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    Clinical Trial Results:
    A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled, Parallel-Arm Study of the Safety and Efficacy of LX3305, a Sphingosine-1-Phosphate Lyase Inhibitor, for Treatment of Darier’s Disease or Hailey-Hailey Disease

    Summary
    EudraCT number
    		 2018-000373-80
    Trial protocol
    		 FR  
    Global end of trial date
    03 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2020
    First version publication date
    03 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DERM-101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dermecular Therapeutics, Inc.
    Sponsor organisation address
    421 Kipling Street, Palo Alto, CA, United States, 94301
    Public contact
    Baird Ruch, Dermecular, +1 978-440-0694, br@dermecular.com
    Scientific contact
    Curtis Scribner MD, Dermecular, +1 510 914 8368, curt@clscribs.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
    31 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Dec 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Dec 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of LX3305 compared to placebo in participants with Darier’s Disease (DD) or Hailey-Hailey Disease (HHD).
    Protection of trial subjects
    The study was performed in accordance with ethical principles that had their origin in the Declaration of Helsinki and were consistent with International Conference for Harmonisation/Good Clinical Practice, applicable regulatory requirements and the Sponsor’s policy on Bioethics.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Jul 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 33
    Worldwide total number of subjects
    33
    EEA total number of subjects
    33
    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)
    32
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 33 participants were enrolled and randomized in this study. Participants were stratified according to disease (DD or HHD) and randomized 2:1 to receive either LX3305 or placebo.

    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
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Darier’s Disease: LX3305
    Arm description
    		 Participants with Darier’s Disease received one 250-milligrams (mg) capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LX3305
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LX3305 was administered per the dose and schedule specified in the arm.

    Arm title
    		 Darier’s Disease: Placebo
    Arm description
    		 Participants with Darier’s Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.
    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
    Placebo matched to LX3305 was administered per schedule specified in the arm.

    Arm title
    		 Hailey-Hailey Disease: LX3305
    Arm description
    		 Participants with Hailey-Hailey Disease received one 250-mg capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LX3305
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    LX3305 was administered per the dose and schedule specified in the arm.

    Arm title
    		 Hailey-Hailey Disease: Placebo
    Arm description
    		 Participants with Hailey-Hailey Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.
    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
    Placebo matched to LX3305 was administered per schedule specified in the arm.

    Number of subjects in period 1
    		Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Started
    12
    5
    10
    6
    Received at least 1 dose of study drug
    12
    5
    10
    6
    mITT population
    12
    5
    10
    6
    Completed
    11
    4
    9
    6
    Not completed
    1
    1
    1
    0
         Adverse event, non-fatal
    1
    1
    -
    -
         Other than specified
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Darier’s Disease: LX3305
    Reporting group description
    		 Participants with Darier’s Disease received one 250-milligrams (mg) capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Darier’s Disease: Placebo
    Reporting group description
    		 Participants with Darier’s Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: LX3305
    Reporting group description
    		 Participants with Hailey-Hailey Disease received one 250-mg capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: Placebo
    Reporting group description
    		 Participants with Hailey-Hailey Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo Total
    Number of subjects
    		 12 5 10 6 33
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ( 12.99 ) 36.8 ( 11.80 ) 50.3 ( 9.92 ) 54.2 ( 6.79 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 3 7 3 21
        Male
    		 4 2 3 3 12

    End points

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    End points reporting groups
    Reporting group title
    Darier’s Disease: LX3305
    Reporting group description
    		 Participants with Darier’s Disease received one 250-milligrams (mg) capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Darier’s Disease: Placebo
    Reporting group description
    		 Participants with Darier’s Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: LX3305
    Reporting group description
    		 Participants with Hailey-Hailey Disease received one 250-mg capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: Placebo
    Reporting group description
    		 Participants with Hailey-Hailey Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to Adverse Events (AEs)

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), Deaths, and Discontinuations Due to Adverse Events (AEs) [1]
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship to the study drug. TEAE was defined as any AE occurring after the first dose of study drug. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. AEs included both SAEs and non-serious AEs. All AEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding system (Version 21.0). A summary of other non-serious AEs and all SAEs, regardless of causality is located in the 'Reported AE section'. Safety population included all participants who were randomized and received any amount of study drug.
    End point type
    Primary
    End point timeframe
    Baseline (Day 1) up to Week 16
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The endpoint is descriptive in nature and statistical analysis is not applicable.
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: participants
        TEAEs
    10
    5
    8
    6
        SAEs
    1
    1
    0
    0
        Death
    0
    0
    0
    0
        Discontinuations Due to AEs
    1
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With at Least a 1-Grade Improvement From Baseline in Investigator’s Global Signs Assessment (IGSA) Score at Any Time During the Trial; and at Weeks 4, 8, and 12

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    End point title
    		 Percentage of Participants With at Least a 1-Grade Improvement From Baseline in Investigator’s Global Signs Assessment (IGSA) Score at Any Time During the Trial; and at Weeks 4, 8, and 12
    End point description
    IGSA uses a 5 point scale to score severity in Darier’s Disease and Hailey-Hailey Disease. IGSA score ranges from 0 to 4, where 0=clear, 1=almost clear, 2=mild,3=moderate, and 4=severe. Higher score indicated worsening. Percentage is based on an IGSA score improvement of at least 1-grade from baseline in the primary lesion. Percentage of participants with at least a 1-grade improvement at each visit are mutually exclusive. Therefore, a participant responding over time may be counted in multiple visits. Clopper Exact 95% confidence interval was used. Modified intent-to-treat (mITT) population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline and at least 1 post-baseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity (that is, a dose limiting toxicity [DLT]) were to be included in the mITT population, even if they did not have a post-baseline IGSA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline; at any time during the trial (up to Week 12); at Weeks 4, 8, and 12
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: percentage of participants
    number (confidence interval 95%)
        At anytime
    33.3 (9.9 to 65.1)
    40.0 (5.3 to 85.3)
    50.0 (18.7 to 81.3)
    83.3 (35.9 to 99.6)
        Week 4
    8.3 (0.2 to 38.5)
    0 (0 to 0)
    20.0 (2.5 to 55.6)
    33.3 (4.3 to 77.7)
        Week 8
    16.7 (2.1 to 48.4)
    20.0 (0.5 to 71.6)
    10.0 (0.3 to 44.5)
    50.0 (11.8 to 88.2)
        Week 12
    25.0 (5.5 to 57.2)
    40.0 (5.3 to 85.3)
    50.0 (18.7 to 81.3)
    83.3 (35.9 to 99.6)
    No statistical analyses for this end point

    Secondary: Percentage of Participants who Achieved at Least a 2-Grade Improvement From Baseline in IGSA Score at Any Time During the Trial, and at Weeks 4, 8, and 12

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    End point title
    		 Percentage of Participants who Achieved at Least a 2-Grade Improvement From Baseline in IGSA Score at Any Time During the Trial, and at Weeks 4, 8, and 12
    End point description
    IGSA uses a 5 point scale to score severity in Darier’s Disease and Hailey-Hailey Disease. IGSA score ranges from 0 to 4, where 0=clear, 1=almost clear, 2=mild,3=moderate, and 4=severe. Higher score indicated worsening. Percentage is based on an IGSA score improvement of at least 1-Grade from baseline in primary lesion. Percentage is based on an IGSA score improvement of at least 2-grades from baseline in primary lesion. Percentage of participants with at least a 2-grade improvement at each visit are mutually exclusive. Therefore, a participant responding over time may be counted in multiple visits. Clopper Exact 95% CI was used. mITT population: all participants who were randomized, received at least 1 dose of study drug, and had a baseline and at least 1 post-baseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity were to be included in mITT population, even if they did not have a post-baseline IGSA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline; at any time during the trial (up to Week 12); Weeks 4, 8, and 12
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: percentage of participants
    number (confidence interval 95%)
        At anytime
    25.0 (5.5 to 57.2)
    40.0 (5.3 to 85.3)
    40.0 (12.2 to 73.8)
    66.7 (22.3 to 95.7)
        Week 4
    8.3 (0.2 to 38.5)
    0 (0 to 0)
    20.0 (2.5 to 55.6)
    16.7 (0.4 to 64.1)
        Week 8
    8.3 (0.2 to 38.5)
    20.0 (0.5 to 71.6)
    10.0 (0.3 to 44.5)
    50.0 (11.8 to 88.2)
        Week 12
    16.7 (2.1 to 48.4)
    40.0 (5.3 to 85.3)
    40.0 (12.2 to 73.8)
    66.7 (22.3 to 95.7)
    No statistical analyses for this end point

    Secondary: Time-to-Response for 1-Grade Improvement From Baseline in IGSA Score

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    End point title
    		 Time-to-Response for 1-Grade Improvement From Baseline in IGSA Score
    End point description
    Time to response for 1-grade improvement in IGSA score in primary lesion: time from date of randomization to first date of IGSA assessment that showed at least a 1-grade improvement from baseline. It was estimated by Kaplan-Meier method. IGSA uses a 5 point scale to score severity in Darier’s Disease and Hailey-Hailey Disease. IGSA score ranges from 0 to 4, where 0=clear,1=almost clear,2=mild,3=moderate,4=severe. Higher score indicated worsening. Participants who did not have at least a 1-grade improvement in primary lesion were censored on date of last IGSA assessment. mITT population:all randomized participants who received at least 1 dose of study drug, had a baseline and at least 1 postbaseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity were to be included in mITT population, even if they did not have a postbaseline IGSA assessment. '99999'=data not calculated due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Randomization until first improvement in IGSA score from baseline of at least 1-grade (up to Week 12)
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: days
        median (confidence interval 95%)
    99999 (57.00 to 99999)
    99999 (57.00 to 99999)
    85.00 (31.00 to 99999)
    69.50 (29.00 to 99999)
    No statistical analyses for this end point

    Secondary: Time-to-Response for 2-Grade Improvement From Baseline in IGSA Score

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    End point title
    		 Time-to-Response for 2-Grade Improvement From Baseline in IGSA Score
    End point description
    Time to response for 2-grade improvement in IGSA score in primary lesion: time from date of randomization to first date of IGSA assessment that showed at least a 2-grade improvement from baseline. It was estimated by Kaplan-Meier method. IGSA uses a 5 point scale to score severity in Darier’s Disease and Hailey-Hailey Disease. IGSA score ranges from 0 to 4, where 0=clear,1=almost clear,2=mild,3=moderate,4=severe. Higher score indicated worsening. Participants who did not have at least a 2-grade improvement in primary lesion were censored on date of last IGSA assessment. mITT population:all randomized participants who received at least 1 dose of study drug, had a baseline and at least 1 postbaseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity were to be included in mITT population, even if they did not have a postbaseline IGSA assessment. '99999'=data not calculated due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    Randomization until first improvement in IGSA score from baseline of at least 2-grade (up to Week 12)
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: days
        median (confidence interval 95%)
    99999 (85.00 to 99999)
    99999 (57.00 to 99999)
    99999 (31.00 to 99999)
    75.50 (29.00 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response for 1-Grade Improvement From Baseline in IGSA Score

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    End point title
    		 Duration of Response for 1-Grade Improvement From Baseline in IGSA Score
    End point description
    Duration of response for 1-grade improvement in IGSA score: time from first occurrence of at least a 1-grade IGSA score improvement in primary lesion to date the score returned to baseline grade or higher. It was estimated by Kaplan-Meier methodology. Responders whose IGSA score return to baseline grade or higher or who dropped out or died prior to their IGSA score returning to baseline or higher were censored on date of last IGSA assessment. mITT population: all randomized participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity were to be included in mITT population, even without a post-baseline IGSA assessment. Here, ‘number of participants analyzed’= participants who experienced at least a 1-grade improvement in IGSA score. '-99999 and 99999'=data not calculated due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    From first improvement in IGSA score from baseline of at least 1-grade until return to baseline grade or higher (up to Week 12)
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    4
    2
    5
    5
    Units: days
        median (confidence interval 95%)
    50.00 (-99999 to 99999)
    99999 (99999 to 99999)
    99999 (34.00 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response for 2-Grade Improvement From Baseline in IGSA Score

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    End point title
    		 Duration of Response for 2-Grade Improvement From Baseline in IGSA Score
    End point description
    Duration of response for 2-grade improvement in IGSA score: time from first occurrence of at least a 2-grade IGSA score improvement in primary lesion to date the score returned to baseline grade or higher. It was estimated by Kaplan-Meier methodology. Responders whose IGSA score return to baseline grade or higher or who dropped out or died prior to their IGSA score returning to baseline or higher were censored on date of last IGSA assessment. mITT population: all randomized participants who received at least 1 dose of study drug, had a baseline and at least 1 post-baseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity were to be included in mITT population, without a post-baseline IGSA assessment. Here, ‘number of participants analyzed’= participants who experienced at least a 2-grade improvement in IGSA score. '-99999 and 99999'=data not calculated due to low number of participants with an event.
    End point type
    Secondary
    End point timeframe
    From first improvement in IGSA score from baseline of at least 2-grade until return to baseline grade or higher (up to Week 12)
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    3
    2
    4
    4
    Units: days
        median (confidence interval 95%)
    50.00 (-99999 to 99999)
    99999 (99999 to 99999)
    99999 (34.00 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Affected Body Surface Area (BSA) at Weeks 4, 8, and 12

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    End point title
    		 Change from Baseline in Affected Body Surface Area (BSA) at Weeks 4, 8, and 12
    End point description
    mITT population included all participants who were randomized, received at least 1 dose of study drug, and had a baseline and at least 1 post-baseline IGSA assessment, unless they discontinued early due to toxicity. Participants who discontinued early due to toxicity (that is, a DLT) were to be included in the mITT population, even if they did not have a post-baseline IGSA assessment.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 4, 8, and 12
    End point values
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Number of subjects analysed
    12
    5
    10
    6
    Units: percentage of BSA
    arithmetic mean (standard deviation)
        Baseline
    25.7 ( 19.95 )
    32.8 ( 17.71 )
    5.4 ( 3.69 )
    7.0 ( 8.07 )
        Change at Week 4 (n=12, 5, 9, 6)
    7.1 ( 8.31 )
    -1.8 ( 13.33 )
    0.2 ( 5.14 )
    2.3 ( 2.66 )
        Change at Week 8 (n=12, 4, 10, 6)
    1.0 ( 15.34 )
    -4.3 ( 12.01 )
    2.2 ( 12.40 )
    -0.7 ( 2.42 )
        Change at Week 12 (n=12, 5, 10, 6)
    1.1 ( 17.17 )
    -6.8 ( 17.20 )
    0.9 ( 7.84 )
    -0.3 ( 1.75 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline (Day 1) up to Week 16
    Adverse event reporting additional description
    Safety population included all participants who were randomized and received any amount of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Darier’s Disease: LX3305
    Reporting group description
    		 Participants with Darier’s Disease received one 250-milligrams (mg) capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Darier’s Disease: Placebo
    Reporting group description
    		 Participants with Darier’s Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: LX3305
    Reporting group description
    		 Participants with Hailey-Hailey Disease received one 250-mg capsule of LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received two 250-mg capsules (total dose of 500 mg) of LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Reporting group title
    Hailey-Hailey Disease: Placebo
    Reporting group description
    		 Participants with Hailey-Hailey Disease received 1 capsule of placebo matched to LX3305 orally once daily for the first 7 days of treatment period. If the participant did not experience any adverse events, then starting on Day 8, participants received 2 capsules of placebo matched to LX3305 orally once daily for the remaining 11 weeks of the treatment period.

    Serious adverse events
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Superinfection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (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
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Darier’s Disease: LX3305 Darier’s Disease: Placebo Hailey-Hailey Disease: LX3305 Hailey-Hailey Disease: Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 12 (83.33%)
    4 / 5 (80.00%)
    8 / 10 (80.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Superficial spreading melanoma stage unspecified
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    1
    0
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Chills
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Condition aggravated
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    2
    Feeling hot
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Congenital, familial and genetic disorders
    Benign familial pemphigus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Keratosis follicular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Headache
         subjects affected / exposed
    0 / 12 (0.00%)
    3 / 5 (60.00%)
    2 / 10 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    4
    9
    2
    Migraine
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Deafness transitory
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Blepharitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry eye
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vitreous floaters
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Aphthous ulcer
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 5 (40.00%)
    3 / 10 (30.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    2
    4
    1
    Faeces soft
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tendonitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Infections and infestations
    Bronchitis haemophilus
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cystitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Herpes virus infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Superinfection
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 5 (20.00%)
    3 / 10 (30.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    3
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    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
    16 May 2018
    Protocol amendment included the following substantive changes to the protocol: • For female participants of childbearing potential and male participants of reproductive potential who were having intercourse with female partners of childbearing potential, the required use of 2 highly effective methods of birth control during the study was lengthened from 1 month to 90 days after the last dose of study drug. • Stopping rules were clarified to explain that laboratory DLT and DLT referred to a lymphocyte laboratory value of Grade greater than or equal to (≥) 3, and that TEAE referred to any non-lymphocyte TEAE of Grade ≥2. • Reporting requirements for TEAEs were clarified. Rather than reporting within 1 business day of the first awareness of an event, SAEs were to be reported to the Sponsor immediately upon the first awareness of the event. Additional follow-up information, if required or available, was to be sent electronically to the Sponsor immediately upon receipt and should have been completed on a follow-up SAE form, placed with the original SAE information, and kept with the appropriate section of the case report form (CRF) and/or study file.

    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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