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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled multicenter dose-ranging study to assess the safety and efficacy of multiple oral ZPL389 doses in patients with moderate to severe atopic dermatitis(ZEST trial)

    Summary
    EudraCT number
    		 2017-002176-75
    Trial protocol
    		 DE   GB   NL   FI   IS   AT   EE   BE   CZ   HU   FR   ES   LV   LT  
    Global end of trial date
    06 Aug 2020

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CZPL389A2203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03517566
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111, novartis.email@novartis.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
    06 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Aug 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To characterize the dose-response relationship of ZPL389 in subjects with moderate to severe AD assessed by IGA response after 16 weeks of treatment
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 2018
    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
    Austria: 3
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Czechia: 7
    Country: Number of subjects enrolled
    Finland: 12
    Country: Number of subjects enrolled
    Germany: 54
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Iceland: 22
    Country: Number of subjects enrolled
    Japan: 55
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Poland: 15
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 20
    Worldwide total number of subjects
    293
    EEA total number of subjects
    143
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    293
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There were 293 subjects randomized at baseline to one of the five treatment arms. Two mis-randomized subjects in the placebo arm were excluded from the baseline analysis population. For that reason, the Randomized and Treated period is considered as the baseline period.

    Period 1
    Period 1 title
    Pre-treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 3mg
    Arm description
    		 Dose 1 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 3mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 10 mg
    Arm description
    		 Dose 2 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 10mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 30mg
    Arm description
    		 Dose 3 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 30mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 50mg
    Arm description
    		 Dose 4 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 50mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Number of subjects in period 1
    		Placebo ZPL389 3mg ZPL389 10 mg ZPL389 30mg ZPL389 50mg
    Started
    74
    37
    36
    73
    73
    Completed
    72
    37
    36
    73
    73
    Not completed
    2
    0
    0
    0
    0
         Lost to follow-up
    2
    -
    -
    -
    -
    Period 2
    Period 2 title
    Randomized and Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo (Placebo)
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 3mg
    Arm description
    		 Dose 1 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 3mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 10mg
    Arm description
    		 Dose 2 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 10mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 30mg
    Arm description
    		 Dose 3 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 30mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Arm title
    		 ZPL389 50mg
    Arm description
    		 Dose 4 of ZPL389
    Arm type
    		 Experimental

    Investigational medicinal product name
    Adriforant
    Investigational medicinal product code
    ZPL389
    Other name
    Pharmaceutical forms
    Oral powder
    Routes of administration
    Oral use
    Dosage and administration details
    ZPL389 50mg administered orally as powder in hydroxypropyl methylcellulose capsules

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Two mis-randomized subjects in the placebo arm were excluded from the baseline analysis population. For that reason, the Randomized and Treated period is considered as the baseline period.
    Number of subjects in period 2 [2]
    		Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Started
    72
    37
    36
    73
    73
    Completed
    42
    16
    21
    39
    41
    Not completed
    30
    21
    15
    34
    32
         Physician decision
    1
    1
    -
    1
    -
         Subject Decision /Guardian Decision
    9
    8
    5
    8
    8
         Study terminated by Sponsor
    11
    5
    6
    14
    12
         Adverse event, non-fatal
    5
    2
    2
    8
    7
         Protocol Deviation
    -
    1
    -
    1
    1
         Pregnancy
    -
    1
    -
    -
    -
         Lost to follow-up
    1
    1
    1
    1
    -
         Lack of efficacy
    3
    2
    1
    1
    4
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two mis-randomized subjects in the placebo arm were excluded from the baseline analysis population.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo (Placebo)
    Reporting group description
    		 Placebo

    Reporting group title
    ZPL389 3mg
    Reporting group description
    		 Dose 1 of ZPL389

    Reporting group title
    ZPL389 10mg
    Reporting group description
    		 Dose 2 of ZPL389

    Reporting group title
    ZPL389 30mg
    Reporting group description
    		 Dose 3 of ZPL389

    Reporting group title
    ZPL389 50mg
    Reporting group description
    		 Dose 4 of ZPL389

    Reporting group values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg Total
    Number of subjects
    		 72 37 36 73 73 291
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 72 37 36 73 73 291
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.9 ( 12.79 ) 38.1 ( 11.86 ) 32.1 ( 9.93 ) 34.9 ( 11.69 ) 35.2 ( 11.91 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 34 17 17 32 25 125
        Male
    		 38 20 19 41 48 166
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 51 26 24 55 52 208
        Black or African American
    		 0 0 3 3 2 8
        Asian
    		 21 11 9 15 17 73
        Multiple
    		 0 0 0 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    ZPL389 3mg
    Reporting group description
    		 Dose 1 of ZPL389

    Reporting group title
    ZPL389 10 mg
    Reporting group description
    		 Dose 2 of ZPL389

    Reporting group title
    ZPL389 30mg
    Reporting group description
    		 Dose 3 of ZPL389

    Reporting group title
    ZPL389 50mg
    Reporting group description
    		 Dose 4 of ZPL389
    Reporting group title
    Placebo (Placebo)
    Reporting group description
    		 Placebo

    Reporting group title
    ZPL389 3mg
    Reporting group description
    		 Dose 1 of ZPL389

    Reporting group title
    ZPL389 10mg
    Reporting group description
    		 Dose 2 of ZPL389

    Reporting group title
    ZPL389 30mg
    Reporting group description
    		 Dose 3 of ZPL389

    Reporting group title
    ZPL389 50mg
    Reporting group description
    		 Dose 4 of ZPL389

    Primary: Percentage of IGA responders at Week 16

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    End point title
    		 Percentage of IGA responders at Week 16 [1]
    End point description
    Investigator's Global Assessment (IGA) score is used to determine the severity of atopic dermatitis symptoms and clinical response to treatment. It reflects a subject's overall disease severity for the whole body. The scale includes 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. It is a static scale and does not refer to previous status of the subject. IGA response is defined as achievement of an IGA score of 0 or 1 with a 2-point reduction from baseline without use of confounding therapy (e.g. rescue medication) up to the assessment time point. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders.
    End point type
    Primary
    End point timeframe
    Week 16
    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: No statistical analysis was planned for this primary outcome
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percentage of participants
        number (confidence interval 95%)
    1.9 (-1.6 to 5.3)
    3.3 (-4.3 to 10.9)
    7.2 (-2.3 to 16.8)
    0.8 (-2.0 to 3.7)
    6.9 (0.6 to 13.2)
    No statistical analyses for this end point

    Secondary: Percent change from baseline in EASI score at week 16

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    End point title
    		 Percent change from baseline in EASI score at week 16
    End point description
    Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 16
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percent change from baseline
        least squares mean (confidence interval 95%)
    -55.0 (-66.9 to -43.1)
    -49.4 (-67.4 to -31.4)
    -50.7 (-67.3 to -34.1)
    -46.2 (-58.8 to -33.6)
    -52.7 (-65.0 to -40.4)
    No statistical analyses for this end point

    Secondary: Percent change from baseline in EASI score over time

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    End point title
    		 Percent change from baseline in EASI score over time
    End point description
    Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 2, Week 4, Week 6, Week 8, Week 12
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percent change from baseline
    least squares mean (confidence interval 95%)
        Week 2
    -17.1 (-26.6 to -7.5)
    -20.1 (-34.2 to -6.1)
    -10.3 (-23.8 to 3.1)
    -14.2 (-24.0 to -4.3)
    -16.7 (-26.4 to -7.1)
        week 4
    -19.7 (-30.6 to -8.9)
    -36.1 (-51.4 to -20.9)
    -25.6 (-40.6 to -10.7)
    -17.7 (-29.0 to -6.4)
    -30.0 (-40.6 to -19.4)
        week 6
    -42.8 (-53.0 to -32.6)
    -47.6 (-62.3 to -32.9)
    -43.2 (-57.3 to -29.0)
    -33.2 (-44.0 to -22.3)
    -43.5 (-54.0 to -33.0)
        week 8
    -49.3 (-61.1 to -37.4)
    -50.1 (-66.8 to -33.4)
    -47.4 (-63.9 to -30.9)
    -38.1 (-50.5 to -25.7)
    -45.5 (-57.4 to -33.6)
        week 12
    -55.4 (-66.0 to -44.8)
    -48.7 (-64.2 to -33.2)
    -54.1 (-69.2 to -39.1)
    -45.1 (-56.4 to -33.8)
    -52.7 (-63.7 to -41.7)
    No statistical analyses for this end point

    Secondary: Percentage of EASI50 responders over time

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    End point title
    		 Percentage of EASI50 responders over time
    End point description
    Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema. EASI50 response is defined as achieving ≥ 50% improvement (reduction) in EASI score compared to baseline without use of confounding therapy (e.g. rescue medication) up to the assessment time point. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 2, Week 4, Week 6, Week 8, Week 12, Week 16
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 2
    7.0 (1.1 to 12.9)
    15.0 (3.1 to 27.0)
    12.6 (1.1 to 24.1)
    5.8 (0.3 to 11.2)
    10.1 (3.1 to 17.2)
        week 4
    13.9 (5.9 to 21.9)
    19.0 (5.4 to 32.5)
    20.1 (6.1 to 34.1)
    9.5 (2.4 to 16.7)
    20.7 (11.4 to 30.1)
        week 6
    18.4 (9.4 to 27.4)
    15.0 (2.5 to 27.5)
    15.1 (2.5 to 27.7)
    9.5 (2.1 to 16.8)
    16.7 (8.0 to 25.4)
        week 8
    18.9 (9.7 to 28.0)
    18.0 (4.5 to 31.5)
    16.4 (3.3 to 29.5)
    9.4 (2.2 to 16.6)
    12.8 (4.8 to 20.7)
        week 12
    20.3 (10.9 to 29.7)
    11.4 (-0.4 to 23.1)
    20.3 (5.8 to 34.9)
    12.6 (4.3 to 20.9)
    12.0 (4.2 to 19.7)
        week 16
    16.8 (7.9 to 25.8)
    14.4 (1.4 to 27.3)
    22.7 (7.5 to 37.9)
    12.1 (3.9 to 20.3)
    12.7 (4.6 to 20.7)
    No statistical analyses for this end point

    Secondary: Percentage of EASI75 responders over time

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    End point title
    		 Percentage of EASI75 responders over time
    End point description
    Eczema Area and Severity Index (EASI) is used to assess the extend and severity of atopic dermatitis on a scale from 0 to 72 where 72 is worst eczema. EASI75 response is defined as achieving ≥ 75% improvement (reduction) in EASI score compared to baseline without use of confounding therapy (e.g. rescue medication) up to the assessment time point. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 2, Week 4, Week 6, Week 8, Week 12, Week 16
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percentage of participants
    number (confidence interval 95%)
        week 2
    0.0 (-0.0 to 0.0)
    0.0 (-3.0 to 4.4)
    0.0 (-3.1 to 4.4)
    1.4 (-1.3 to 4.1)
    1.5 (-1.4 to 4.3)
        week 4
    2.8 (-1.0 to 6.6)
    7.0 (-2.0 to 16.0)
    1.7 (-3.9 to 7.2)
    1.8 (-1.6 to 5.2)
    1.4 (-1.3 to 4.2)
        week 6
    5.6 (0.3 to 10.9)
    10.3 (-0.4 to 21.0)
    7.1 (-1.9 to 16.1)
    1.8 (-2.0 to 5.7)
    7.4 (1.2 to 13.6)
        week 8
    6.0 (0.4 to 11.6)
    10.9 (-0.2 to 21.9)
    8.5 (-1.8 to 18.8)
    2.5 (-1.8 to 6.8)
    6.1 (0.4 to 11.9)
        week 12
    4.6 (-0.4 to 9.6)
    6.2 (-3.1 to 15.6)
    10.6 (-0.9 to 22.0)
    2.8 (-1.6 to 7.2)
    5.8 (-0.0 to 11.7)
        week 16
    9.7 (2.6 to 16.8)
    7.1 (-2.8 to 16.9)
    12.9 (0.3 to 25.5)
    3.1 (-1.7 to 7.8)
    9.3 (2.1 to 16.6)
    No statistical analyses for this end point

    Secondary: Percentage of IGA responders over time

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    End point title
    		 Percentage of IGA responders over time
    End point description
    Investigator's Global Assessment (IGA) score is used to determine the severity of atopic dermatitis symptoms and clinical response to treatment. It reflects a subject's overall disease severity for the whole body. The scale includes 0 = clear, 1 = almost clear, 2 = mild, 3 = moderate and 4 = severe. It is a static scale and does not refer to previous status of the subject. IGA response is defined as achievement of an IGA score of 0 or 1 with a 2-point reduction from baseline without use of confounding therapy (e.g. rescue medication) up to the assessment time point. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders.
    End point type
    Secondary
    End point timeframe
    Week 2, Week 4, Week 6, Week 8, Week 12
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Percentage of participants
    number (confidence interval 95%)
        week 2
    0.0 (-0.0 to 0.0)
    2.7 (-2.5 to 7.9)
    0.0 (-0.7 to 0.8)
    0.0 (-0.0 to 0.0)
    0.0 (-0.0 to 0.0)
        week 4
    0.0 (-0.0 to 0.0)
    2.8 (-2.6 to 8.3)
    0.0 (-1.4 to 1.6)
    0.0 (-0.6 to 0.7)
    0.0 (-0.4 to 0.4)
        week 6
    1.4 (-1.3 to 4.1)
    6.1 (-2.1 to 14.4)
    5.9 (-2.0 to 13.8)
    0.0 (-1.9 to 2.9)
    0.0 (-1.2 to 1.6)
        week 8
    1.6 (-1.4 to 4.5)
    3.8 (-3.1 to 10.7)
    6.5 (-2.1 to 15.0)
    0.0 (-1.7 to 2.7)
    2.0 (-1.6 to 5.6)
        week 12
    1.5 (-1.4 to 4.4)
    4.0 (-3.3 to 11.3)
    5.6 (-3.1 to 14.2)
    1.9 (-1.6 to 5.5)
    1.0 (-2.1 to 4.1)
    No statistical analyses for this end point

    Secondary: Number of patients with adverse events

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    End point title
    		 Number of patients with adverse events
    End point description
    An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or clinical investigation subject after providing written informed consent for participation in the study until the end of study visit. Therefore, an AE may or may not be temporally or causally associated with the use of a medicinal (investigational) product.
    End point type
    Secondary
    End point timeframe
    Up to week 20
    End point values
    		 Placebo (Placebo) ZPL389 3mg ZPL389 10mg ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    72
    37
    36
    73
    73
    Units: Participants
        AE
    44
    22
    18
    48
    43
        SAE
    2
    1
    3
    1
    3
        AEs leading to discontinuation
    7
    3
    2
    11
    12
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from first dose of study treatment until end of study treatment plus 4 weeks  post treatment, up to maximum duration of 20 weeks
    Adverse event reporting additional description
    Any sign or symptom that occurs during the study treatment plus the 4 weeks post treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    ZPL389 3 mg
    Reporting group description
    		 ZPL389 3 mg

    Reporting group title
    ZPL389 10 mg
    Reporting group description
    		 ZPL389 10 mg

    Reporting group title
    ZPL389 30 mg
    Reporting group description
    		 ZPL389 30 mg

    Reporting group title
    ZPL389 50 mg
    Reporting group description
    		 ZPL389 50 mg

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 Placebo ZPL389 3 mg ZPL389 10 mg ZPL389 30 mg ZPL389 50 mg All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 37 (2.70%)
    3 / 36 (8.33%)
    1 / 73 (1.37%)
    3 / 73 (4.11%)
    10 / 291 (3.44%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Pregnancy, puerperium and perinatal conditions
    Risk of future pregnancy miscarriage
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 37 (2.70%)
    1 / 36 (2.78%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    5 / 291 (1.72%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastrointestinal infection
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    1 / 73 (1.37%)
    0 / 73 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes dermatitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    1 / 36 (2.78%)
    0 / 73 (0.00%)
    0 / 73 (0.00%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    0 / 36 (0.00%)
    0 / 73 (0.00%)
    1 / 73 (1.37%)
    1 / 291 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo ZPL389 3 mg ZPL389 10 mg ZPL389 30 mg ZPL389 50 mg All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 72 (37.50%)
    14 / 37 (37.84%)
    8 / 36 (22.22%)
    30 / 73 (41.10%)
    26 / 73 (35.62%)
    105 / 291 (36.08%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    2 / 36 (5.56%)
    1 / 73 (1.37%)
    3 / 73 (4.11%)
    6 / 291 (2.06%)
         occurrences all number
    0
    0
    2
    1
    3
    6
    Headache
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 37 (2.70%)
    1 / 36 (2.78%)
    2 / 73 (2.74%)
    4 / 73 (5.48%)
    13 / 291 (4.47%)
         occurrences all number
    6
    1
    1
    2
    4
    14
    General disorders and administration site conditions
    Influenza like illness
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 37 (0.00%)
    2 / 36 (5.56%)
    3 / 73 (4.11%)
    3 / 73 (4.11%)
    9 / 291 (3.09%)
         occurrences all number
    1
    0
    3
    4
    4
    12
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 37 (2.70%)
    0 / 36 (0.00%)
    1 / 73 (1.37%)
    5 / 73 (6.85%)
    9 / 291 (3.09%)
         occurrences all number
    2
    1
    0
    1
    6
    10
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 37 (5.41%)
    0 / 36 (0.00%)
    3 / 73 (4.11%)
    1 / 73 (1.37%)
    8 / 291 (2.75%)
         occurrences all number
    2
    2
    0
    6
    1
    11
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    11 / 72 (15.28%)
    6 / 37 (16.22%)
    2 / 36 (5.56%)
    14 / 73 (19.18%)
    8 / 73 (10.96%)
    41 / 291 (14.09%)
         occurrences all number
    15
    8
    3
    16
    9
    51
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 37 (5.41%)
    1 / 36 (2.78%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    5 / 291 (1.72%)
         occurrences all number
    0
    2
    1
    1
    1
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    8 / 72 (11.11%)
    2 / 37 (5.41%)
    2 / 36 (5.56%)
    4 / 73 (5.48%)
    4 / 73 (5.48%)
    20 / 291 (6.87%)
         occurrences all number
    8
    2
    2
    4
    5
    21
    Rhinitis
         subjects affected / exposed
    0 / 72 (0.00%)
    0 / 37 (0.00%)
    2 / 36 (5.56%)
    1 / 73 (1.37%)
    1 / 73 (1.37%)
    4 / 291 (1.37%)
         occurrences all number
    0
    0
    2
    2
    1
    5
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 37 (2.70%)
    2 / 36 (5.56%)
    6 / 73 (8.22%)
    1 / 73 (1.37%)
    12 / 291 (4.12%)
         occurrences all number
    3
    1
    2
    6
    1
    13

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jan 2018
    - The Epworth Sleepiness Scale was added to assess the effect of ZPL389 on patient reported outcomes. - EASI score at Screening visit for inclusion into trial changed from 12 to 16 - Exclusion threshold and notable value for resting QTcF for female changed from ≥460 to ≥470 msec - Discontinuation criteria for cardiac disorders aligned with CTCAE grade 2 events - Time of Post dose ECG at Baseline and Week 4 changed to 30 mins post dose
    11 Sep 2018
    - Endpoints for exploratory objective on CYP2D6 genotyping has been clarified. CYP2D6 genotyping test at screening has been added - Optional tape strips sub-study has been added - Exploration of the effect of ZPL389 on asthma episodes has been added - The screening period has been extended up to 4 weeks (to allow time to get the CYP2D6 genotyping results before randomization), extending the total study duration from 23 to 24 weeks - The use of bland emollient has been changed to once daily instead of twice - Updated with relevant interim data from study CZPL389A2101 - Exclusion criteria #15 has been modified to prohibit hormonal contraception for poor CYP2D6 metabolizers (as hormonal contraception is moderate inhibitor of CYP1A2). Deletion of the text about additional exclusion applied by investigator
    02 Sep 2019
    - Updated with results of pivotal Embryo-fetal development toxicology studies and CZPL389A2101 study - Clarification added to exclusion criterion - Removal of Vitamin E as prohibited component of moisturizers - Clarification on dosing time versus PK/ biomarker sampling and timing of the tape strip sample collection. Appendix 16.1.1-Protocol-Table 6-2 revised to clarify PK and biomarker sample collection time points - Clarification added for use of an alternative TCS as rescue medication - For subjects who discontinued early, action taken on prohibited medication during followup period has been modified. Clarification on the use of H1 Antihistamines Information on use of ibuprofen or topical NSAID has been added - Clarification added for collection of subject’s baseline characteristics - Clarification on the type of test done for Hep C - PT/INR has been added to unscheduled visit - Clarification on the requirement of availability of CYP2D6 test results before randomization for subjects taking moderate CYP1A2 inhibitor and adherence to wash out period - In case of a Liver event, requirement of completion of applicable questionnaire for adjudication has been added - Any increase from Baseline of 30 msec in QTcF (Fridericia) interval for males and females has been added to the definition of a notable QTc value

    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.
    Terminated trial because of lack of efficacy
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