology (hemoglobin, hematocrit, red blood cell, platelet and white blood cell count, neutrophils, eosinophils, monocytes, basophils and lymphocytes), chemistry (blood urea nitrogen, creatinine, sodium, potassium, aspartate aminotransferase, alanine aminotransferase, total bilirubin, alkaline phosphatase, albumin, total protein and urine (urine pregnancy test [for all female subjects of childbearing potential only]). Clinical significance of laboratory parameters was determined at the investigator's discretion. Safety analysis set included all subjects who received at least one confirmed dose of study drug and had at least one post-baseline assessment. Here, "number of subjects analysed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Other pre-specified
    End point timeframe
    Baseline up to end of study (up to 48 weeks)
    End point values
    		 AN2728 Ointment, 2 percent
    Number of subjects analysed
    517
    Units: subjects
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to end of study (up to 48 weeks)
    Adverse event reporting additional description
    Same event may appear as both an adverse event (AE) and serious adverse event (SAE). 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
    AN2728 Ointment, 2 percent
    Reporting group description
    		 AN2728 ointment 2 percent was applied topically to treatment-targeted lesions in subjects with mild to moderate AD, twice daily for up to 28 days. Lesions were identified at Baseline (Day 1) by investigator.

    Serious adverse events
    		 AN2728 Ointment, 2 percent
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 517 (1.74%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CNS ventriculitis
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Application site infection
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 517 (0.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 AN2728 Ointment, 2 percent
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    243 / 517 (47.00%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    11 / 517 (2.13%)
         occurrences all number
    14
    General disorders and administration site conditions
    Application site pain
         subjects affected / exposed
    12 / 517 (2.32%)
         occurrences all number
    14
    Pyrexia
         subjects affected / exposed
    29 / 517 (5.61%)
         occurrences all number
    40
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    11 / 517 (2.13%)
         occurrences all number
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    12 / 517 (2.32%)
         occurrences all number
    12
    Vomiting
         subjects affected / exposed
    15 / 517 (2.90%)
         occurrences all number
    16
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    15 / 517 (2.90%)
         occurrences all number
    18
    Cough
         subjects affected / exposed
    35 / 517 (6.77%)
         occurrences all number
    42
    Oropharyngeal pain
         subjects affected / exposed
    19 / 517 (3.68%)
         occurrences all number
    19
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    58 / 517 (11.22%)
         occurrences all number
    72
    Dermatitis contact
         subjects affected / exposed
    16 / 517 (3.09%)
         occurrences all number
    17
    Eczema
         subjects affected / exposed
    13 / 517 (2.51%)
         occurrences all number
    17
    Infections and infestations
    Application site infection
         subjects affected / exposed
    18 / 517 (3.48%)
         occurrences all number
    20
    Ear infection
         subjects affected / exposed
    12 / 517 (2.32%)
         occurrences all number
    12
    Influenza
         subjects affected / exposed
    12 / 517 (2.32%)
         occurrences all number
    13
    Nasopharyngitis
         subjects affected / exposed
    40 / 517 (7.74%)
         occurrences all number
    46
    Otitis media
         subjects affected / exposed
    11 / 517 (2.13%)
         occurrences all number
    12
    Pharyngitis
         subjects affected / exposed
    12 / 517 (2.32%)
         occurrences all number
    17
    Pharyngitis streptococcal
         subjects affected / exposed
    20 / 517 (3.87%)
         occurrences all number
    22
    Sinusitis
         subjects affected / exposed
    25 / 517 (4.84%)
         occurrences all number
    29
    Upper respiratory tract infection
         subjects affected / exposed
    52 / 517 (10.06%)
         occurrences all number
    69
    Viral infection
         subjects affected / exposed
    11 / 517 (2.13%)
         occurrences all number
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2014
    1) Grading of local tolerability safety assessment included at scheduled in-clinic visits of each On- and Off-Treatment Period for safety assessment. 2) Description revised for subjects requiring pregnancy test from "postmenarchal females" to "females of childbearing potential".
    25 Jul 2014
    1) A complete physical examination was added at Study Day 337 (End-of-Study) and the early discontinuation visit to collect more comprehensive safety data. 2) Added requirement for women who become of childbearing potential during the study who were previously considered of nonchildbearing potential (ie, menses begins), a urine pregnancy test should be performed at the next study visit to clarify the birth control requirements. 3) Additional procedures visits added to the study Day 85 (Week 12) and study Day 253 (Week 36) to the schedule of events table in order to obtain additional clinical laboratory test results.

    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.
    Data not reported since disease severity assessments were not evaluated as primary endpoint because this was only to determine need for treatment.
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