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    Clinical Trial Results:
    The ASCEND Study: A Phase III, Multicenter, Double Blinded Vehicle Controlled Study of TMB-001 - with a Parallel Optional Maximal Use Arm - in the Treatment of RXLI (Xlinked) or ARCI Ichthyosis in Subjects Aged ≥6 Years

    Summary
    EudraCT number
    		 2022-000459-35
    Trial protocol
    		 DE   FR   IT  
    Global end of trial date
    23 Sep 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2025
    First version publication date
    28 Jun 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TMB01-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05295732
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Timber Pharmaceuticals, Inc
    Sponsor organisation address
    7 Giralda Farms, Madison, NJ, United States, 07940
    Public contact
    Clinical Disclosure, LEO Pharma A/S, 45 4494 5888, disclosure@leo-pharma.com
    Scientific contact
    Clinical Disclosure, LEO Pharma A/S, 45 4494 5888, disclosure@leo-pharma.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
    24 Feb 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To ascertain the efficacy of TMB-001 0.05% topical ointment as a treatment for congenital ichthyosis (CI) compared with Vehicle during a 12-week treatment.
    Protection of trial subjects
    This study was conducted in accordance with the protocol and consensus ethical principles derived from international guidelines including the Declaration of Helsinki (2013), CIOMS International Ethical Guidelines, applicable ICH GCP Guidelines, and other applicable laws and regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Jun 2022
    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
    France: 20
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Italy: 22
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    United States: 44
    Worldwide total number of subjects
    116
    EEA total number of subjects
    65
    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)
    24
    Adolescents (12-17 years)
    29
    Adults (18-64 years)
    58
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 34 sites across the United States, Canada, Germany, France, and Italy enrolled subjects, and 33 of these sites randomized subjects.

    Pre-assignment
    Screening details
    		 34 study centers recruited subjects.

    Period 1
    Period 1 title
    double-blind 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
    		 TMB-001 0.05%
    Arm description
    		 In the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to TMB-001 0.05% QD with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12 week double-blind primary dosing period, the subjects continued with TMB-001 0.05% at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TMB-001 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use, Topical use
    Dosage and administration details
    QD for 3 weeks in period 1 and then BID for 9 weeks in period 2

    Arm title
    		 Vehicle
    Arm description
    		 For the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to Vehicle QD treatment, with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12-week double-blind primary dosing period, the subjects continued with Vehicle at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Vehicle
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use
    Dosage and administration details
    QD for 3 weeks in period 1 and then BID for 9 weeks in period 2

    Number of subjects in period 1
    		TMB-001 0.05% Vehicle
    Started
    78
    38
    Completed
    65
    36
    Not completed
    13
    2
         Various reasons
    13
    2
    Period 2
    Period 2 title
    Open-label
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TMB-001 0.05% QD
    Arm description
    		 At Week 12, TMB-001 0.05% BID treatment responders (who had achieved a ≥1-point reduction in IGA score from baseline) were re-randomized (1:1 ratio) to 12 weeks of open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. Subjects with less than a 1-point reduction in IGA score from baseline were discontinued from the study. Vehicle-treated subjects who achieved <1-point reduction in IGA score from baseline by week 12, were eligible to cross over to 12 weeks of open-label treatment with TMB-001 0.05% BID treatment. Subjects with a ≥1-point reduction in IGA score from baseline on vehicle were discontinued from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TMB-001 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use, Topical use
    Dosage and administration details
    TMB-001 0.05% QD for 12 weeks.

    Arm title
    		 TMB-001 0.05% BID
    Arm description
    		 At Week 12, TMB-001 0.05% BID treatment responders (who had achieved a ≥1-point reduction in IGA score from baseline) were re-randomized (1:1 ratio) to 12 weeks of open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. Subjects with less than a 1-point reduction in IGA score from baseline were discontinued from the study. Vehicle-treated subjects who achieved <1-point reduction in IGA score from baseline by week 12, were eligible to cross over to 12 weeks of open-label treatment with TMB-001 0.05% BID treatment. Subjects with a ≥1-point reduction in IGA score from baseline on vehicle were discontinued from the study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    TMB-001 0.05%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ointment
    Routes of administration
    Cutaneous use, Topical use
    Dosage and administration details
    TMB-001 0.05% BID for 12 weeks.

    Number of subjects in period 2 [1]
    		TMB-001 0.05% QD TMB-001 0.05% BID
    Started
    28
    38
    Completed
    28
    37
    Not completed
    0
    1
         Discontinued IMP before week 12
    -
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: TMB-001 0.05% treated subjects with less than a 1-point reduction in IGA score from baseline were discontinued from the study. Vehicle-treated subjects with a ≥1-point reduction in IGA score from baseline were discontinued from the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TMB-001 0.05%
    Reporting group description
    		 In the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to TMB-001 0.05% QD with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12 week double-blind primary dosing period, the subjects continued with TMB-001 0.05% at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.

    Reporting group title
    Vehicle
    Reporting group description
    		 For the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to Vehicle QD treatment, with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12-week double-blind primary dosing period, the subjects continued with Vehicle at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.

    Reporting group values
    		 TMB-001 0.05% Vehicle Total
    Number of subjects
    		 78 38 116
    Age categorical
    Units: Subjects
        6-11 years
    		 16 8 24
        12-16 years
    		 19 8 27
        >=17 years
    		 43 22 65
    Gender categorical
    Units: Subjects
        Female
    		 29 15 44
        Male
    		 49 23 72
    Race
    Units: Subjects
        White
    		 57 25 82
        Black or African American
    		 2 5 7
        Asian
    		 3 2 5
        American Indian or Alaska Native
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 1 1
        Other
    		 1 0 1
        Missing
    		 15 5 20
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 2 4
        Not Hispanic or Latino
    		 28 19 47
        Unknown/Missing
    		 48 17 65
    BMI
    BMI=Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 22.903 ( 5.4218 ) 24.092 ( 7.6000 ) -
    Subject analysis sets

    Subject analysis set title
    Maximal Use
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The optional maximal use arm part of the trial was conducted under the same protocol number for operational reasons, but with separate design, objective, and patients. Adult and pediatric subjects, at a subset of preselected centers, were enrolled in an open-label Optional Maximal Use Arm to evaluate the systemic exposure and safety of TMB-001 0.05% for the treatment of congenital ichthyosis under maximal use conditions. Initially, adult and pediatric subjects with congenital ichthyosis were dosed for 14 days with TMB-001 0.05% BID. Following an interim pharmacokinetic (PK) analysis and based on the exposure data for subjects aged ≥12 years, pediatric subjects aged 6 to 11 years began dosing with TMB-001 0.05% BID for 14 days. Following the 14-day PK assessment period, subjects received TMB-001 0.05% BID treatment for 10 weeks to provide additional safety and limited efficacy data.

    Subject analysis sets values
    		 Maximal Use
    Number of subjects
    34
    Age categorical
    Units: Subjects
        6-11 years
    9
        12-16 years
    7
        >=17 years
    18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    Gender categorical
    Units: Subjects
        Female
    16
        Male
    18
    Race
    Units: Subjects
        White
    21
        Black or African American
    7
        Asian
    3
        American Indian or Alaska Native
    1
        Native Hawaiian or Other Pacific Islander
    0
        Other
    1
        Missing
    1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    2
        Not Hispanic or Latino
    25
        Unknown/Missing
    7
    BMI
    BMI=Body Mass Index
    Units: kg/m2
        arithmetic mean (standard deviation)
    24.468 ( 8.6960 )

    End points

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    End points reporting groups
    Reporting group title
    TMB-001 0.05%
    Reporting group description
    		 In the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to TMB-001 0.05% QD with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12 week double-blind primary dosing period, the subjects continued with TMB-001 0.05% at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.

    Reporting group title
    Vehicle
    Reporting group description
    		 For the first 3 weeks of the 12-week double-blind primary dosing period, subjects were randomized to Vehicle QD treatment, with use of mandatory standardized bland emollient (Cetaphil™). For the last 9 weeks of the 12-week double-blind primary dosing period, the subjects continued with Vehicle at the increased dosing frequency of BID. Mandatory bland emollient was discontinued.
    Reporting group title
    TMB-001 0.05% QD
    Reporting group description
    		 At Week 12, TMB-001 0.05% BID treatment responders (who had achieved a ≥1-point reduction in IGA score from baseline) were re-randomized (1:1 ratio) to 12 weeks of open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. Subjects with less than a 1-point reduction in IGA score from baseline were discontinued from the study. Vehicle-treated subjects who achieved <1-point reduction in IGA score from baseline by week 12, were eligible to cross over to 12 weeks of open-label treatment with TMB-001 0.05% BID treatment. Subjects with a ≥1-point reduction in IGA score from baseline on vehicle were discontinued from the study.

    Reporting group title
    TMB-001 0.05% BID
    Reporting group description
    		 At Week 12, TMB-001 0.05% BID treatment responders (who had achieved a ≥1-point reduction in IGA score from baseline) were re-randomized (1:1 ratio) to 12 weeks of open-label treatment with TMB-001 0.05% BID or TMB-001 0.05% QD. Subjects with less than a 1-point reduction in IGA score from baseline were discontinued from the study. Vehicle-treated subjects who achieved <1-point reduction in IGA score from baseline by week 12, were eligible to cross over to 12 weeks of open-label treatment with TMB-001 0.05% BID treatment. Subjects with a ≥1-point reduction in IGA score from baseline on vehicle were discontinued from the study.

    Subject analysis set title
    Maximal Use
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The optional maximal use arm part of the trial was conducted under the same protocol number for operational reasons, but with separate design, objective, and patients. Adult and pediatric subjects, at a subset of preselected centers, were enrolled in an open-label Optional Maximal Use Arm to evaluate the systemic exposure and safety of TMB-001 0.05% for the treatment of congenital ichthyosis under maximal use conditions. Initially, adult and pediatric subjects with congenital ichthyosis were dosed for 14 days with TMB-001 0.05% BID. Following an interim pharmacokinetic (PK) analysis and based on the exposure data for subjects aged ≥12 years, pediatric subjects aged 6 to 11 years began dosing with TMB-001 0.05% BID for 14 days. Following the 14-day PK assessment period, subjects received TMB-001 0.05% BID treatment for 10 weeks to provide additional safety and limited efficacy data.

    Primary: Change in Investigator Global Assessment (IGA) Score

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    End point title
    		 Change in Investigator Global Assessment (IGA) Score
    End point description
    Comparison of proportions of subjects with ≥2-point changes from Baseline in Investigator Global Assessment (IGA)-scaling and fissuring scores in the Treatment Area at Week 12 between TMB-001 0.05% and vehicle-treated subjects. Investigator's Global Assessment Score is a 0-4 scale, where 0 is clear and 4 is severe.
    End point type
    Primary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    78
    38
    Units: percentage of responders
        number (not applicable)
    41.4
    44.9
    Statistical analysis title
    		 statistical analysis 1
    Comparison groups
    TMB-001 0.05% v Vehicle
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.39
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 treatment difference
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.4
         upper limit
    		 16.5

    Secondary: Number of Subjects With IGA Scores

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    End point title
    		 Number of Subjects With IGA Scores
    End point description
    Comparison of proportion of subjects with IGA scores of clear or almost clear at Week 12 between TMB-001 0.05% and vehicle-treated subjects. Investigator's Global Assessment Score is a 0-4 scale, where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    78
    38
    Units: percentage of responders
        number (not applicable)
    35.8
    38.9
    No statistical analyses for this end point

    Secondary: Change in IGA-scaling Severity Sub-score

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    End point title
    		 Change in IGA-scaling Severity Sub-score
    End point description
    Comparison of proportion of subjects who achieve IGA-scaling severity sub-score improvement ≥ 2-points from Baseline to Week 12 between TMB-001 0.05% and vehicle-treated subjects. Investigator's Global Assessment Score is a 0-4 scale, where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    75
    36
    Units: percentage of responders
        number (not applicable)
    40.4
    36.4
    No statistical analyses for this end point

    Secondary: Change in Worst Itch-Quality of Life (QoL) Scores

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    End point title
    		 Change in Worst Itch-Quality of Life (QoL) Scores
    End point description
    Comparison of proportion of subjects with ≥4-point improvement from baseline in Worst Itch-QoL scores at Week 12 in subjects with baseline WI-NRS of ≥7 between TMB-001 0.05% and vehicle-treated subjects. Itch-Numeric Rating Scale (I-NRS) and Worst Itch-Numeric Rating Scale (WI-NRS) is an 0-10 scale where 0 is "no itching" and 10 is "worst itch imaginable".
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    19
    9
    Units: percentage of responders
        number (not applicable)
    54.4
    68.7
    No statistical analyses for this end point

    Secondary: Change in Visual Index of Ichthyosis Severity (VIIS) Score

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    End point title
    		 Change in Visual Index of Ichthyosis Severity (VIIS) Score
    End point description
    Comparison of proportion of subjects who achieve 50% reduction from Baseline in VIIS-scaling scores at Week 12 in all areas with Baseline VIIS score ≥3 between TMB-001 0.05% and vehicle-treated subjects. Visual Index for Ichthyosis Severity Score is a 0-4 scale where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    74
    38
    Units: percentage of responders
        number (not applicable)
    47.2
    42.7
    No statistical analyses for this end point

    Secondary: Change in VIIS Score

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    End point title
    		 Change in VIIS Score
    End point description
    Comparison of proportion of subjects who achieve 25% reduction from Baseline in VIIS-scaling scores at Week 12 in all areas with Baseline VIIS score ≥3 between TMB-001 0.05% and vehicle-treated subjects. Visual Index for Ichthyosis Severity Score is a 0-4 scale where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    74
    38
    Units: percentage of responders
        number (not applicable)
    71.3
    64.1
    No statistical analyses for this end point

    Secondary: Change in IGA-fissuring Severity Sub-scores

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    End point title
    		 Change in IGA-fissuring Severity Sub-scores
    End point description
    Comparison of proportion of subjects achieving ≥2 point improvement in IGA-fissuring severity sub-scores from Baseline to Week 12 between TMB-001 0.05% and vehicle-treated subjects. Investigator's Global Assessment Score is a 0-4 scale, where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    30
    17
    Units: percentage of responders
        number (not applicable)
    54.1
    57.9
    No statistical analyses for this end point

    Secondary: Change in IGA Score

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    End point title
    		 Change in IGA Score
    End point description
    Comparison of proportions of subjects achieving ≥2-point improvement from Baseline in IGA scores at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing. Investigator's Global Assessment Score is a 0-4 scale, where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    28
    27
    Units: percentage (%) of responders
        number (confidence interval 95%)
    57.1 (38.8 to 75.5)
    85.2 (71.8 to 98.6)
    No statistical analyses for this end point

    Secondary: Change in VIIS Score

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    End point title
    		 Change in VIIS Score
    End point description
    Comparison of proportion of subjects who achieve 50% reduction from Baseline in VIIS-scaling scores at Week 24 in all areas with Baseline VIIS score ≥3 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing. Visual Index for Ichthyosis Severity Score is a 0-4 scale where 0 is clear and 4 is severe.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    28
    27
    Units: percentage of responders
        number (confidence interval 95%)
    63.0 (44.7 to 81.2)
    85.2 (71.8 to 98.6)
    No statistical analyses for this end point

    Secondary: Change in Ichthyosis Quality of Life (IQoL)-32 Scores

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    End point title
    		 Change in Ichthyosis Quality of Life (IQoL)-32 Scores
    End point description
    Comparison of proportions of subjects with ≥11-point changes from Baseline in IQOL-32 scores at Week 12 between TMB-001 0.05% and vehicle-treated subjects. The IQoL-32 is a questionnaire containing 32, each scored from 0 to 4 ('not applicable', 'not at all', 'a little', 'a lot', 'tremendously') for a total score that varies between 0 and 128. A higher score, the higher impact on quality of life.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    34
    21
    Units: percentage of responders
        number (not applicable)
    47.1
    9.5
    No statistical analyses for this end point

    Secondary: Change in Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (CDLQI) Scores

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    End point title
    		 Change in Dermatology Life Quality Index (DLQI) or Children’s Dermatology Life Quality Index (CDLQI) Scores
    End point description
    Comparison of proportion of subjects with reduction from Baseline in DLQI or CDLQI ≥4 points at Week 12 between TMB-001 0.05% and vehicle-treated subjects in adult subjects with Baseline scores ≥11 and pediatric subjects with Baseline scores of ≥13. The age-appropriate questionnaire contains 10 questions scored from 0 (no impact of skin disease on QoL) to 30 (maximum impact on QoL).
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    15
    8
    Units: percentage of responders
    number (not applicable)
        DLQI, n=15, 8
    86.7
    37.5
        CDLQI, n=5, 0
    80.0
    0.0
    No statistical analyses for this end point

    Secondary: Change in Itch-Quality of Life Scores - WI-NRS

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    End point title
    		 Change in Itch-Quality of Life Scores - WI-NRS
    End point description
    Comparison of proportions of subjects with WI-NRS improvement ≥4 points from Baseline in Itch-QoL scores (in subjects with Baseline WI-NRS ≥7) at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    3
    4
    Units: percentage of responders
        number (confidence interval 95%)
    66.7 (0.00 to 100.0)
    75.0 (19.2 to 100.0)
    No statistical analyses for this end point

    Secondary: Change in DLQI or CDLQI Scores

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    End point title
    		 Change in DLQI or CDLQI Scores
    End point description
    Comparison of changes from Baseline in DLQI or CDLQI at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing in adult subjects with Baseline scores ≥11 and pediatric subjects with Baseline scores of ≥13. The age-appropriate questionnaire contains 10 questions scored from 0 (no impact of skin disease on QoL) to 30 (maximum impact on QoL).
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    4
    4
    Units: percentage of responders
    number (confidence interval 95%)
        DLQI, n=4, 4
    75.0 (32.6 to 100.0)
    100 (100.0 to 100.0)
        CDLQI, n=1, 3
    100 (100.0 to 100.0)
    100 (100.0 to 100.0)
    No statistical analyses for this end point

    Secondary: Change in IQoL-32 Scores

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    End point title
    		 Change in IQoL-32 Scores
    End point description
    Proportions of subjects with ≥11-point change from Baseline in IQoL-32 at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing in adult subjects. The IQoL-32 is a questionnaire containing 32, each scored from 0 to 4 ('not applicable', 'not at all', 'a little', 'a lot', 'tremendously') for a total score that varies between 0 and 128. A higher score, the higher impact on quality of life.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    10
    10
    Units: percentage of responders
        number (confidence interval 95%)
    40.0 (9.6 to 70.4)
    60.0 (29.6 to 90.4)
    No statistical analyses for this end point

    Secondary: To Investigate the Proportion of Subjects Experiencing Local Skin Reactions (LSRs) With Topically Applied TMB-001 0.05% Ointment

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    End point title
    		 To Investigate the Proportion of Subjects Experiencing Local Skin Reactions (LSRs) With Topically Applied TMB-001 0.05% Ointment
    End point description
    Comparison of proportion of subjects experiencing LSRs through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    78
    38
    Units: percentage of participants
        number (confidence interval 95%)
    64.1 (52.4 to 74.7)
    36.8 (21.8 to 54.0)
    No statistical analyses for this end point

    Secondary: To Investigate the Proportion of Subjects Experiencing Treatment-emergent Adverse Events (TEAEs)

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    End point title
    		 To Investigate the Proportion of Subjects Experiencing Treatment-emergent Adverse Events (TEAEs)
    End point description
    Comparison of proportion of subjects experiencing TEAEs through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    78
    38
    Units: percentage of participants
        number (not applicable)
    76.9
    63.2
    No statistical analyses for this end point

    Secondary: To Investigate the Proportion of Subjects Experiencing LSRs With Topically Applied TMB-001 0.05% Ointment.

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    End point title
    		 To Investigate the Proportion of Subjects Experiencing LSRs With Topically Applied TMB-001 0.05% Ointment.
    End point description
    Comparison of proportion of subjects experiencing LSRs through Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    28
    27
    Units: percentage of participants
        number (confidence interval 95%)
    32.1 (15.9 to 52.4)
    40.7 (22.4 to 61.2)
    No statistical analyses for this end point

    Secondary: To Investigate the Proportion of Subjects Experiencing TEAEs

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    End point title
    		 To Investigate the Proportion of Subjects Experiencing TEAEs
    End point description
    Comparison of proportion of subjects experiencing TEAEs through Week 24.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    28
    27
    Units: percentage of participants
        number (confidence interval 95%)
    53.6 (33.9 to 72.5)
    48.1 (28.7 to 68.1)
    No statistical analyses for this end point

    Secondary: To Investigate the Proportion of Subjects Demonstrating Clinically Confirmed Allergic Contact Dermatitis

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    End point title
    		 To Investigate the Proportion of Subjects Demonstrating Clinically Confirmed Allergic Contact Dermatitis
    End point description
    Comparison of proportion of subjects demonstrating clinically confirmed allergic contact dermatitis by patch testing through Week 12 between TMB-001 0.05% and vehicle-treated subjects.
    End point type
    Secondary
    End point timeframe
    during week 12
    End point values
    		 TMB-001 0.05% Vehicle
    Number of subjects analysed
    78
    38
    Units: percentage of participants
        number (not applicable)
    0
    0
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Cmax After Multiple Dosing - Adults

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Cmax After Multiple Dosing - Adults
    End point description
    maximal observed plasma concentration. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Mean values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    10
    Units: ng/mL
    number (not applicable)
        Isotretinoin
    4.13
        4-oxo-isotretinoin
    16.7
        Tretinoin
    0.04
        4-oxo-tretinoin
    0.00
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Cmax After Multiple Dosing - Adolescents

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Cmax After Multiple Dosing - Adolescents
    End point description
    maximal observed plasma concentration. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Mean values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    2
    Units: ng/mL
    number (not applicable)
        Isotretinoin
    7.7
        4-oxo-isotretinoin
    25.44
        Tretinoin
    4.52
        4-oxo-tretinoin
    3.60
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - AUC0-24 After Multiple Dosing - Adults

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - AUC0-24 After Multiple Dosing - Adults
    End point description
    AUC0-24 = area under the curve over the first 24 hours post dose. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Mean values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    10
    Units: hr*ng/mL
    number (not applicable)
        Isotretinoin
    78.44
        4-Oxo-Isotretinoin
    352.95
        Tretinoin
    0.17
        4-oxo-tretinoin
    0.00
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - AUC0-24 After Multiple Dosing - Adolescents

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - AUC0-24 After Multiple Dosing - Adolescents
    End point description
    AUC0-24 = area under the curve over the first 24 hours post dose. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Mean values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    2
    Units: hr*ng/mL
    number (not applicable)
        Isotretinoin
    101.34
        4-oxo-isotretinoin
    432.96
        Tretinoin
    13.74
        4-oxo-tretinoin
    10.15
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Tmax After Multiple Dosing - Adults

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Tmax After Multiple Dosing - Adults
    End point description
    Tmax = time to maximal plasma concentration. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Median values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    10
    Units: hours
    number (not applicable)
        Isotretinoin
    1.5
        4-oxo-isotretinoin
    5
        Tretinoin
    0.00
        4-oxo-tretinoin
    0.00
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Tmax After Multiple Dosing - Adolescents

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Tmax After Multiple Dosing - Adolescents
    End point description
    Tmax = time to maximal plasma concentration. Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Median values are presented.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    2
    Units: hours
    number (not applicable)
        Isotretinoin
    14
        4-oxo-isotretinoin
    18
        Tretinoin
    2.00
        4-oxo-tretinoin
    1.00
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Steady State Concentration After Multiple Dosing - Children

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    End point title
    		 Maximal Use Arm: Isotretinoin, Tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin - Steady State Concentration After Multiple Dosing - Children
    End point description
    Assessment of concentrations of isotretinoin, tretinoin, 4-oxo-tretinion and 4-oxo-isotretinoin. Values for the metabolites 4-Oxo-Isotretinoin, Tretinoin and 4-oxo-tretinoin could not be plotted due to the sparse sampling schedule.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    7
    Units: ng/mL
    arithmetic mean (standard deviation)
        Isotretinoin
    1.27 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Assessment of the Exposure of TMB-001 and Oral Isotretinoin - Cmax

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    End point title
    		 Maximal Use Arm: Assessment of the Exposure of TMB-001 and Oral Isotretinoin - Cmax
    End point description
    Cmax: maximal observed plasma concentration. The exposure levels observed for TMB-001 0.05% topical ointment after multiple dosing were compared with the cross-trial for PK parameters obtained for oral isotretinoin (single dose 80 mg) in healthy volunteers.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    19
    Units: ng/mL
    number (not applicable)
        Oral 80 mg Isotretinoin, single dose
    1110.00
        TMB-001 0.05% topical, multiple dose, adolescents
    7.70
        TMB-001 0.05% topical, multiple dose, adults
    4.13
        ratio (oral/topical) - adolescents
    144
        ratio (oral/topical) - adults
    269
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Assessment of the Exposure of TMB-001 and Oral Isotretinoin - AUC0-24

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    End point title
    		 Maximal Use Arm: Assessment of the Exposure of TMB-001 and Oral Isotretinoin - AUC0-24
    End point description
    AUC0-24: area under the curve over the first 24 hours post dose The exposure levels observed for TMB-001 0.05% topical ointment after multiple dosing were compared with the cross-trial for PK parameters obtained for oral isotretinoin (single dose 80 mg) in healthy volunteers.
    End point type
    Secondary
    End point timeframe
    14 days
    End point values
    		 Maximal Use
    Number of subjects analysed
    19
    Units: h*ng/mL
    number (not applicable)
        Oral 80 mg Isotretinoin, single dose
    10700.00
        TMB-001 0.05% topical, multiple dose, adolescents
    101.34
        TMB-001 0.05% topical, multiple dose, adults
    78.44
        ratio (oral/topical) - adolescents
    106
        ratio (oral/topical) - adults
    136
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Safety and Tolerability - LSRs

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    End point title
    		 Maximal Use Arm: Safety and Tolerability - LSRs
    End point description
    Local skin reactions (burnings/stinging, erythema, erosions and edema) are reported as LSRs.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Maximal Use
    Number of subjects analysed
    34
    Units: events
        Erythema
    16
        Erosions
    7
        Edema
    2
        Burning/stinging
    17
    No statistical analyses for this end point

    Secondary: Maximal Use Arm: Safety and Tolerability - TEAEs

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    End point title
    		 Maximal Use Arm: Safety and Tolerability - TEAEs
    End point description
    Local safety are reported as severe TEAEs related to treatment area.
    End point type
    Secondary
    End point timeframe
    12 weeks
    End point values
    		 Maximal Use
    Number of subjects analysed
    34
    Units: events
        Pruritus
    2
        Administration site reactions
    8
    No statistical analyses for this end point

    Secondary: Change in Itch-Quality of Life scores - I-NRS

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    End point title
    		 Change in Itch-Quality of Life scores - I-NRS
    End point description
    Comparison of proportions of subjects with I-NRS improvement ≥4 points from Baseline in Itch-QoL scores (in subjects with Baseline I-NRS ≥7) at Week 24 between subjects randomized to TMB-001 0.05% BID and QD maintenance dosing.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 TMB-001 0.05% QD TMB-001 0.05% BID
    Number of subjects analysed
    0 [1]
    1
    Units: percentage of responders
        number (confidence interval 95%)
    ( to )
    100 (100.0 to 100.0)
    Notes
    [1] - No data available.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 weeks for the phase 3 trial part (TMB-001 0.005% and vehicle arms) and 12 weeks for the Maximal use arm
    Adverse event reporting additional description
    TEAEs. An AE is defined as treatment emergent if the AE start on or after treatment start until 30 days after treatment end date.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    TMB-001 0.05%
    Reporting group description
    		 Safety Population = all subjects randomly assigned to study treatment and who received at least 1 dose of study medication.

    Reporting group title
    Vehicle
    Reporting group description
    		 Safety Population = all subjects randomly assigned to study treatment and who received at least 1 dose of study medication.

    Reporting group title
    Maximal Use
    Reporting group description
    		 Safety population = all subjects enrolled in the maximal use arm who received at least 1 dose of study medication.

    Serious adverse events
    		 TMB-001 0.05% Vehicle Maximal Use
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 38 (0.00%)
    0 / 34 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Viral rash
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 38 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TMB-001 0.05% Vehicle Maximal Use
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    53 / 78 (67.95%)
    20 / 38 (52.63%)
    22 / 34 (64.71%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 78 (10.26%)
    1 / 38 (2.63%)
    1 / 34 (2.94%)
         occurrences all number
    10
    4
    1
    General disorders and administration site conditions
    Application site dermatitis
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 38 (5.26%)
    1 / 34 (2.94%)
         occurrences all number
    2
    2
    1
    Application site erosion
         subjects affected / exposed
    14 / 78 (17.95%)
    4 / 38 (10.53%)
    7 / 34 (20.59%)
         occurrences all number
    21
    7
    7
    Application site erythema
         subjects affected / exposed
    31 / 78 (39.74%)
    6 / 38 (15.79%)
    11 / 34 (32.35%)
         occurrences all number
    55
    9
    16
    Application site oedema
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 38 (2.63%)
    2 / 34 (5.88%)
         occurrences all number
    8
    1
    2
    Application site pain
         subjects affected / exposed
    29 / 78 (37.18%)
    5 / 38 (13.16%)
    13 / 34 (38.24%)
         occurrences all number
    56
    6
    17
    Application site pruritus
         subjects affected / exposed
    13 / 78 (16.67%)
    3 / 38 (7.89%)
    5 / 34 (14.71%)
         occurrences all number
    17
    4
    7
    Pyrexia
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 38 (2.63%)
    2 / 34 (5.88%)
         occurrences all number
    4
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 38 (2.63%)
    0 / 34 (0.00%)
         occurrences all number
    4
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 38 (5.26%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 38 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    6
    0
    0
    Pruritus
         subjects affected / exposed
    31 / 78 (39.74%)
    2 / 38 (5.26%)
    2 / 34 (5.88%)
         occurrences all number
    3
    2
    2
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 38 (5.26%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 38 (5.26%)
    0 / 34 (0.00%)
         occurrences all number
    4
    2
    0
    Influenza
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 38 (2.63%)
    0 / 34 (0.00%)
         occurrences all number
    4
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    6 / 78 (7.69%)
    4 / 38 (10.53%)
    1 / 34 (2.94%)
         occurrences all number
    8
    4
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Jul 2022
    Monthly UPT, INRS daily, Risk section

    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
    For support, Contact us.
    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
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