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    Clinical Trial Results:
    A randomized, double blind, multicenter extension to CZPL389A2203 dose-ranging study to assess the shortterm and long-term safety and efficacy of oral ZPL389 with concomitant or intermittent use of TCS and/or TCI in adult patients with atopic dermatitis (ZEST Extension)

    Summary
    EudraCT number
    		 2018-000595-15
    Trial protocol
    		 GB   FI   DE   IS   NL   SK   BE   EE   CZ   FR  
    Global end of trial date
    25 Aug 2020

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CZPL389A2203E1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03948334
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    NovartisPharmaceuticals, ClinicalDisclosure Office, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Study Director, 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
    25 Aug 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Aug 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the short-term and long-term safety of 30 mg o.d. and 50 mg o.d. ZPL389 with concomitant or intermittent use of TCS and/or TCI up to total of 32 weeks and 116 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
    04 Apr 2019
    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
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Iceland: 13
    Country: Number of subjects enrolled
    Japan: 36
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Russian Federation: 15
    Country: Number of subjects enrolled
    Slovakia: 9
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    United States: 2
    Worldwide total number of subjects
    123
    EEA total number of subjects
    64
    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)
    123
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who had received ZPL389 30 mg or 50 mg doses in the core study, continued to receive the same doses in double-blinded fashion. Subjects who had received ZPL389 3 mg, 10 mg or placebo in the core study were randomized to 30 mg or 50 mg ZPL389 in a 1:1 ratio.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ZPL389 30mg
    Arm description
    		 Dose 1 of ZPL389 + TCS and/or TCI
    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 aspowder in hydroxypropyl methylcellulosecapsules

    Arm title
    		 ZPL389 50mg
    Arm description
    		 Dose 2 of ZPL389 + TCS and/or TCI
    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 aspowder in hydroxypropyl methylcellulosecapsules

    Number of subjects in period 1
    		ZPL389 30mg ZPL389 50mg
    Started
    60
    63
    Completed
    0
    0
    Not completed
    60
    63
         Physician decision
    1
    -
         Study terminated by Sponsor
    50
    51
         Subject Decision /Guardian Decision
    4
    7
         Adverse event, non-fatal
    1
    4
         Protocol Deviation
    1
    -
         Pregnancy
    -
    1
         Lost to follow-up
    1
    -
         Lack of efficacy
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ZPL389 30mg
    Reporting group description
    		 Dose 1 of ZPL389 + TCS and/or TCI

    Reporting group title
    ZPL389 50mg
    Reporting group description
    		 Dose 2 of ZPL389 + TCS and/or TCI

    Reporting group values
    		 ZPL389 30mg ZPL389 50mg Total
    Number of subjects
    		 60 63 123
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 60 63 123
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 34.8 ± 12.18 34.4 ± 11.24 -
    Sex: Female, Male
    Units: participants
        Female
    		 24 20 44
        Male
    		 36 43 79
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 36 42 78
        Black or African American
    		 1 1 2
        Asian
    		 23 20 43

    End points

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    End points reporting groups
    Reporting group title
    ZPL389 30mg
    Reporting group description
    		 Dose 1 of ZPL389 + TCS and/or TCI

    Reporting group title
    ZPL389 50mg
    Reporting group description
    		 Dose 2 of ZPL389 + TCS and/or TCI

    Subject analysis set title
    ZPL389 30mg re-randomized after core study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    30mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ ZPL389 3mg/ 10mg in the core study)

    Subject analysis set title
    ZPL389 50mg re-randomized after core study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    50mg of ZPL389 + TCS and/or TCI for patients re-randomized from the core study (received placebo/ ZPL389 3mg/ 10mg in the core study)

    Subject analysis set title
    ZPL389 30mg continuing after core study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    30mg of ZPL389 + TCS and/or TCI for patients continuing in the same arm from the core study

    Subject analysis set title
    ZPL389 50mg continuing after core study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    50mg of ZPL389 + TCS and/or TCI for patients continuing in the same arm from the core study

    Primary: Frequency of Adverse Events in the first 16 weeks of this Extension study

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    End point title
    		 Frequency of Adverse Events in the first 16 weeks of this Extension study [1]
    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. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis.
    End point type
    Primary
    End point timeframe
    16 weeks (week 16 to week 32 referring to core study)
    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
    		 ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    60
    63
    Units: Participants
        Adverse events
    29
    33
        SAEs
    2
    5
        AEs leading to discontinuation
    2
    3
    No statistical analyses for this end point

    Primary: Frequency of Adverse Events after 16 weeks of treatment in this Extension study

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    End point title
    		 Frequency of Adverse Events after 16 weeks of treatment in this Extension study [2]
    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. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis.
    End point type
    Primary
    End point timeframe
    From week 16 to week 67 of this extension study (week 32 to week 83 referring to core study)
    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: No statistical analysis was planned for this primary outcome
    End point values
    		 ZPL389 30mg ZPL389 50mg
    Number of subjects analysed
    60
    63
    Units: Participants
        Adverse events
    18
    20
        SAEs
    0
    2
        AEs leading to discontinuation
    0
    1
    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 up to the assessment time point. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders. Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study)
    End point values
    		 ZPL389 30mg re-randomized after core study ZPL389 50mg re-randomized after core study ZPL389 30mg continuing after core study ZPL389 50mg continuing after core study
    Number of subjects analysed
    34
    30
    26
    33
    Units: Percentage of participants
    number (confidence interval 95%)
        week 4 (week 20 referring to core study)
    2.9 (-2.7 to 8.6)
    5.2 (-3.4 to 13.8)
    0.0 (-0.0 to 0.0)
    3.0 (-2.8 to 8.9)
        Week 8 (week 24 referring to core study)
    2.9 (-2.7 to 8.6)
    4.8 (-3.9 to 13.5)
    0.0 (-0.0 to 0.0)
    3.1 (-2.8 to 9.0)
        Week 12 (week 28 referring to core study)
    3.5 (-3.1 to 10.1)
    4.0 (-4.4 to 12.4)
    0.0 (-1.0 to 1.1)
    3.0 (-2.8 to 8.9)
        Week 16 (week 32 referring to core study)
    3.9 (-3.3 to 11.0)
    5.9 (-3.7 to 15.5)
    0.0 (-1.7 to 1.9)
    0.0 (-2.0 to 2.4)
        Week 28 (week 44 referring to core study)
    0.0 (-3.7 to 6.4)
    7.5 (-3.7 to 18.7)
    0.0 (-1.4 to 1.6)
    1.5 (-3.8 to 6.9)
        Week 40 (week 56 referring to core study)
    3.4 (-4.4 to 11.2)
    9.1 (-2.7 to 20.8)
    0.0 (-4.3 to 7.0)
    0.0 (-4.2 to 7.0)
    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. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders. Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study)
    End point values
    		 ZPL389 30mg re-randomized after core study ZPL389 50mg re-randomized after core study ZPL389 30mg continuing after core study ZPL389 50mg continuing after core study
    Number of subjects analysed
    34
    30
    26
    33
    Units: Percentage of participants
    number (confidence interval 95%)
        week 4 (week 20 referring to core study)
    14.7 (2.8 to 26.6)
    13.0 (0.8 to 25.2)
    7.7 (-2.6 to 17.9)
    12.1 (1.0 to 23.3)
        Week 8 (week 24 referring to core study)
    17.6 (4.8 to 30.5)
    15.6 (2.2 to 29.0)
    11.5 (-0.7 to 23.8)
    12.1 (1.0 to 23.3)
        Week 12 (week 28 referring to core study)
    22.3 (8.0 to 36.6)
    15.9 (2.5 to 29.3)
    10.7 (-1.5 to 23.0)
    12.1 (1.0 to 23.3)
        Week 16 (week 32 referring to core study)
    19.6 (5.7 to 33.4)
    18.2 (3.8 to 32.6)
    10.1 (-2.0 to 22.2)
    11.9 (0.5 to 23.3)
        Week 28 (week 44 referring to core study)
    10.8 (-1.0 to 22.6)
    14.8 (0.8 to 28.8)
    14.0 (0.1 to 27.8)
    14.2 (1.6 to 26.8)
        Week 40 (week 56 referring to core study)
    14.8 (1.4 to 28.2)
    20.3 (4.6 to 36.1)
    12.3 (-0.9 to 25.5)
    13.8 (0.9 to 26.6)
    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 a reduction from baseline of ≥ 75% in EASI score. Treatment discontinuations for lack of efficacy or adverse event are considered non-responders. Presentation of the results is stratified by if patients were re-randomized from the core study or not. As all patients were rolling over from the core study CZPL389A2203, in addition to the time frame referring to the start in this extension study, the time frame corresponding to the start in the core study (+16 weeks) are provided in parenthesis.
    End point type
    Secondary
    End point timeframe
    Week 4, Week 8, Week 12, Week 16, Week 28, Week 40 (Week 20, Week 24, Week 28 ,Week 32, Week 44, Week 56 referring to core study)
    End point values
    		 ZPL389 30mg re-randomized after core study ZPL389 50mg re-randomized after core study ZPL389 30mg continuing after core study ZPL389 50mg continuing after core study
    Number of subjects analysed
    34
    30
    26
    33
    Units: Percentage of participants
    number (confidence interval 95%)
        week 4 (week 20 referring to core study)
    5.9 (-2.0 to 13.8)
    8.8 (-1.8 to 19.4)
    0.0 (-0.0 to 0.0)
    12.1 (1.0 to 23.3)
        Week 8 (week 24 referring to core study)
    5.9 (-2.0 to 13.8)
    14.2 (1.0 to 27.4)
    0.0 (-0.0 to 0.0)
    9.1 (-0.7 to 18.9)
        Week 12 (week 28 referring to core study)
    12.0 (1.0 to 23.1)
    11.4 (-0.6 to 23.4)
    4.6 (-4.0 to 13.2)
    12.1 (1.0 to 23.3)
        Week 16 (week 32 referring to core study)
    8.4 (-1.8 to 18.7)
    10.3 (-1.3 to 22.0)
    0.0 (-4.2 to 6.6)
    4.9 (-3.0 to 12.8)
        Week 28 (week 44 referring to core study)
    8.2 (-2.0 to 18.5)
    8.9 (-2.9 to 20.8)
    0.0 (-4.0 to 5.9)
    2.6 (-4.6 to 9.9)
        Week 40 (week 56 referring to core study)
    10.0 (-2.4 to 22.3)
    13.5 (-0.2 to 27.3)
    6.1 (-4.0 to 16.2)
    3.2 (-4.4 to 10.8)
    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 in this extension study until end of study treatment plus 4 weeks post treatment, up to maximum duration of 67 weeks (week 16 to week 83 referring to core study).
    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
    ZPL389 30mg in the first 16 weeks of this Extension study
    Reporting group description
    		 AEs starting up to week 16 of this extension study (week 16 to week 32 referring to core study)

    Reporting group title
    ZPL389 30 mg after 16 weeks of treatment in this Ext. study
    Reporting group description
    		 AEs from week 16 to week 67 of this extension study (week 32 to week 83 referring to core study)

    Reporting group title
    ZPL389 50 mg after 16 weeks of treatment in this Ext. study
    Reporting group description
    		 AEs from week 16 to week 67 of this extension study (week 32 to week 83 referring to core study)

    Reporting group title
    ZPL389 50mg in the first 16 weeks of this Extension study
    Reporting group description
    		 AEs starting up to week 16 of this extension study (week 16 to week 32 referring to core study)

    Serious adverse events
    		 ZPL389 30mg in the first 16 weeks of this Extension study ZPL389 30 mg after 16 weeks of treatment in this Ext. study ZPL389 50 mg after 16 weeks of treatment in this Ext. study ZPL389 50mg in the first 16 weeks of this Extension study
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
    2 / 63 (3.17%)
    5 / 63 (7.94%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Steatohepatitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 63 (1.59%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    0 / 63 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchiolitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 63 (0.00%)
    1 / 63 (1.59%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ZPL389 30mg in the first 16 weeks of this Extension study ZPL389 30 mg after 16 weeks of treatment in this Ext. study ZPL389 50 mg after 16 weeks of treatment in this Ext. study ZPL389 50mg in the first 16 weeks of this Extension study
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 60 (10.00%)
    9 / 60 (15.00%)
    6 / 63 (9.52%)
    8 / 63 (12.70%)
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
    3 / 63 (4.76%)
    4 / 63 (6.35%)
         occurrences all number
    1
    2
    3
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 60 (10.00%)
    8 / 60 (13.33%)
    3 / 63 (4.76%)
    4 / 63 (6.35%)
         occurrences all number
    6
    9
    3
    6

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2020
    - Added optional sub-study to explore the effect of ZPL389 on sleep disturbance and/or nocturnal scratching as measured by actigraphy and corresponding endpoints and related text throughout the protocol. - The Epworth Sleepiness Scale was added to assess the effect of ZPL389 on patient reported outcomes - Updated with results of pivotal Embryo-fetal development toxicology studies and CZPL389A2101 study - Expected number of patients updated based on the core and extension study discontinuation and dropout rates - Added the term “active” in exclusion criterion 3 to define skin disease. Clarified contraception criteria - Vitamin E as a prohibited medication was removed Regarding QTc interval prolonging, hepatotoxic, strong (potent) or moderate CYP1A2 inhibitors drugs, the prohibition period mentioned for core study baseline was removed, as it was not applicable for extension. Clarification on the use of H1 Antihistamines Information on use of ibuprofen or topical NSAID has been added Details pertaining to corticosteroids nasal sprays and eye drops corrected in the footnote - Addition of example for instances requiring dose modifications - Clarification about what physical examination comprises - PT/INR has been added to unscheduled visit - Microscopy result entry in CRF has been removed as the result will be available in central laboratory data - Clarification on how study treatment discontinuation will be managed - SAE reporting language updated as “immediately (without undue delay), and within 24 hours of learning of its occurrence” to accommodate health authority regulations - In case of a Liver event, requirement of completion of applicable questionnaire for adjudication has been added - Cardiac safety monitoring language clarified - Sample size and chances to detect at least one AE in extension study updated considering the core and extension studies discontinuation and dropout rates

    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.
    Core terminated due to lack of efficacy
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