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    Clinical Trial Results:
    A RANDOMIZED, DOUBLE-BLIND, PLACEBO CONTROLLED, PARALLEL GROUP STUDY TO DETERMINE THE EFFECTS OF 8 WEEKS TREATMENT WITH ORAL ZPL-3893787 (30 MG OD X 56 DAYS) ON PRURITUS IN ADULT SUBJECTS WITH MODERATE TO SEVERE ATOPIC DERMATITIS.

    Summary
    EudraCT number
    		 2014-005057-39
    Trial protocol
    		 GB   BE   DE   PL  
    Global end of trial date
    03 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2017
    First version publication date
    17 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZPL389/101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Ziarco Pharma Ltd
    Sponsor organisation address
    Innovation House, Discovery Park, Ramsgate Road, Sandwich, United Kingdom, CT13 9ND
    Public contact
    Lynn Purkins, Ziarco Pharma Ltd, +44 1304 806889, lynn.purkins@ziarcopharma.com
    Scientific contact
    Lynn Purkins, Ziarco Pharma Ltd, +44 1304 806889, lynn.purkins@ziarcopharma.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
    15 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 8 weeks treatment of 30 mg od ZPL-3893787 on pruritus in adult subjects with moderate to severe atopic dermatitis.
    Protection of trial subjects
    The study was conducted in accordance with the relevant articles of the "Declaration of Helsinki" and International Council for Harmonisation Good Clinical Practices consolidated guidelines, in addition to relevant European and UK regulations.
    Background therapy
    		 Not applicable
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    18 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    United Kingdom: 48
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Germany: 20
    Worldwide total number of subjects
    98
    EEA total number of subjects
    98
    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)
    98
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first informed consent was on 18 May 2015. Subjects were randomly assigned 2:1 to receive either 30 mg ZPL-3893787 or matching placebo. The randomization was stratified by baseline worst daily pruritus NRS score (≤ 7.5 and > 7.5) determined from the mean pruritus score (worst itch over 24 hours) collected during the 7-day Run-in Period.

    Pre-assignment
    Screening details
    		 Healthy male and female subjects of any ethnic origin, aged between 18 and 65 years, with a history or diagnosis of moderate to severe atopic dermatitis for at least 12 months prior to Screening, were selected according to the protocol inclusion and exclusion criteria.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject, Monitor
    Blinding implementation details
    Both ZPL-3893787 and matching placebo capsules were packed in bottles containing 7 capsules. All study drugs were supplied in identical bottles (similar in color and appearance), thereby enabling double-blind conditions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ZPL-3893787
    Arm description
    		 Active treatment group.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ZPL-3893787
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg ZPL-3893787 orally once daily for 8 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo group.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1 capsule orally once daily for 8 weeks.

    Number of subjects in period 1
    		ZPL-3893787 Placebo
    Started
    65
    33
    Completed
    54
    24
    Not completed
    11
    9
         Consent withdrawn by subject
    4
    1
         Physician decision
    2
    -
         Adverse event, non-fatal
    2
    -
         Compliance problems
    1
    -
         Other
    1
    -
         Lost to follow-up
    1
    1
         Lack of efficacy
    -
    7

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ZPL-3893787
    Reporting group description
    		 Active treatment group.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group.

    Reporting group values
    		 ZPL-3893787 Placebo Total
    Number of subjects
    		 65 33 98
    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)
    		 65 33 98
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 33.7 ± 11.22 35.5 ± 12.52 -
    Gender categorical
    Units: Subjects
        Female
    		 36 20 56
        Male
    		 29 13 42
    Fitzpatrick Skin Type
    Units: Subjects
        Type I
    		 2 4 6
        Type II
    		 24 11 35
        Type III
    		 32 14 46
        Type IV
    		 3 2 5
        Type V
    		 3 1 4
        Type VI
    		 1 1 2

    End points

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    End points reporting groups
    Reporting group title
    ZPL-3893787
    Reporting group description
    		 Active treatment group.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group.

    Primary: Worst Pruritus Score (NRS): Change from Baseline to Week 8 - MI FAS

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    End point title
    		 Worst Pruritus Score (NRS): Change from Baseline to Week 8 - MI FAS
    End point description
    NRS: Numerical Rating Scales FAS: Full Analysis Set MI: Missing values were imputed using Markov Chain Monte Carlo (MCMC) multiple imputation methods.
    End point type
    Primary
    End point timeframe
    Baseline to Week 8
    End point values
    		 ZPL-3893787 Placebo
    Number of subjects analysed
    65
    33
    Units: NRS
    arithmetic mean (standard deviation)
        Week 8 Summary
    4.27 ± 2.253
    4.6 ± 1.95
        Week 8 Baseline Summary
    7.3 ± 1.139
    7.26 ± 1.054
        Change from Baseline
    -3.03 ± 2.186
    -2.66 ± 2.057
    Statistical analysis title
    		 Change from baseline
    Statistical analysis description
    NRS LS Means (standard error) Change from Baseline values are: ZPL-3893787 (N=65): -3.02 (±0.291) Placebo (N=33): -2.67 (±0.437)
    Comparison groups
    ZPL-3893787 v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.249 [1]
    Method
    		 ANCOVA
    Parameter type
    		 LS Difference
    Point estimate
    -0.35
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -1.21
         upper limit
    		 0.51
    Notes
    [1] - 1-sided p-value. The ANCOVA model included baseline value and treatment.

    Secondary: Eczema Area and Severity Index (EASI): Change from Baseline to Week 8 - MI FAS

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    End point title
    		 Eczema Area and Severity Index (EASI): Change from Baseline to Week 8 - MI FAS
    End point description
    Summary of change in Eczema Area and Severity Index (EASI) from Baseline to Week 8. The EASI is used to measure the severity and extent of atopic eczema over 4 body regions (head and neck, upper limbs, trunk, and lower limbs). FAS: Full Analysis Set MI: Missing values were imputed using Markov Chain Monte Carlo (MCMC) multiple imputation methods.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 8.
    End point values
    		 ZPL-3893787 Placebo
    Number of subjects analysed
    65
    33
    Units: EASI
    arithmetic mean (standard deviation)
        Week 8 summary
    10.67 ± 9.541
    15.06 ± 11.159
        Week 8 baseline summary
    21.39 ± 7.889
    20.44 ± 6.868
        Week 8 change from baseline
    -10.72 ± 9.679
    -5.38 ± 9.922
    Statistical analysis title
    		 Change from baseline analysis
    Statistical analysis description
    NRS LS Means (standard error) Change from Baseline values are: ZPL-3893787 (N=65): -10.47 (±1.267) Placebo (N=33): -5.41 (±1.773)
    Comparison groups
    ZPL-3893787 v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01 [2]
    Method
    		 ANCOVA
    Parameter type
    		 LS Difference
    Point estimate
    -5.06
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -8.66
         upper limit
    		 -1.46
    Notes
    [2] - 1-sided p-value. The ANCOVA model included baseline EASI, stratification variable (worst daily pruritus NRS ≤ 7.5 or > 7.5) and treatment.

    Secondary: Treatment Emergent Adverse Events

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    End point title
    		 Treatment Emergent Adverse Events
    End point description
    Abbreviations: IMP = investigational medicinal product; MedDRA = Medical Dictionary for Regulatory Activities; TEAE = treatment-emergent adverse event Note: Multiple events for the same preferred term were counted once for each subject. A subject with the same TEAE at different intensities was summarized at the most severe intensity. Treatment-related TEAEs were defined as those considered “possibly related” or “probably related” by the Investigator. Adverse events were coded with MedDRA version 18.0.
    End point type
    Secondary
    End point timeframe
    Entire duration of the study. Treatment-emergent AEs (TEAEs) are defined as AEs that started or worsened on or after the date of first administration of study drug.
    End point values
    		 ZPL-3893787 Placebo
    Number of subjects analysed
    65
    33
    Units: Subjects
        Subjects with any TEAE
    43
    21
        Subjects with any serious TEAE
    0
    1
        Subjects with any severe TEAE
    2
    3
        Subjects with treatment-related TEAEs
    15
    10
        Subjects with TEAEs leading to IMP discontinuation
    2
    3
        Subjects with TEAEs leading to death
    0
    0
    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 Screening to up to 28 days post last dose.
    Adverse event reporting additional description
    Treatment-emergent AEs (TEAEs) are defined as AEs that started or worsened on or after the date of first administration of study drug. Non-serious adverse events: TEAEs considered related to IMP (Safety Analysis Set) are provided.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    ZPL-3893787
    Reporting group description
    		 Active treatment group. Non-serious adverse events: Data for non-serious adverse events that are treatment-emergent and considered related to IMP are provided. A subject is only counted once in each system organ class and system organ class/preferred term combination. Related TEAEs are defined as those considered by the investigator as possibly related or probably related.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group. Non-serious adverse events: Data for non-serious adverse events that are treatment-emergent and considered related to IMP are provided. A subject is only counted once in each system organ class and system organ class/preferred term combination. Related TEAEs are defined as those considered by the investigator as possibly related or probably related.

    Serious adverse events
    		 ZPL-3893787 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Eye disorders
    Ulcerative keratitis
    Additional description: ulcus corneae left eye)
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 ZPL-3893787 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 65 (23.08%)
    10 / 33 (30.30%)
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sinus arrhythmia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 65 (9.23%)
    4 / 33 (12.12%)
         occurrences all number
    6
    4
    Somnolence
         subjects affected / exposed
    2 / 65 (3.08%)
    1 / 33 (3.03%)
         occurrences all number
    2
    1
    Dizziness
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Thirst
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Drug ineffective
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Decreased activity
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 65 (3.08%)
    0 / 33 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Urticaria
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Dermatitis atopic
         subjects affected / exposed
    0 / 65 (0.00%)
    2 / 33 (6.06%)
         occurrences all number
    0
    2
    Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 65 (1.54%)
    1 / 33 (3.03%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 65 (1.54%)
    0 / 33 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 65 (0.00%)
    1 / 33 (3.03%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Feb 2015
    Global Amendment 1 Extended the Follow-up Period to ≥ 20 days Clarified the length of time the eDiary would be used Clarified the circumstances when abstinence is an appropriate method of contraception Clarified the number of ECGs performed at each time point. Clarified the reporting time for AEs
    02 Sep 2015
    Global Amendment 2.1 Clarified the duration of washout of the prohibited medications Updated the Sponsor’s Chief Medical Officer information Note: Global Amendment 2 was approved on 22 July 2015, but was not enacted due to typographical errors, and was replaced by Global Amendment 2.1.

    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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