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    Clinical Trial Results:
    A Randomised, Adaptive Design, Double-Blind (3rd Party Open), Placebo Controlled, Sequential Group Study to Determine the Safety, Tolerability, Pharmacokinetics and Efficacy of Twice Daily Application of a Topical ZPL-5212372 (1.0% w/w) Ointment Administered for up to 2 Weeks in Adult Healthy Volunteers and Patients with Moderate to Severe Atopic Dermatitis

    Summary
    EudraCT number
    		 2016-000376-26
    Trial protocol
    		 GB  
    Global end of trial date
    01 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2018
    First version publication date
    11 Mar 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ZPL521/101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02795832
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +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
    01 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohorts 1 and 2 To assess the safety and tolerability, local and systemic, of ZPL-5212372 administered as a topical ointment (containing 1.0% (w/w) concentration of ZPL-5212372) twice daily, for 1 week, to healthy subjects and patients with moderate to severe AD. Cohort 3 To evaluate the efficacy of ZPL-5212372 administered as a topical ointment (containing 1.0% (w/w) concentration of ZPL-5212372) twice daily, for 2 weeks, to patients with moderate to severe AD.
    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 subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jun 2016
    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
    United Kingdom: 53
    Worldwide total number of subjects
    53
    EEA total number of subjects
    53
    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)
    53
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 hkiniono

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 (ZPL-5212372)
    Arm description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZPL-5212372 (Cohort 1 and 2)
    Investigational medicinal product code
    Other name
    Ziarco
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    ZPL-5212372 (1.0% w/w) ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Healthy volunteer subjects Cohorts 1 were to receive treatment for 7 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Arm title
    		 Cohort 1 (Placebo)
    Arm description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (Cohorts 1 and 2)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Matching placebo ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Healthy volunteer subjects in Cohort 1 were to receive treatment for 7 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Arm title
    		 Cohort 2 (ZPL-5212372)
    Arm description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZPL-5212372 (Cohort 1 and 2)
    Investigational medicinal product code
    Other name
    Ziarco
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    ZPL-5212372 (1.0% w/w) ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Patients with AD in Cohort 2 were to receive treatment for 7 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Arm title
    		 Cohort 2 (Placebo)
    Arm description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (Cohorts 1 and 2)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Matching placebo ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Patients with AD in Cohort 2 were to receive treatment for 7 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Arm title
    		 Cohort 3 (ZPL-5212372)
    Arm description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 2 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZPL-5212372 (Cohort 1 and 2)
    Investigational medicinal product code
    Other name
    Ziarco
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    ZPL-5212372 (1.0% w/w) ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Patients with AD in Cohort 3 were to receive treatment for 14 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Arm title
    		 Cohort 3 (Placebo)
    Arm description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 2 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (Cohort 3)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Topical use
    Dosage and administration details
    Matching placebo ointment was manufactured by Quotient Clinical Ltd, UK for administration as a topical ointment, to be applied twice daily for up to 2 weeks, approximately 12 hours apart. Patients with AD in Cohort 3 were to receive treatment for 14 days. Ointment was packaged in 125 mL screw top amber glass jars with plastic lids supplied by Quotient Clinical Ltd, UK. Each jar contained 100 g of ointment.

    Number of subjects in period 1
    		Cohort 1 (ZPL-5212372) Cohort 1 (Placebo) Cohort 2 (ZPL-5212372) Cohort 2 (Placebo) Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Started
    8
    4
    8
    3
    20
    10
    Completed
    8
    4
    8
    3
    20
    7
    Not completed
    0
    0
    0
    0
    0
    3
         Adverse event, non-fatal
    -
    -
    -
    -
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    overall period
    Reporting group description
    		 -

    Reporting group values
    		 overall period Total
    Number of subjects
    		 53 53
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 53 53
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.1 ± 7.57 -
    Gender categorical
    Units: Subjects
        Female
    		 29 29
        Male
    		 24 24

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 (ZPL-5212372)
    Reporting group description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.

    Reporting group title
    Cohort 1 (Placebo)
    Reporting group description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.

    Reporting group title
    Cohort 2 (ZPL-5212372)
    Reporting group description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.

    Reporting group title
    Cohort 2 (Placebo)
    Reporting group description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 1 week.

    Reporting group title
    Cohort 3 (ZPL-5212372)
    Reporting group description
    		 The 1.0% (w/w) concentration of ZPL-5212372 was selected to be 3-fold lower than the maximum concentration applied twice daily for 2 weeks.

    Reporting group title
    Cohort 3 (Placebo)
    Reporting group description
    		 Placebo was selected to be 3-fold lower than the maximum concentration applied twice daily for 2 weeks.

    Subject analysis set title
    Day 5 - Cohort 3 (ZPL-5212372)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Subject analysis set title
    Day 8 - Cohort 3 (ZPL-5212372)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Subject analysis set title
    Day 10 - Cohort 3 (ZPL-5212372)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Subject analysis set title
    Day 15 - Cohort 3 (ZPL-5212372)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Subject analysis set title
    Day 1 - Cohort 2 (ZPL-32123721)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Subject analysis set title
    Day 7 - Cohort 2 (ZPL-32123721)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Pharmacokinetic analysis set

    Primary: Percent change from baseline in EASI Score in Cohort 3

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    End point title
    		 Percent change from baseline in EASI Score in Cohort 3 [1]
    End point description
    The EASI is a validated tool used to measure the severity and extent of atopic eczema. Patients in Cohort 3 completed the EASI at screening and baseline to determine eligibility for the study, and at each study visit during treatment to assess efficacy. The total score incorporates the extent of body regions affected and the intensity of a representative area of eczema. The approximate percentages affected by eczema were calculated for each region. A higher score indicates more severe disease.
    End point type
    Primary
    End point timeframe
    Week 0 to Week 2
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10 [2]
    Units: EASI scores
    arithmetic mean (standard error)
        Observed case
    -34.24 ± 6.288
    -34.29 ± 10.680
        Multiple imputations
    -34.04 ± 6.445
    -31.03 ± 11.207
        Last observation carried forward
    -34.04 ± 7.564
    -15.77 ± 10.712
        Worst case imputation
    -33.94 ± 10.794
    3.66 ± 15.286
    Notes
    [2] - N=7 for observed case
    Statistical analysis title
    		 Treatment comparison - Observed case
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.5016 [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -21.24
         upper limit
    		 21.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.441
    Notes
    [3] - ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    [4] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Treatment comparison - Multiple imputation
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.4082 [6]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -3.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -24.39
         upper limit
    		 18.36
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.964
    Notes
    [5] - ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    [6] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Treatment comparison-Last observa. carried forward
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.0878 [8]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -18.27
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -40.65
         upper limit
    		 4.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.138
    Notes
    [7] - ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    [8] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Treatment comparison - Worst case imputation
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.0275 [10]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -37.6
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -69.53
         upper limit
    		 -5.66
    Variability estimate
    Standard error of the mean
    Dispersion value
    18.748
    Notes
    [9] - ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    [10] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.

    Primary: Percentage Change From Baseline in EASI Score Over Time in Cohort 3 - Observed Case

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    End point title
    		 Percentage Change From Baseline in EASI Score Over Time in Cohort 3 - Observed Case [11]
    End point description
    Full Analysis Set
    End point type
    Primary
    End point timeframe
    Days 5, 8, 10, and 15
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: EASI score
    arithmetic mean (standard deviation)
        Day 5
    -16.68 ± 5.823
    -4.96 ± 8.247
        Day 8 (N=20, 8)
    -27.36 ± 5.284
    -21.41 ± 8.358
        Day 10 (N=20, 8)
    -32.50 ± 5.339
    -26.49 ± 8.445
        Day 15 (N=20, 7)
    -34.24 ± 6.228
    -34.49 ± 8.445
    Statistical analysis title
    		 Day 5
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1284 [12]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -11.72
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -28.85
         upper limit
    		 5.51
    Notes
    [12] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Day 8
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2765 [13]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -5.95
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -22.85
         upper limit
    		 10.95
    Notes
    [13] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Day 10
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2765 [14]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -6.01
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -23.08
         upper limit
    		 11.06
    Notes
    [14] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.
    Statistical analysis title
    		 Day 15
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5016 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -21.24
         upper limit
    		 21.34
    Notes
    [15] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < the placebo LS mean.

    Secondary: Summary of EASI-50 and EASI-75 Responders at Week 2 - Cohort 3

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    End point title
    		 Summary of EASI-50 and EASI-75 Responders at Week 2 - Cohort 3 [16]
    End point description
    The proportion of subjects who achieved EASI-50 and EASI-75 responses at Week 2 were compared between treatment groups. EASI-50 was defined as a ≥50% reduction from baseline in EASI score at Week 2. EASI-75 was defined as a ≥75% reduction from baseline in EASI score at Week 2.
    End point type
    Secondary
    End point timeframe
    Day 14
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: Participants
        EASI-50 responder
    7
    3
        EASI-50 Non-responder
    13
    7
        EASI-75 responder
    3
    0
        EASI-75 Non-responder
    17
    10
    Statistical analysis title
    		 EASI 50
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4789 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.55
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.28
         upper limit
    		 10.75
    Notes
    [17] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < placebo LS mean.
    Statistical analysis title
    		 EASI 75
    Statistical analysis description
    ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [18]
    P-value
    		 = 0.3 [19]
    Method
    		 ANCOVA
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 999
    Notes
    [18] - ANCOVA model was fitted with percent change from baseline to Week 2 in EASI score as the dependent variable. Explanatory variables fitted were: treatment group (ZPL-5212372, placebo) and baseline EASI score as a continuous variable.
    [19] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < placebo LS mean.

    Secondary: Logistic Regression of Investigators Global Assessment - Responder and Success in Cohort 3

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    End point title
    		 Logistic Regression of Investigators Global Assessment - Responder and Success in Cohort 3 [20]
    End point description
    The following secondary endpoints were assessed for IGA: A subject was considered as having IGA success if they achieved a score of ‘Clear’ or ‘Almost clear’; note, as subjects required a score of ≥3 to enter the study they must have had a reduction of ≥2 from baseline to achieve success A subject was considered as having an IGA response if they achieved a score of ‘Clear’ or ‘Almost clear’, or a reduction of ≥2 from baseline IGA was summarized for the FAS with counts and percentages by treatment at each visit.
    End point type
    Secondary
    End point timeframe
    Day 14
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: Precentage of responders
        arithmetic mean (confidence interval 95%)
    5.0 (0.13 to 24.87)
    10.0 (0.25 to 44.50)
    Statistical analysis title
    		 Logistic Regression of Investigators Global Assess
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 = 0.5 [22]
    Method
    		 Shapiro-Wilkes test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 19.2
    Notes
    [21] - Results for the ZPL-5212372 and placebo groups are estimated adjusted LS means from the fitted model.
    [22] - The p-value tests if the residuals are normally distributed.

    Secondary: Change From Baseline in NRS for Pruritus at Week 2 - Observed Case in Cohort 3

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    End point title
    		 Change From Baseline in NRS for Pruritus at Week 2 - Observed Case in Cohort 3 [23]
    End point description
    Numerical Rating Scale (NRS) for Pruritus (worst itch).
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: Change from baseline
        least squares mean (standard error)
    -2.46 ± 0.692
    -2.54 ± 1.075
    Statistical analysis title
    		 Change From Baseline in NRS for Pruritus at Week 2
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5233
    Method
    		 Shapiro-Wilkes test
    Parameter type
    		 Median difference (net)
    Point estimate
    0.07
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -2.02
         upper limit
    		 2.16
    Variability estimate
    Standard deviation
    Dispersion value
    1.22

    Secondary: Summary of Patient Global Impression of Change and Logistic Regression of Patient Global Impression of Change in Cohort 3

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    End point title
    		 Summary of Patient Global Impression of Change and Logistic Regression of Patient Global Impression of Change in Cohort 3 [24]
    End point description
    Patient Global Impression of Change (PGIC) The PGIC scores were summarised for the FAS with counts and percentages in each treatment group. All data collected were included. The PGIC was dichotomized into responders, defined as responses of ‘Very Much Improved’, ‘Much Improved’ or ‘Minimally improved’ and non-responders (all other responses plus missing data).
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: Participants
        Very much improved
    4
    1
        Much improved
    5
    1
        Minimally improved
    7
    4
        No change
    3
    1
        Minimally worse
    1
    1
        Much worse
    0
    2
        Very much worse
    0
    0
        Missing
    0
    0
    Statistical analysis title
    		 Change in Cohort 3
    Statistical analysis description
    Patient Global Impression of Change and Logistic Regression of Patient Global Impression of Change in Cohort 3
    Comparison groups
    Cohort 3 (ZPL-5212372) v Cohort 3 (Placebo)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1.2455
    Method
    		 t-test, 1-sided
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    2.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 13.26

    Secondary: Change From Baseline in Body Surface Area at Week 2 - Observed Case in Cohort 3

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    End point title
    		 Change From Baseline in Body Surface Area at Week 2 - Observed Case in Cohort 3 [25]
    End point description
    Body Surface Area (BSA). The percentage BSA affected was summarised at each visit, including change and percentage change from baseline, by treatment group, using the Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 14
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistical analyses provided.
    End point values
    		 Cohort 3 (ZPL-5212372) Cohort 3 (Placebo)
    Number of subjects analysed
    20
    10
    Units: Change from baeline in BSA
        least squares mean (standard error)
    -6.26 ± 2.588
    -3.61 ± 4.075
    Statistical analysis title
    		 Cahnge from baseline in BSA - week 2
    Comparison groups
    Cohort 3 (Placebo) v Cohort 3 (ZPL-5212372)
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2812 [26]
    Method
    		 Shapiro-Wilkes test
    Parameter type
    		 Median difference (net)
    Point estimate
    -2.66
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -10.4
         upper limit
    		 5.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.521
    Notes
    [26] - The 1-sided p-value tests if the ZPL-5212372 LS mean is < placebo LS mean.

    Other pre-specified: ZPL-5212372 Cmax for Patients in Cohort 2

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    End point title
    		 ZPL-5212372 Cmax for Patients in Cohort 2
    End point description
    PK parameters for patients who had ointment applied over 40% BSA.
    End point type
    Other pre-specified
    End point timeframe
    Day 14
    End point values
    		 Day 1 - Cohort 2 (ZPL-32123721) Day 7 - Cohort 2 (ZPL-32123721)
    Number of subjects analysed
    1
    6
    Units: pg/mL
        median (full range (min-max))
    300.6 (300.6 to 300.6)
    135.3 (69.31 to 495.2)
    No statistical analyses for this end point

    Other pre-specified: ZPL-5212372 AUCt for Patients in Cohort 2

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    End point title
    		 ZPL-5212372 AUCt for Patients in Cohort 2
    End point description
    PK parameters for patients who had ointment applied over 40% BSA.
    End point type
    Other pre-specified
    End point timeframe
    Day 1, Day 7
    End point values
    		 Day 1 - Cohort 2 (ZPL-32123721) Day 7 - Cohort 2 (ZPL-32123721)
    Number of subjects analysed
    1
    6
    Units: h*pg/mL
        median (full range (min-max))
    1301 (1301 to 1301)
    1249 (139.2 to 4789)
    No statistical analyses for this end point

    Other pre-specified: ZPL-5212372 Trough Plasma Concentrations in Cohort 3

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    End point title
    		 ZPL-5212372 Trough Plasma Concentrations in Cohort 3
    End point description
    PK parameters for patients who had ointment applied over 40% BSA.
    End point type
    Other pre-specified
    End point timeframe
    Day 1, Day 7
    End point values
    		 Day 5 - Cohort 3 (ZPL-5212372) Day 8 - Cohort 3 (ZPL-5212372) Day 10 - Cohort 3 (ZPL-5212372) Day 15 - Cohort 3 (ZPL-5212372)
    Number of subjects analysed
    20
    20
    19
    20
    Units: pg/mL
        median (full range (min-max))
    88.985 (0.00 to 644.39)
    114.700 (0.00 to 380.42)
    113.920 (0.00 to 287.07)
    90.825 (0.00 to 456.01)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events (AEs) are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All AEs reported in this record are from date of First Patient First Treatment until Last Patient Last Visit) up to approximately 1 year.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Cohort 1 ZPL-5212372 10% BSA
    Reporting group description
    		 Cohort 1 ZPL-5212372 10% BSA

    Reporting group title
    Cohort 1 ZPL-5212372 40% BSA
    Reporting group description
    		 Cohort 1 ZPL-5212372 40% BSA

    Reporting group title
    Cohort 1 Placebo 10% BSA
    Reporting group description
    		 Cohort 1 Placebo 10% BSA

    Reporting group title
    Cohort 1 Placebo 40% BSA
    Reporting group description
    		 Cohort 1 Placebo 40% BSA

    Reporting group title
    Cohort 2 ZPL-5212372 10% BSA
    Reporting group description
    		 Cohort 2 ZPL-5212372 10% BSA

    Reporting group title
    Cohort 2 ZPL-5212372 40% BSA
    Reporting group description
    		 Cohort 2 ZPL-5212372 40% BSA

    Reporting group title
    Cohort 2 Placebo 10% BSA
    Reporting group description
    		 Cohort 2 Placebo 10% BSA

    Reporting group title
    Cohort 2 Placebo 40% BSA
    Reporting group description
    		 Cohort 2 Placebo 40% BSA

    Reporting group title
    Cohort 3 ZPL-5212372
    Reporting group description
    		 Cohort 3 ZPL-5212372

    Reporting group title
    Cohort 3 Placebo
    Reporting group description
    		 Cohort 3 Placebo

    Serious adverse events
    		 Cohort 1 ZPL-5212372 10% BSA Cohort 1 ZPL-5212372 40% BSA Cohort 1 Placebo 10% BSA Cohort 1 Placebo 40% BSA Cohort 2 ZPL-5212372 10% BSA Cohort 2 ZPL-5212372 40% BSA Cohort 2 Placebo 10% BSA Cohort 2 Placebo 40% BSA Cohort 3 ZPL-5212372 Cohort 3 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Cohort 1 ZPL-5212372 10% BSA Cohort 1 ZPL-5212372 40% BSA Cohort 1 Placebo 10% BSA Cohort 1 Placebo 40% BSA Cohort 2 ZPL-5212372 10% BSA Cohort 2 ZPL-5212372 40% BSA Cohort 2 Placebo 10% BSA Cohort 2 Placebo 40% BSA Cohort 3 ZPL-5212372 Cohort 3 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    3 / 6 (50.00%)
    1 / 1 (100.00%)
    1 / 3 (33.33%)
    2 / 2 (100.00%)
    4 / 6 (66.67%)
    1 / 1 (100.00%)
    2 / 2 (100.00%)
    17 / 20 (85.00%)
    9 / 10 (90.00%)
    Injury, poisoning and procedural complications
    ARTHROPOD BITE
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    TACHYCARDIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Surgical and medical procedures
    TOOTH EXTRACTION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    0
    HEADACHE
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    3 / 20 (15.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    3
    0
    PRESYNCOPE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    Blood and lymphatic system disorders
    INCREASED TENDENCY TO BRUISE
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    2 / 20 (10.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    2
    1
    LYMPHADENOPATHY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    NEUTROPENIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    2
    NEUTROPHILIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    General disorders and administration site conditions
    APPLICATION SITE PARAESTHESIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    CATHETER SITE HAEMATOMA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    FEELING ABNORMAL
         subjects affected / exposed
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    NAUSEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    DYSPNOEA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    WHEEZING
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    0
    DERMATITIS ALLERGIC
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    3 / 10 (30.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    0
    0
    4
    DERMATITIS ATOPIC
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    3 / 6 (50.00%)
    1 / 1 (100.00%)
    1 / 2 (50.00%)
    1 / 20 (5.00%)
    2 / 10 (20.00%)
         occurrences all number
    0
    0
    0
    0
    1
    3
    1
    1
    1
    2
    DRY SKIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    4 / 20 (20.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    1
    ERYTHEMA
         subjects affected / exposed
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    PRURITUS
         subjects affected / exposed
    1 / 2 (50.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    6 / 20 (30.00%)
    6 / 10 (60.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    1
    6
    6
    RASH
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    RASH PRURITIC
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    1 / 3 (33.33%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    REBOUND ATOPIC DERMATITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    1 / 2 (50.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    SKIN BURNING SENSATION
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    1 / 20 (5.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    1 / 1 (100.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    3 / 20 (15.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    3
    0
    PARONYCHIA
         subjects affected / exposed
    0 / 2 (0.00%)
    0 / 6 (0.00%)
    0 / 1 (0.00%)
    0 / 3 (0.00%)
    0 / 2 (0.00%)
    1 / 6 (16.67%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 20 (0.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jul 2016
    Documented a change to the study emollient for Cohort 3 patients as a consequence of unforeseen hypersensitivity reactions to the E45 study emollient by some patients in Cohort 2. This amendment allowed patients to use an alternative study emollient if they had a potential (or known) hypersensitivity reaction to E45 lotion. In addition, the following pre-defined adaptive features of the protocol were enacted: 1) For Cohorts 2 and 3, the ‘study emollient application’ adaptive study design category was used. 2) For Cohort 2, a second pre-defined adaptive feature of the original protocol was enacted.

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

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

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