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    Clinical Trial Results:
    A PHASE 2, MULTICENTER, GLOBAL, RANDOMIZED, DOUBLE-BLIND, PLACEBO-ONTROLLED, PARALLEL-GROUP STUDY TO EVALUATE THE SAFETY AND EFFICACY OF CENDAKIMAB (CC-93538) IN ADULT SUBJECTS WITH MODERATE TO SEVERE ATOPIC DERMATITIS

    Summary
    EudraCT number
    		 2020-005212-22
    Trial protocol
    		 CZ  
    Global end of trial date
    09 Nov 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Nov 2023
    First version publication date
    24 Nov 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CC-93538-AD-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussée de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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
    09 Mar 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Nov 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the clinical efficacy of 3 dosage regimens of CC-93538 compared with placebo on the change in the core clinical outcome measure, Eczema Area and Severity Index (EASI), in subjects with moderate to severe atopic dermatitis (AD)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 May 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 64
    Country: Number of subjects enrolled
    Czechia: 44
    Country: Number of subjects enrolled
    Poland: 43
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Japan: 36
    Worldwide total number of subjects
    220
    EEA total number of subjects
    87
    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)
    208
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 221 participants Randomized, 220 Participants Treated

    Period 1
    Period 1 title
    Randomization
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment 1
    Arm description
    		 CC-93538 High Dose QW
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    High Dose QW

    Arm title
    		 Treatment 2
    Arm description
    		 CC-93538 High Dose Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    High Dose Q2W

    Arm title
    		 Treatment 3
    Arm description
    		 CC-93538 Low Dose Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Low Dose Q2W

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		Treatment 1 Treatment 2 Treatment 3 Placebo
    Started
    55
    55
    55
    56
    Completed
    54
    55
    55
    56
    Not completed
    1
    0
    0
    0
         Did not receive study treatment
    1
    -
    -
    -
    Period 2
    Period 2 title
    Treatment Period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment 1
    Arm description
    		 CC-93538 High Dose QW
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    High Dose QW

    Arm title
    		 Treatment 2
    Arm description
    		 CC-93538 High Dose Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    High Dose Q2W

    Arm title
    		 Treatment 3
    Arm description
    		 CC-93538 Low Dose Q2W
    Arm type
    		 Experimental

    Investigational medicinal product name
    CC-93538
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Low Dose Q2W

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 2 is the baseline period. mITT population
    Number of subjects in period 2
    		Treatment 1 Treatment 2 Treatment 3 Placebo
    Started
    54
    55
    55
    56
    Completed
    49
    50
    52
    44
    Not completed
    5
    5
    3
    12
         Adverse event, non-fatal
    4
    2
    1
    2
         Other Reasons
    -
    2
    -
    1
         Withdrawal by participant
    -
    -
    -
    4
         Lost to follow-up
    -
    1
    2
    2
         Lack of efficacy
    1
    -
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 CC-93538 High Dose QW

    Reporting group title
    Treatment 2
    Reporting group description
    		 CC-93538 High Dose Q2W

    Reporting group title
    Treatment 3
    Reporting group description
    		 CC-93538 Low Dose Q2W

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo Total
    Number of subjects
    		 54 55 55 56 220
    Age Categorical
    Units: Participants
        Between 18 and 65 years
    		 52 52 51 53 208
        >=65 years
    		 2 3 4 3 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 36.3 ( 13.0 ) 34.5 ( 13.76 ) 40.3 ( 14.18 ) 39.5 ( 14.22 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 19 26 29 21 95
        Male
    		 35 29 26 35 125
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 0 0 1
        Asian
    		 19 14 14 13 60
        Black or African American
    		 4 8 5 6 23
        White
    		 30 33 36 37 136
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 1 2 0 3 6
        Not Hispanic or Latino
    		 53 53 55 53 214
        Unknown or Not Reported
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 CC-93538 High Dose QW

    Reporting group title
    Treatment 2
    Reporting group description
    		 CC-93538 High Dose Q2W

    Reporting group title
    Treatment 3
    Reporting group description
    		 CC-93538 Low Dose Q2W

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Treatment 1
    Reporting group description
    		 CC-93538 High Dose QW

    Reporting group title
    Treatment 2
    Reporting group description
    		 CC-93538 High Dose Q2W

    Reporting group title
    Treatment 3
    Reporting group description
    		 CC-93538 Low Dose Q2W

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Primary: Mean percentage change from baseline in EASI at week 16

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    End point title
    		 Mean percentage change from baseline in EASI at week 16
    End point description
    The Eczema Area and Severity Index (EASI) is a composite scoring system assessed by the Investigator based on the proportion of each of the 4 body regions (head and neck, upper limbs, lower limbs, and trunk) affected with Atopic Dermatitis (AD) and the intensity of each of 4 main signs of AD (eg, erythema, induration/papulation, excoriation, and lichenification) and is based on a 4-point scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe). The sum of the scores is totaled (0 to 72), the lower the score the better.
    End point type
    Primary
    End point timeframe
    From initial EASI measurement to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Percentage
        arithmetic mean (standard error)
    -84.41 ( 5.07 )
    -76.03 ( 4.20 )
    -78.93 ( 4.53 )
    -62.65 ( 5.53 )
    Statistical analysis title
    		 EASI - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.003
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -21.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.81
         upper limit
    		 -7.7
    Statistical analysis title
    		 EASI - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.029
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -16.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.88
         upper limit
    		 -1.68
    Statistical analysis title
    		 EASI - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.057
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -13.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.19
         upper limit
    		 0.43

    Secondary: Percent change from baseline in pruritus NRS at Week 16

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    End point title
    		 Percent change from baseline in pruritus NRS at Week 16
    End point description
    Pruritus will be assessed by the subject using the Pruritus NRS, which was developed and validated as a single item, patient reported outcome (PRO) of itch severity. Clinical response is indicated by a ≥ 2 to 4-point change from baseline in Peak Pruritus NRS score. The intensity of pruritus will be assessed based on last 24 hours using a validated 11-point NRS, ranging from 0 (“no pruritus”) to 10 (“the worst pruritus imaginable”).
    End point type
    Secondary
    End point timeframe
    From initial NRS measurement to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Mean Percentage Change from baseline
        arithmetic mean (standard error)
    -55.48 ( 6.22 )
    -46.15 ( 5.32 )
    -49.30 ( 5.89 )
    -32.98 ( 7.46 )
    Statistical analysis title
    		 Pruritis NRS - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference VS Placebo
    Point estimate
    -13.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -30.67
         upper limit
    		 4.33
    Notes
    [1] - Adjusted Mean Difference VS Placebo
    Statistical analysis title
    		 Pruritis NRS - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference VS Placebo
    Point estimate
    -16.32
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.4
         upper limit
    		 3.75
    Notes
    [2] - Adjusted Mean Difference VS Placebo
    Statistical analysis title
    		 Pruritis NRS - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted Mean Difference VS Placebo
    Point estimate
    -22.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.46
         upper limit
    		 -3.54
    Notes
    [3] - Adjusted Mean Difference VS Placebo

    Secondary: Time to achieve at least 4 points of improvement in the severity of pruritus NRS scale in the first 16 weeks of treatment

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    End point title
    		 Time to achieve at least 4 points of improvement in the severity of pruritus NRS scale in the first 16 weeks of treatment
    End point description
    Pruritus will be assessed by the subject using the Pruritus NRS, which was developed and validated as a single item, patient reported outcome (PRO) of itch severity. Clinical response is indicated by a ≥ 2 to 4-point change from baseline in Peak Pruritus NRS score. The intensity of pruritus will be assessed based on last 24 hours using a validated 11-point NRS, ranging from 0 (“no pruritus”) to 10 (“the worst pruritus imaginable”). Here "99999" means NA
    End point type
    Secondary
    End point timeframe
    From initial NRS assessment to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Days
        median (confidence interval 95%)
    54.0 (28.0 to 93.0)
    76.0 (42.0 to 105.0)
    50.0 (27.0 to 111.0)
    123.0 (119.0 to 99999)
    No statistical analyses for this end point

    Secondary: Number of participants with treatment emergent adverse events

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    End point title
    		 Number of participants with treatment emergent adverse events
    End point description
    Treatment emergent adverse events
    End point type
    Secondary
    End point timeframe
    From first treatment to the end of follow up, approximately 32 weeks
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Participants
        Any TEAE
    40
    41
    38
    41
        Any TEAE leading to discontinuation
    4
    2
    1
    2
        Any TEAE of special interest
    9
    10
    8
    10
        Any TESAE
    2
    1
    2
    4
    No statistical analyses for this end point

    Secondary: Number of participants with the presence of serum antibodies to CC-93538

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    End point title
    		 Number of participants with the presence of serum antibodies to CC-93538
    End point description
    End point type
    Secondary
    End point timeframe
    From first treatment to the end of follow up, approximately 32 weeks
    End point values
    		 Treatment 1 Treatment 2 Treatment 3
    Number of subjects analysed
    54
    55
    55
    Units: Participants
        Baseline ADA Positive
    0
    3
    1
        Post Baseline Positive
    22
    35
    28
        Post Baseline Negative
    32
    20
    27
    No statistical analyses for this end point

    Secondary: Serum trough concentration at week 16

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    End point title
    		 Serum trough concentration at week 16
    End point description
    End point type
    Secondary
    End point timeframe
    At week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3
    Number of subjects analysed
    43
    45
    45
    Units: ng/mL
        geometric mean (geometric coefficient of variation)
    274180.6 ( 88.0 )
    140413.6 ( 44.0 )
    57046.4 ( 106.8 )
    No statistical analyses for this end point

    Secondary: Percent Change in Mean SCORAD scores from baseline at week 16

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    End point title
    		 Percent Change in Mean SCORAD scores from baseline at week 16
    End point description
    The SCORAD is a validated scoring index for atopic dermatitis, which combines extent (0 to 100), severity (0 to 18), and subjective symptoms (0 to 20) based on pruritus and sleep loss, each scored (0 to 10). The subject will assess the subjective symptoms (itch and sleepless) part of the assessment. SCORing Atopic Dermatitis Index (SCORAD) score ranges from 0 to 103, higher scores indicate more severe disease.
    End point type
    Secondary
    End point timeframe
    From initial SCORAD measurement to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Mean Percentage Change from baseline
        arithmetic mean (standard error)
    -69.28 ( 4.64 )
    -55.47 ( 4.08 )
    -60.19 ( 4.38 )
    -41.11 ( 5.61 )
    Statistical analysis title
    		 SCORAD - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -28.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.89
         upper limit
    		 -14.44
    Statistical analysis title
    		 SCORAD - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -19.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -33.53
         upper limit
    		 -4.62
    Statistical analysis title
    		 SCORAD - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -27.26
         upper limit
    		 -1.46

    Secondary: Number of participants with clinically significant laboratory abnormalities

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    End point title
    		 Number of participants with clinically significant laboratory abnormalities
    End point description
    End point type
    Secondary
    End point timeframe
    From first treatment to the end of follow up, approximately 32 weeks
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Number of Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of responders with an vIGA-AD score of 0 (clear) or 1 (almost clear) and a reduction ≥ 2 points from Baseline at Week 16

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    End point title
    		 Percentage of responders with an vIGA-AD score of 0 (clear) or 1 (almost clear) and a reduction ≥ 2 points from Baseline at Week 16
    End point description
    The Validated Investigator Global Assessment (vIGA-AD) is a validated 5-point assessment intended to assess the global severities of key acute clinical signs of AD, including erythema, induration/papulation, oozing/crusting (lichenification excluded). The rating of clear (0), almost clear (1), mild (2), moderate (3) and severe (4), will be assessed at scheduled visits. The vIGA-AD must be conducted before the EASI assessment. The vIGA-AD is a static evaluation conducted without regard to the score obtained at a previous visit.
    End point type
    Secondary
    End point timeframe
    From initial vIGA-AD assessment to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Percentage of Participants
        number (not applicable)
    33.3
    24.4
    38.2
    9.4
    Statistical analysis title
    		 vIGA-AD - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.004
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.8
         upper limit
    		 39.2
    Notes
    [4] - Risk Difference
    Statistical analysis title
    		 vIGA-AD - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [5]
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    28.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 13.6
         upper limit
    		 44.2
    Notes
    [5] - Risk Difference
    Statistical analysis title
    		 vIGA-AD - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [6]
    P-value
    		 = 0.061
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    15.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 29.8
    Notes
    [6] - Risk Difference

    Secondary: Percentage of EASI-75 responders at week 16

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    End point title
    		 Percentage of EASI-75 responders at week 16
    End point description
    The EASI is a composite scoring system assessed by the Investigator based on the proportion of each of the 4 body regions (head and neck, upper limbs, lower limbs, and trunk) affected with AD and the intensity of each of 4 main signs of AD (eg, erythema, induration/papulation, excoriation, and lichenification) and is based on a 4-point scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe). The sum of the scores is totaled (0 to 72), the lower the score the better.
    End point type
    Secondary
    End point timeframe
    From initial EASI measurement to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Percentage of Participants
        number (not applicable)
    50.0
    48.2
    52.7
    26.3
    Statistical analysis title
    		 EASI75 - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [7]
    P-value
    		 = 0.018
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference VS Placebo
    Point estimate
    23.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.2
         upper limit
    		 41.2
    Notes
    [7] - Risk Difference
    Statistical analysis title
    		 EASI75 - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.033
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference VS Placebo
    Point estimate
    21.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.3
         upper limit
    		 39.3
    Notes
    [8] - Risk Difference
    Statistical analysis title
    		 EASI75 - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [9]
    P-value
    		 = 0.006
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference VS Placebo
    Point estimate
    26.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.3
         upper limit
    		 44
    Notes
    [9] - Risk Difference

    Secondary: Percentage of EASI-90 responders at week 16

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    End point title
    		 Percentage of EASI-90 responders at week 16
    End point description
    The Eczema Area and Severity Index (EASI) is a composite scoring system assessed by the Investigator based on the proportion of each of the 4 body regions (head and neck, upper limbs, lower limbs, and trunk) affected with Atopic Dermatitis (AD) and the intensity of each of 4 main signs of AD (eg, erythema, induration/papulation, excoriation, and lichenification) and is based on a 4-point scale of 0 (none), 1 (mild), 2 (moderate), and 3 (severe). The sum of the scores is totaled (0 to 72), the lower the score the better.
    End point type
    Secondary
    End point timeframe
    From initial EASI measurement to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Percentage of participants
        number (not applicable)
    31.5
    24.0
    29.1
    13.4
    Statistical analysis title
    		 EASI90 - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [10]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference
    Point estimate
    18.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 33.9
    Notes
    [10] - Risk Difference
    Statistical analysis title
    		 EASI90 - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference
    Point estimate
    15.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 31.4
    Statistical analysis title
    		 EASI90 - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [11]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference
    Point estimate
    10.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.6
         upper limit
    		 25.7
    Notes
    [11] - Risk Difference

    Secondary: Percentage of participants with a response and pruritus NRS change of ≥ 4 points from Baseline at Week 16

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    End point title
    		 Percentage of participants with a response and pruritus NRS change of ≥ 4 points from Baseline at Week 16
    End point description
    Pruritus will be assessed by the subject using the Pruritus NRS, which was developed and validated as a single item, patient reported outcome (PRO) of itch severity. Clinical response is indicated by a ≥ 2 to 4-point change from baseline in Peak Pruritus NRS score. The intensity of pruritus will be assessed based on last 24 hours using a validated 11-point NRS, ranging from 0 (“no pruritus”) to 10 (“the worst pruritus imaginable”).
    End point type
    Secondary
    End point timeframe
    From initial NRS assessment to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: Percentage of Participants
        number (not applicable)
    33.3
    34.5
    32.7
    14.8
    Statistical analysis title
    		 Pruritis - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    P-value
    		 = 0.042
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.7
         upper limit
    		 34.3
    Notes
    [12] - Risk Difference VS Placebo
    Statistical analysis title
    		 Pruritis - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    P-value
    		 = 0.052
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    18
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 33.6
    Notes
    [13] - Risk Difference VS Placebo
    Statistical analysis title
    		 Pruritis - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [14]
    P-value
    		 = 0.029
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Risk Difference VS Placebo
    Point estimate
    19.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.1
         upper limit
    		 35.7
    Notes
    [14] - Risk Difference VS Placebo

    Secondary: Adjust mean percentage change in BSA in atopic dermatitis from Baseline at Week 16

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    End point title
    		 Adjust mean percentage change in BSA in atopic dermatitis from Baseline at Week 16
    End point description
    Body Surface Area involvement will be calculated from the sum of the number of handprints of skin afflicted with atopic dermatitis in a body region. The number of handprints of skin afflicted with atopic dermatitis in a body region can be used to determine the extent (%) to which a body region is involved with AD. When measuring, the handprint unit refers to the size of each individual subject’s hand with fingers in a closed position. BSA will be calculated by the Investigator or qualified designee using the 1% handprint rule, in which the area represented by the palm with all 5 digits adducted together is approximately 1% of the subject's BSA.
    End point type
    Secondary
    End point timeframe
    From initial BSA assessment to week 16
    End point values
    		 Treatment 1 Treatment 2 Treatment 3 Placebo
    Number of subjects analysed
    54
    55
    55
    56
    Units: mean percentage
        arithmetic mean (standard error)
    -78.85 ( 6.13 )
    -64.01 ( 5.30 )
    -66.60 ( 6.03 )
    -55.73 ( 6.90 )
    Statistical analysis title
    		 BSA - Statistical Analysis 1
    Comparison groups
    Treatment 1 v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 [15]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference VS Placebo
    Point estimate
    -23.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -41.48
         upper limit
    		 -4.76
    Notes
    [15] - Adjusted mean difference VS Placebo
    Statistical analysis title
    		 BSA - Statistical Analysis 3
    Comparison groups
    Treatment 3 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [16]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference VS Placebo
    Point estimate
    -10.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.39
         upper limit
    		 7.66
    Notes
    [16] - Adjusted mean difference VS Placebo
    Statistical analysis title
    		 BSA - Statistical Analysis 2
    Comparison groups
    Treatment 2 v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 [17]
    Method
    		 ANCOVA
    Parameter type
    		 Adjusted mean difference VS Placebo
    Point estimate
    -8.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -25.16
         upper limit
    		 8.59
    Notes
    [17] - Adjusted mean difference VS Placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events and Serious Adverse Events (From first treatment to end of study): Approximately 32 Weeks All-Cause mortality (From randomization to end of study): Approximately 33 Weeks
    Adverse event reporting additional description
    The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    Treatment 1
    Reporting group description
    		 High Dose QW

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Treatment 3
    Reporting group description
    		 Low Dose Q2W

    Reporting group title
    Treatment 2
    Reporting group description
    		 High Dose Q2W

    Serious adverse events
    		 Treatment 1 Placebo Treatment 3 Treatment 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 54 (3.70%)
    4 / 56 (7.14%)
    2 / 55 (3.64%)
    1 / 55 (1.82%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 55 (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
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Large intestine polyp
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 55 (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
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 55 (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
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 54 (1.85%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Treatment 1 Placebo Treatment 3 Treatment 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 54 (62.96%)
    34 / 56 (60.71%)
    29 / 55 (52.73%)
    35 / 55 (63.64%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    3 / 55 (5.45%)
         occurrences all number
    3
    0
    1
    4
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 54 (5.56%)
    0 / 56 (0.00%)
    0 / 55 (0.00%)
    2 / 55 (3.64%)
         occurrences all number
    3
    0
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 56 (3.57%)
    2 / 55 (3.64%)
    4 / 55 (7.27%)
         occurrences all number
    2
    2
    2
    5
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    1 / 54 (1.85%)
    0 / 56 (0.00%)
    3 / 55 (5.45%)
    0 / 55 (0.00%)
         occurrences all number
    5
    0
    7
    0
    Fatigue
         subjects affected / exposed
    3 / 54 (5.56%)
    1 / 56 (1.79%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 54 (0.00%)
    5 / 56 (8.93%)
    1 / 55 (1.82%)
    4 / 55 (7.27%)
         occurrences all number
    0
    5
    1
    5
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    4 / 54 (7.41%)
    2 / 56 (3.57%)
    5 / 55 (9.09%)
    7 / 55 (12.73%)
         occurrences all number
    4
    2
    6
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 54 (0.00%)
    1 / 56 (1.79%)
    1 / 55 (1.82%)
    3 / 55 (5.45%)
         occurrences all number
    0
    1
    1
    3
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 54 (0.00%)
    0 / 56 (0.00%)
    1 / 55 (1.82%)
    3 / 55 (5.45%)
         occurrences all number
    0
    0
    1
    6
    Dermatitis atopic
         subjects affected / exposed
    20 / 54 (37.04%)
    20 / 56 (35.71%)
    19 / 55 (34.55%)
    15 / 55 (27.27%)
         occurrences all number
    27
    41
    27
    15
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 54 (3.70%)
    1 / 56 (1.79%)
    3 / 55 (5.45%)
    2 / 55 (3.64%)
         occurrences all number
    2
    1
    4
    2
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    3 / 54 (5.56%)
    2 / 56 (3.57%)
    1 / 55 (1.82%)
    2 / 55 (3.64%)
         occurrences all number
    3
    2
    1
    2
    COVID-19
         subjects affected / exposed
    4 / 54 (7.41%)
    9 / 56 (16.07%)
    3 / 55 (5.45%)
    4 / 55 (7.27%)
         occurrences all number
    4
    9
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 54 (7.41%)
    5 / 56 (8.93%)
    5 / 55 (9.09%)
    6 / 55 (10.91%)
         occurrences all number
    5
    5
    6
    9
    Nasopharyngitis
         subjects affected / exposed
    2 / 54 (3.70%)
    2 / 56 (3.57%)
    3 / 55 (5.45%)
    1 / 55 (1.82%)
         occurrences all number
    2
    2
    4
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
    3 / 56 (5.36%)
    0 / 55 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    1
    3
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Aug 2021
    This is a country specific amendment for the Czech Republic. As a result of questions raised by State Institute for Drug Control (SUKL), Ministry of Health in Czech Republic during the clinical trial application review process, changes have been incorporated in the protocol CC- 93538-AD-001. As requested by the Czech Republic Health Authority, significant changes included in this amendment are summarized below:  Reduction in upper end age limit for inclusion into the study  Increase in the required weight threshold for inclusion into the study  Update to Criteria for Discontinuation of Dosing  Update to Required Weight Assessments During the Treatment Phase  Addition of Supplemental Laboratory Information

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

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

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