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    Clinical Trial Results:
    A randomised, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy and safety of tralokinumab monotherapy in subjects with moderate to severe atopic dermatitis who are candidates for systemic therapy

    Summary
    EudraCT number
    2016-004200-65
    Trial protocol
    ES   FR  
    Global end of trial date
    10 Oct 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Oct 2020
    First version publication date
    01 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LP0162-1325
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    LEO Pharma A/S
    Sponsor organisation address
    Industriparken 55, Ballerup, Denmark, 2750
    Public contact
    Clinical disclosure specialist, LEO Pharma A/S, +45 44945888, disclosure@leo-pharma.com
    Scientific contact
    disclosure@leo-pharma.com, LEO Pharma A/S, +45 44945888, 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
    23 Feb 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Oct 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of tralokinumab compared with placebo in treating moderate-to-severe Atopic dermatitis.
    Protection of trial subjects
    This clinical trial was conducted to conform to the principles of the Declaration of Helsinki as adopted by the 18th World Medical Association General Assembly, 1964, and subsequent amendments. All subjects received written and verbal information concerning the clinical trial. Subjects were asked to consent that their personal data were recorded, collected, processed and could be transferred to EU and non-EU countries in accordance with any national legislation regulating privacy and data protection. Both during the initial treatment period and the maintenance treatment period, some subjects were randomised to placebo treatment. If medically necessary (i.e. to control intolerable atopic dermatitis [AD] symptoms), rescue treatment for AD could be provided to subjects throughout the trial, both during the initial treatment period and the maintenance treatment period, at the discretion of the investigator. For the first 3 investigational medicinal product (IMP) dosing visits in both the initial treatment period (i.e. Weeks 0, 2, and 4) and in open-label treatment, subjects were monitored after IMP administration for immediate drug reactions for a minimum of 2 hours with vital signs taken every 30 minutes or until stable, whichever was later. Vital signs were documented in the electronic case report forms. Appropriate drugs, such as epinephrine, antihistamines, corticosteroids, etc., and medical equipment to treat acute anaphylactic reactions were immediately available at trial sites, and trial personnel was trained to recognise and respond to anaphylaxis according to local guidelines.
    Background therapy
    All subjects were to use an emollient twice daily (or more, as needed) for at least 14 days before randomisation and were to continue this treatment throughout the trial.
    Evidence for comparator
    -
    Actual start date of recruitment
    31 Mar 2017
    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
    Spain: 96
    Country: Number of subjects enrolled
    France: 108
    Country: Number of subjects enrolled
    Germany: 273
    Country: Number of subjects enrolled
    United States: 198
    Country: Number of subjects enrolled
    Japan: 127
    Worldwide total number of subjects
    802
    EEA total number of subjects
    477
    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)
    759
    From 65 to 84 years
    42
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    Trial start date: May 30, 2017 Primary completion date: August 7, 2018 Trial completion date: October 14, 2019 The trial was conducted in 5 countries: Germany, France, Spain, the United States, and Japan.

    Pre-assignment
    Screening details
    The screening period was 2 to 6 weeks and included 1 or 2 visits. The exact duration depended on the wash-out period defined by the exclusion criteria. If no wash-out or only a 2-week wash-out was required, screening Visits 1 and 2 were combined. Eligibility was assessed at the (first) screening visit and on Day 0 prior to randomisation.

    Period 1
    Period 1 title
    Initial treatment period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This was a double-blind trial in which tralokinumab and placebo were visually distinct from each other. The IMP was handled and administered by a qualified, unblinded healthcare professional (HCP) at the site who was not involved in the management of trial subjects and who did not perform any of the assessments.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Initial treatment period - Tralokinumab 300 mg Q2W
    Arm description
    Week 0 to Week 16: Tralokinumab 300 mg Q2W Tralokinumab: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for SC administration.
    Arm type
    Experimental

    Investigational medicinal product name
    Tralokinumb 300 mg Q2W
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At Day 0, each subject received 4 SC injections (each 1.0 mL) of 150 mg tralokinumab to receive a total loading dose of 600 mg tralokinumab (4.0 mL). At subsequent visits (Q2W) each subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab to receive a total dose of 300 mg tralokinumab. IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Arm title
    Initial treatment period - Placebo Q2W
    Arm description
    Week 0 to Week 16: Placebo Q2W Placebo: Placebo contains the same excipients, in the same concentration, only lacking tralokinumab.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo Q2W
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Dosage and administration details: At Day 0, each subject received 4 SC injections (each 1.0 mL) of placebo to receive a total loading dose (4.0 mL). At subsequent visits (Q2W) each subject received 2 SC injections (each 1.0 mL) of placebo IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Number of subjects in period 1
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Started
    603
    199
    Completed
    550
    179
    Not completed
    53
    20
         Not dosed
    2
    2
         Discontinued IMP before Week 16
    51
    18
    Period 2
    Period 2 title
    Open-label treatment
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Open-label Treatment: Tralokinumab 300 mg Q2W + optional TCS
    Arm description
    Week 16 to Week 52: Subjects receiving initial treatment with tralokinumab/placebo Q2W who did not achieve protocol-defined clinical response assigned to open-label treatment at Week 16 with tralokinumab 300 mg Q2W regimen + optional topical corticosteroids (TCS) OR Subjects receiving maintenance treatment with tralokinumab 300 mg Q2W/Q4W or placebo Q2W assigned to open-label treatment after Week 16 with tralokinumab 300 mg Q2W regimen + optional TCS if: -IGA of at least 2 and not achieving EASI75 over at least a 4-week period (over 3 consecutive visits) for subjects with IGA=0 at Week 16; OR -IGA of at least 3 and not achieving EASI75 over at least a 4-week period (i.e. over 3 consecutive visits) for subjects with IGA=1 at Week 16; OR -Not achieving EASI75 over at least a 4-week period (over 3 consecutive visits) for subjects with IGA>1 at Week 16.
    Arm type
    Experimental

    Investigational medicinal product name
    Open-label Tralokinumab 300 mg Q2W + Optional TCS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab Q2W to receive a total dose of 300 mg. IMP was administered by a qualified HCP. Subjects had the option to self-administer tralokinumab – or have tralokinumab administered by a caregiver – in their home after adequate training by site staff at the investigator’s discretion. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Number of subjects in period 2 [1]
    Open-label Treatment: Tralokinumab 300 mg Q2W + optional TCS
    Started
    564
    Completed
    446
    Not completed
    118
         Completed Week 50
    6
         Discontinued IMP
    112
    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: The open-label treatment period was in parallel to the maintenance treatment period. Subjects from the initial treatment period entered either into the open-label treatment period or maintenance treatment period.
    Period 3
    Period 3 title
    Maintenance treatment period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    This was a double-blind trial in which tralokinumab and placebo were visually distinct from each other. The IMP was handled and administered by a qualified, unblinded HCP at the site who was not involved in the management of trial subjects and who did not perform any of the assessments. Maintenance treatment period was in parallel to the Open-label period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W
    Arm description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to tralokinumab 300 mg Q2W maintenance dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Maintenance Tralokinumab 300 mg Q2W
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab Q2W to receive a total dose of 300 mg tralokinumab. IMP was administered by a qualified, unblinded HCP. IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Arm title
    Maintenance Treatment Period - Tralokinumab 300 mg Q4W
    Arm description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to tralokinumab 300 mg Q4W maintenance dosing regimen.
    Arm type
    Experimental

    Investigational medicinal product name
    Maintenance Tralokinumab 300 mg Q4W
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received alternating dose administrations: 2 SC injections (each 1.0 mL) of 150 mg tralokinumab to receive a total dose of 300 mg tralokinumab and 2 SC injections (each 1.0 mL) of placebo. IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Arm title
    Maintenance Treatment Period - Placebo Q2W
    Arm description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to placebo Q2W dosing regimen.
    Arm type
    Placebo

    Investigational medicinal product name
    Maintenance Placebo Q2W
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received 2 SC injections (each 1.0 mL) of placebo Q2W to receive a total dose of placebo. IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Arm title
    Maintenance Treatment Period -Placebo Q2W - Tralokinumab Naive
    Arm description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to placebo re-assigned to placebo Q2W.
    Arm type
    Placebo

    Investigational medicinal product name
    Maintenance Placebo Q2W - Tralokinumab Naive
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received 2 SC injections (each 1.0 mL) of placebo Q2W to receive a total dose of placebo. IMP was administered by a qualified, unblinded HCP. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Number of subjects in period 3 [2]
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W Maintenance Treatment Period - Tralokinumab 300 mg Q4W Maintenance Treatment Period - Placebo Q2W Maintenance Treatment Period -Placebo Q2W - Tralokinumab Naive
    Started
    71
    78
    36
    29
    Completed
    44
    53
    21
    15
    Not completed
    27
    25
    15
    14
         Completed Week 50
    -
    -
    1
    -
         Transfer to open-label treatment
    21
    18
    9
    10
         Discontinued IMP
    4
    6
    4
    4
         Not dosed - transfer to open-label
    2
    1
    1
    -
    Notes
    [2] - 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: The maintenance treatment period was in parallel to the open-label treatment period. Subjects from the initial treatment phase entered either into the maintenance treatment period or the open-label treatment period.
    Period 4
    Period 4 title
    Open-label (Short-term extension)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Open-label Treatment - Tralokinumab 300 mg Q2W + Optional TCS
    Arm description
    Week 52 to Week 66 [Short term extension (Japan only)]: Japanese subjects who did not achieve protocol-defined clinical response assigned to open-label treatment at Week 16 with tralokinumab 300 mg Q2W regimen + optional topical corticosteroids (TCS) continued an additional 16 weeks (Week 52 to Week 66) of open-label treatment to receive 52 weeks of active therapy. Each subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab Q2W to receive a total dose of 300 mg tralokinumab.
    Arm type
    Experimental

    Investigational medicinal product name
    Open-label Tralokinumab 300 mg Q2W + Optional TCS
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    At each visit, subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab Q2W to receive a total dose of 300 mg. IMP was administered by a qualified HCP. Subjects had the option to self-administer tralokinumab – or have tralokinumab administered by a caregiver – in their home after adequate training by site staff at the investigator’s discretion. The injections were administered into the SC tissue of the upper arm, anterior thigh, or abdomen, separated by at least 3 cm.

    Number of subjects in period 4 [3]
    Open-label Treatment - Tralokinumab 300 mg Q2W + Optional TCS
    Started
    65
    Completed
    62
    Not completed
    3
         Discontinued IMP
    3
    Notes
    [3] - 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: The open-label treatment period was in parallel to the maintenance treatment period. Subjects from the initial treatment period entered either into the open-label treatment period or maintenance treatment period. This period was relevant only for selected Japanese subjects transferring to open-label treatment after Week 16, so they could receive 52 weeks of active treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Initial treatment period - Tralokinumab 300 mg Q2W
    Reporting group description
    Week 0 to Week 16: Tralokinumab 300 mg Q2W Tralokinumab: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for SC administration.

    Reporting group title
    Initial treatment period - Placebo Q2W
    Reporting group description
    Week 0 to Week 16: Placebo Q2W Placebo: Placebo contains the same excipients, in the same concentration, only lacking tralokinumab.

    Reporting group values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W Total
    Number of subjects
    603 199 802
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    574 185 759
        From 65-84 years
    28 14 42
        85 years and over
    1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.6 ± 13.7 39.4 ± 15.2 -
    Gender categorical
    Units: Subjects
        Female
    252 76 328
        Male
    351 123 474
    Race/Ethnicity
    Units: Subjects
        White
    426 138 564
        Black or african american
    41 18 59
        Asian
    120 40 160
        American indian or alaska native
    1 0 1
        Native hawaiian or other pacific islander
    5 0 5
        Other
    8 0 8
        Missing
    2 3 5
    Investigator's Global Assessment
    Measure description: The Investigator's Global Assessment (IGA) is an instrument used in clinical trials to rate the severity of the subject's global atopic dermatitis and is based on a 5-point scale ranging from 0 (clear) to 4 (severe).
    Units: Subjects
        Clear
    0 0 0
        Almost clear
    0 0 0
        Mild
    0 0 0
        Moderate
    296 95 391
        Severe
    305 102 407
        Missing
    2 2 4
    Eczema Area and Severity Index
    Measure description: The Eczema Area and Severity Index (EASI) is a validated measure used in clinical practice and clinical trials to assess the severity and extent of atopic dermatitis. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition. Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    32.2 ± 13.7 32.9 ± 13.9 -
    Scoring Atopic Dermatitis
    The Scoring Atopic Dermatitis (SCORAD) is a validated tool to evaluate the extent and severity of AD lesions, along with subjective symptoms. The maximum total score is 103, with higher values indicating more severe disease. Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    70.3 ± 13.0 71.7 ± 12.5 -
    Dermatology Life Quality Index
    The Dermatology Life Quality Index (DLQI) consists of 10 items addressing the subject’s perception of the impact of their skin disease on different aspects of their health-related quality of life over the last week such as dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment. Each item is scored on a 4-point Likert scale (0=‘not at all/not relevant’; 1=‘a little’; 2=‘a lot’; 3=‘very much’). The total score is the sum of the 10 items (0 to 30); a high score is indicative of a poor health-related quality of life.
    Units: Units on a scale
        arithmetic mean (standard deviation)
    16.8 ± 7.1 17.0 ± 6.6 -
    Worst Daily Pruritus Numeric rating scale (weekly average)
    Measure description: Subjects assess their worst itch severity over the past 24 hours using an 11-point NRS (Numeric rating scale; 'Worst Daily Pruritus NRS') with 0 indicating 'no itch' and 10 indicating 'worst itch imaginable'. Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter
    Units: Units on a scale
        arithmetic mean (standard deviation)
    7.7 ± 1.4 7.7 ± 1.4 -
    Body surface area affected by AD
    Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter.
    Units: percentage affected
        arithmetic mean (standard deviation)
    52.7 ± 24.1 54.2 ± 25.6 -
    Age of onset of atopic dermatitis (AD)
    Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter.
    Units: Years
        median (inter-quartile range (Q1-Q3))
    3.0 (1.0 to 14.0) 3.0 (0.0 to 13.0) -
    Duration of atopic dermatitis
    Measure Analysis Population Description: Number of subjects analysed = subjects with available data for the baseline parameter.
    Units: Years
        arithmetic mean (standard deviation)
    27.9 ± 14.5 29.6 ± 15.1 -

    End points

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    End points reporting groups
    Reporting group title
    Initial treatment period - Tralokinumab 300 mg Q2W
    Reporting group description
    Week 0 to Week 16: Tralokinumab 300 mg Q2W Tralokinumab: Tralokinumab is a human recombinant monoclonal antibody of the IgG4 subclass that specifically binds to human IL-13 and blocks interaction with the IL-13 receptors. It is presented as a liquid formulation for SC administration.

    Reporting group title
    Initial treatment period - Placebo Q2W
    Reporting group description
    Week 0 to Week 16: Placebo Q2W Placebo: Placebo contains the same excipients, in the same concentration, only lacking tralokinumab.
    Reporting group title
    Open-label Treatment: Tralokinumab 300 mg Q2W + optional TCS
    Reporting group description
    Week 16 to Week 52: Subjects receiving initial treatment with tralokinumab/placebo Q2W who did not achieve protocol-defined clinical response assigned to open-label treatment at Week 16 with tralokinumab 300 mg Q2W regimen + optional topical corticosteroids (TCS) OR Subjects receiving maintenance treatment with tralokinumab 300 mg Q2W/Q4W or placebo Q2W assigned to open-label treatment after Week 16 with tralokinumab 300 mg Q2W regimen + optional TCS if: -IGA of at least 2 and not achieving EASI75 over at least a 4-week period (over 3 consecutive visits) for subjects with IGA=0 at Week 16; OR -IGA of at least 3 and not achieving EASI75 over at least a 4-week period (i.e. over 3 consecutive visits) for subjects with IGA=1 at Week 16; OR -Not achieving EASI75 over at least a 4-week period (over 3 consecutive visits) for subjects with IGA>1 at Week 16.
    Reporting group title
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W
    Reporting group description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to tralokinumab 300 mg Q2W maintenance dosing regimen.

    Reporting group title
    Maintenance Treatment Period - Tralokinumab 300 mg Q4W
    Reporting group description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to tralokinumab 300 mg Q4W maintenance dosing regimen.

    Reporting group title
    Maintenance Treatment Period - Placebo Q2W
    Reporting group description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to tralokinumab re-randomised to placebo Q2W dosing regimen.

    Reporting group title
    Maintenance Treatment Period -Placebo Q2W - Tralokinumab Naive
    Reporting group description
    Week 16 to Week 52: Subjects achieving a clinical response at Week 16 and initially randomised to placebo re-assigned to placebo Q2W.
    Reporting group title
    Open-label Treatment - Tralokinumab 300 mg Q2W + Optional TCS
    Reporting group description
    Week 52 to Week 66 [Short term extension (Japan only)]: Japanese subjects who did not achieve protocol-defined clinical response assigned to open-label treatment at Week 16 with tralokinumab 300 mg Q2W regimen + optional topical corticosteroids (TCS) continued an additional 16 weeks (Week 52 to Week 66) of open-label treatment to receive 52 weeks of active therapy. Each subject received 2 SC injections (each 1.0 mL) of 150 mg tralokinumab Q2W to receive a total dose of 300 mg tralokinumab.

    Primary: Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16

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    End point title
    Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 16
    End point description
    The IGA is an instrument used in clinical trials to rate the severity of the subject's global AD and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). The full analysis set (FAS: all subjects randomised to initial treatment who were exposed to IMP) was used for the primary analysis; 802 subjects were randomised to initial treatment and 798 received IMP, thus the FAS comprised of 798 subjects.
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    95
    14
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    The analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity. The null hypothesis of no difference in response rates between tralokinumab and placebo were tested against the 2-sided alternative that there is a difference.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.002 [2]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    8.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.1
         upper limit
    13.1
    Notes
    [1] - Primary endpoints tested sequentially at a 5% significance level.
    [2] - Based on primary analysis of primary estimand composite. Subjects with missing data or subjects who received res cue medication prior to Week 16 were considered non-responders. Primary endpoints tested sequentially at a 5% significance level.

    Primary: Subjects Achieving at Least 75% Reduction in Eczema Area and Severity Index [EASI] at Week 16

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    End point title
    Subjects Achieving at Least 75% Reduction in Eczema Area and Severity Index [EASI] at Week 16
    End point description
    The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition. The FAS was used for the primary analysis; 802 subjects were randomised to initial treatment and 798 received IMP, thus the FAS comprised of 798 subjects.
    End point type
    Primary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    150
    25
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Analysis was performed using Cochran-Mantel-Haenszel test stratified by region and baseline disease severity. The null hypothesis of no difference in response rates between tralokinumab and placebo were tested against the 2-sided alternative that there is a difference.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [3]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    12.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.5
         upper limit
    17.7
    Notes
    [3] - Based on the primary analysis of primary estimand 'composite'. Subjects with missing data or subjects who received rescue medication prior to Week 16 were considered non-responders. Primary endpoints tested sequentially at a 5% significance level.

    Secondary: Change in Scoring Atopic Dermatitis (SCORAD) From Baseline to Week 16

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    End point title
    Change in Scoring Atopic Dermatitis (SCORAD) From Baseline to Week 16
    End point description
    SCORAD was used to assess the extent and severity of AD. The maximum total score is 103, with higher values indicating more severe disease. The FAS included all randomised subjects.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Adjusted mean change
        arithmetic mean (standard error)
    -25.2 ± 0.94
    -14.7 ± 1.80
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Data collected after permanent discontinuation of IMP or initiation of rescue medication not included.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    < 0.001 [5]
    Method
    Repeated measurements model
    Parameter type
    Difference
    Point estimate
    -10.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.4
         upper limit
    -6.5
    Notes
    [4] - Multiplicity adjustment using the Holm method.
    [5] - Based on the primary analysis of the primary estimand 'hypothetical'. Repeated measurements model on post-baseline data. In case of no post-baseline assessments before initiation of rescue medication, the Week 2 change was imputed as 0.

    Secondary: Reduction of Worst Daily Pruritus Numeric Rating Scale (Weekly Average) of at Least 4 From Baseline to Week 16.

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    End point title
    Reduction of Worst Daily Pruritus Numeric Rating Scale (Weekly Average) of at Least 4 From Baseline to Week 16.
    End point description
    Subjects assessed their worst itch severity over the past 24 hours using an 11point NRS (‘Worst Daily Pruritus NRS’) with 0 indicating ‘no itch’ and 10 indicating ‘worst itch imaginable’. Number of subjects analysed = subjects with baseline pruritus NRS weekly average ≥4.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    594
    194
    Units: Number of subjects
    119
    20
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    788
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.002 [7]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    9.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.4
         upper limit
    15
    Notes
    [6] - Multiplicity adjustment using Holm method.
    [7] - Based on the primary analysis of the primary estimand 'Composite', subjects who received rescue medication prior to Week 16 or have missing data at Week 16 were considered as non-responders'.

    Secondary: Change in Dermatology Life Quality Index (DLQI) Score From Baseline to Week 16

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    End point title
    Change in Dermatology Life Quality Index (DLQI) Score From Baseline to Week 16
    End point description
    The Dermatology Life Quality Index (DLQI) was a validated questionnaire with content specific to those with dermatology conditions. It consisted of 10 items addressing the subject’s perception of the impact of their skin disease on different aspects of their quality of life (QoL) over the last week such as dermatology-related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment. Each item is scored on a 4 point Likert scale (0 = not at all ⁄not relevant; 1 = a little; 2 = a lot; 3 = very much). The total score is the sum of the 10 items (0 to 30); a high score is indicative of a poor QoL.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Adjusted mean change
        arithmetic mean (standard error)
    -7.1 ± 0.31
    -5.0 ± 0.59
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Data collected after permanent discontinuation of IMP or initiation of rescue medication not included.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.002 [9]
    Method
    Repeated Measurements Model
    Parameter type
    Difference
    Point estimate
    -2.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.4
         upper limit
    -0.8
    Notes
    [8] - Multiplicity adjustment using Holm method.
    [9] - Based on the primary analysis of the primary estimand 'hypothetical'. Repeated measurements model on post-baseline data. In case of no post-baseline assessments before initiation of rescue medication, the Week 2 change was imputed as 0.

    Secondary: Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 52 Among Subjects With IGA of 0/1 at Week 16

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    End point title
    Subjects With Investigator's Global Assessment (IGA) Score of 0 (Clear) or 1 (Almost Clear) at Week 52 Among Subjects With IGA of 0/1 at Week 16
    End point description
    The IGA is an instrument used in clinical trials to rate the severity of the subject’s global AD and is based on a 5-point scale ranging from 0 (clear) to 4 (severe). Maintenance analysis set - Subjects who achieved IGA 0/1 at Week 16 after initial treatment with tralokinumab without use of rescue medication.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W Maintenance Treatment Period - Tralokinumab 300 mg Q4W Maintenance Treatment Period - Placebo Q2W
    Number of subjects analysed
    39
    36
    19
    Units: Number of subjects
    20
    14
    9
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure in the order: IGA 0/1 at Week 52 between Q2W vs Placebo, EASI75 at Week 52 between Q2W vs Placebo, IGA 0/1 at Week 52 between Q4W vs Placebo, and EASI75 at Week 52 between Q4W vs Placebo.
    Comparison groups
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W v Maintenance Treatment Period - Placebo Q2W
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.68 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.8
         upper limit
    33.7
    Notes
    [10] - This test was not statistically significant and hence next maintenance endpoint in the sequential testing procedure was not evaluated.
    [11] - Based on the primary analysis of the 'composite' estimand. Subjects who received rescue medication or were transferred to open-labe l treatment were considered non-responders. The P value was considered non-significant.
    Statistical analysis title
    Tralokinumab 300 mg Q4W versus Placebo
    Comparison groups
    Maintenance Treatment Period - Placebo Q2W v Maintenance Treatment Period - Tralokinumab 300 mg Q4W
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.5
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    -9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -37.1
         upper limit
    18

    Secondary: Subjects With at Least 75% Reduction in Eczema Area and Severity Index [EASI] at Week 52 Among Subjects With EASI75 at Week 16

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    End point title
    Subjects With at Least 75% Reduction in Eczema Area and Severity Index [EASI] at Week 52 Among Subjects With EASI75 at Week 16
    End point description
    The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
    End point type
    Secondary
    End point timeframe
    At Week 52
    End point values
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W Maintenance Treatment Period - Tralokinumab 300 mg Q4W Maintenance Treatment Period - Placebo Q2W
    Number of subjects analysed
    47
    57
    30
    Units: Number of subjects
    28
    28
    10
    Statistical analysis title
    Tralokinumab 300 mg Q2W versus Placebo
    Statistical analysis description
    Testing according to the hierarchical testing procedure in the order: IGA 0/1 at Week 52 between Q2W vs Placebo, EASI75 at Week 52 between Q2W vs Placebo, IGA 0/1 at Week 52 between Q4W vs Placebo, and EASI75 at Week 52 between Q4W vs Placebo.
    Comparison groups
    Maintenance Treatment Period - Tralokinumab 300 mg Q2W v Maintenance Treatment Period - Placebo Q2W
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.056 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    21.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    42.6
    Notes
    [12] - Test not evaluated for statistical significance. Based on the primary analysis of the 'composite' estimand. Subjects who received rescue medication or were transferred to open-labe l treatment were considered non-responders.
    Statistical analysis title
    Tralokinumab 300 mg Q4W versus Placebo
    Comparison groups
    Maintenance Treatment Period - Tralokinumab 300 mg Q4W v Maintenance Treatment Period - Placebo Q2W
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.27 [13]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    11.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    32
    Notes
    [13] - Test not evaluated for statisitical significance. Based on the primary analysis of the 'composite' estimand. Subjects who received rescue medication or were transferred to open-labe l treatment were considered non-responders.

    Secondary: Safety and Tolerability: Adverse event (AE) /Serious adverse event (SAE) Frequency

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    End point title
    Safety and Tolerability: Adverse event (AE) /Serious adverse event (SAE) Frequency
    End point description
    Overall summary of AEs and SAEs during the Initial treatment period is presented. For list of AEs and SAEs by MedDRA system organ class (SOC) and preferred term (PT) during the entire trial period (including safety follow-up), see Adverse Events Overview section.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    602
    196
    Units: Number of subjects
        AE
    411
    133
        SAE
    23
    8
    No statistical analyses for this end point

    Secondary: Frequency of Anti-drug Antibodies

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    End point title
    Frequency of Anti-drug Antibodies
    End point description
    Anti-tralokinumab antibody levels were analysed using a validated bioanalytical method.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    602
    196
    Units: Number of subjects
        Total positive
    10
    3
        Pre-existing
    0
    2
        Treatment-boosted
    0
    0
        Treatment emergent
    10
    1
        Perishing
    5
    3
        Negative
    564
    177
        No post-baseline anti-drug antibody assessment
    23
    13
    No statistical analyses for this end point

    Secondary: Subjects Achieving at Least 50% Reduction in Eczema Area and Severity Index [EASI] at Week 16

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    End point title
    Subjects Achieving at Least 50% Reduction in Eczema Area and Severity Index [EASI] at Week 16
    End point description
    The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    250
    42
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Based on the primary analysis of the primary estimand 'composite'. Subjects with missing data or subjects who received rescue medication prior to Week 16 were considered non-responders.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [14]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    20.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.3
         upper limit
    26.8
    Notes
    [14] - The statistical test was not controlled for multiplicity.

    Secondary: Subjects Achieving at Least 90% Reduction in Eczema Area and Severity Index [EASI] at Week 16

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    End point title
    Subjects Achieving at Least 90% Reduction in Eczema Area and Severity Index [EASI] at Week 16
    End point description
    The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    87
    8
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [15]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    10.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6.4
         upper limit
    14.1
    Notes
    [15] - Based on the primary analysis of the primary estimand 'composite'. Subjects with missing data or subjects who received rescue medication prior to Week 16 were considered non-responders. The statistical test was not controlled for multiplicity.

    Secondary: Change From Baseline to Week 16 in Eczema Area and Severity Index [EASI] Score

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    End point title
    Change From Baseline to Week 16 in Eczema Area and Severity Index [EASI] Score
    End point description
    The EASI is a validated measure used in clinical practice and clinical trials to assess the severity and extent of AD. The EASI is a composite index with scores ranging from 0 to 72, with higher values indicating more severe and/or more extensive condition.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    -15.5 (-16.6 to -14.4)
    -9.0 (-11.1 to -7.0)
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Data collected after permanent discontinuation of IMP or initiation of rescue medication not included. In case of no post-baseline assessments before initiation of rescue medication, the Week 2 change will be imputed as 0.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [16]
    Method
    Repeated measurements model
    Parameter type
    Difference of least square means
    Point estimate
    -6.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.8
         upper limit
    -4.1
    Notes
    [16] - The statistical test was not controlled for multiplicity.

    Secondary: Subjects Achieving at Least 75% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16

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    End point title
    Subjects Achieving at Least 75% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16
    End point description
    The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with subjective symptoms. The maximum total score is 103, with higher values indicating more severe disease.
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    53
    6
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007 [17]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    5.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.5
         upper limit
    8.9
    Notes
    [17] - Based on the primary analysis of the 'composite' estimand. Subjects who received rescue medication prior to Week 16 or with missing data at Week 16 were considered nonresponders. The statistical test was not controlled for multiplicity.

    Secondary: Subjects Achieving at Least 50% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16

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    End point title
    Subjects Achieving at Least 50% Reduction in Scoring Atopic Dermatitis (SCORAD) at Week 16
    End point description
    The SCORAD is a validated tool to evaluate the extent and severity of AD lesions, along with subjective symptoms. The maximum total score is 103, with higher values indicating more severe disease.
    End point type
    Secondary
    End point timeframe
    At Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    601
    197
    Units: Number of subjects
    156
    23
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    798
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [18]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    14.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    8.6
         upper limit
    19.6
    Notes
    [18] - Based on the primary analysis of the 'composite' estimand. Subjects who received rescue medication prior to Week 16 or with missing data at Week 16 were considered non-responders. The statistical test was not controlled for multiplicity.

    Secondary: Change From Baseline to Week 16 in Worst Daily Pruritus NRS (Weekly Average)

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    End point title
    Change From Baseline to Week 16 in Worst Daily Pruritus NRS (Weekly Average)
    End point description
    Subjects will assess their worst itch severity over the past 24 hours using an 11 point NRS ('Worst Daily Pruritus NRS') with 0 indicating 'no itch' and 10 indicating 'worst itch imaginable'
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    598
    195
    Units: Units on a scale
        least squares mean (confidence interval 95%)
    -2.6 (-2.8 to -2.4)
    -1.7 (-2.1 to -1.3)
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Statistical analysis description
    Data collected after permanent discontinuation of IMP or initiation of rescue medication not included. In case of no post-baseline assessments before initiation of rescue medication, the Week 1 change will be imputed as 0.
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    793
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [19]
    Method
    Repeated measurements model
    Parameter type
    Difference of least square means
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    -0.4
    Notes
    [19] - The statistical test was not controlled for multiplicity.

    Secondary: Reduction of Worst Daily Pruritus NRS (Weekly Average) ≥3 From Baseline to Week 16

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    End point title
    Reduction of Worst Daily Pruritus NRS (Weekly Average) ≥3 From Baseline to Week 16
    End point description
    Subjects will assess their worst itch severity over the past 24 hours using an 11 point NRS ('Worst Daily Pruritus NRS') with 0 indicating 'no itch' and 10 indicating 'worst itch imaginable'. Number of subjects analysed = subjects with baseline Pruritus NRS weekly average of at least 3.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    597
    195
    Units: Number of subjects
    177
    28
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    792
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [20]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    15.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    9.2
         upper limit
    21.3
    Notes
    [20] - Subjects who received rescue medication prior to Week 16 or have missing data at Week 16 were considered as non-responders. The statistical test was not controlled for multiplicity.

    Secondary: Reduction From Baseline to Week 16 of Dermatology Life Quality Index (DLQI) of ≥4 Points Among Subjects With Baseline DLQI ≥4

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    End point title
    Reduction From Baseline to Week 16 of Dermatology Life Quality Index (DLQI) of ≥4 Points Among Subjects With Baseline DLQI ≥4
    End point description
    The DLQI is a validated questionnaire with content specific to those with dermatology conditions. It consists of 10 items addressing the subject's perception of the impact of their skin disease on different aspects of their QoL over the last week such as dermatology related symptoms and feelings, daily activities, leisure, work or school, personal relationships, and the treatment. Each item is scored on a 4 point Likert scale (0 = not at all/not relevant; 1 = a little; 2 = a lot; 3 = very much). The total score is the sum of the 10 items (0 to 30); a high score is indicative of a poor QoL. Number of subjects analysed = subjects with baseline DLQI ≥4.
    End point type
    Secondary
    End point timeframe
    Week 0 to Week 16
    End point values
    Initial treatment period - Tralokinumab 300 mg Q2W Initial treatment period - Placebo Q2W
    Number of subjects analysed
    578
    190
    Units: Number of subjects
    258
    60
    Statistical analysis title
    Tralokinumab 300 mg Q2W vs Placebo Q2W
    Comparison groups
    Initial treatment period - Tralokinumab 300 mg Q2W v Initial treatment period - Placebo Q2W
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [21]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Risk difference (RD)
    Point estimate
    13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.4
         upper limit
    20.5
    Notes
    [21] - Subjects who received rescue medication prior to Week 16 or have missing data at Week 16 were considered as non-responders. The statistical test was not controlled for multiplicity.

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Initial Period - Tralokinumab Q2W
    Reporting group description
    -

    Reporting group title
    Initial Period - Placebo
    Reporting group description
    -

    Reporting group title
    Maintenance Period - Tralokinumab Q2W
    Reporting group description
    -

    Reporting group title
    Maintenance Period - Tralokinumab Q4W
    Reporting group description
    -

    Reporting group title
    Maintenance Period - Placebo
    Reporting group description
    -

    Reporting group title
    Maintenance Period - Placebo - Tralokinumab Naive
    Reporting group description
    -

    Reporting group title
    Open-label Period - Tralokinumab Q2W + Optional TCS
    Reporting group description
    -

    Reporting group title
    Safety Follow-up
    Reporting group description
    -

    Serious adverse events
    Initial Period - Tralokinumab Q2W Initial Period - Placebo Maintenance Period - Tralokinumab Q2W Maintenance Period - Tralokinumab Q4W Maintenance Period - Placebo Maintenance Period - Placebo - Tralokinumab Naive Open-label Period - Tralokinumab Q2W + Optional TCS Safety Follow-up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 602 (3.82%)
    8 / 196 (4.08%)
    1 / 68 (1.47%)
    3 / 76 (3.95%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    27 / 563 (4.80%)
    16 / 595 (2.69%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive breast carcinoma
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 563 (0.36%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Granuloma
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injection site reaction
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Strangulated hernia
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Troponin increased
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Accessory cardiac pathway
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    3 / 563 (0.53%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 602 (0.17%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    1 / 76 (1.32%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    1 / 76 (1.32%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Eosinophilia
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Lens dislocation
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulcerative keratitis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Incarcerated umbilical hernia
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stag horn calculus
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    4 / 602 (0.66%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 563 (0.36%)
    3 / 595 (0.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis exfoliative generalised
         subjects affected / exposed
    2 / 602 (0.33%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    2 / 595 (0.34%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatomyositis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperhidrosis
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyoderma gangrenosum
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    1 / 76 (1.32%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polymyalgia rheumatica
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 602 (0.17%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    2 / 563 (0.36%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    1 / 68 (1.47%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 602 (0.00%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Furuncle
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis bacterial
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis bacterial
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Keratitis viral
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    1 / 595 (0.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leishmaniasis
         subjects affected / exposed
    1 / 602 (0.17%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 602 (0.00%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    1 / 76 (1.32%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    0 / 563 (0.00%)
    0 / 595 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Initial Period - Tralokinumab Q2W Initial Period - Placebo Maintenance Period - Tralokinumab Q2W Maintenance Period - Tralokinumab Q4W Maintenance Period - Placebo Maintenance Period - Placebo - Tralokinumab Naive Open-label Period - Tralokinumab Q2W + Optional TCS Safety Follow-up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    351 / 602 (58.31%)
    114 / 196 (58.16%)
    37 / 68 (54.41%)
    39 / 76 (51.32%)
    20 / 35 (57.14%)
    9 / 29 (31.03%)
    304 / 563 (54.00%)
    29 / 595 (4.87%)
    Injury, poisoning and procedural complications
    Wrong patient received medication
         subjects affected / exposed
    8 / 602 (1.33%)
    1 / 196 (0.51%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    2 / 563 (0.36%)
    0 / 595 (0.00%)
         occurrences all number
    13
    1
    0
    0
    0
    2
    2
    0
    Investigations
    Liver function test increased
         subjects affected / exposed
    4 / 602 (0.66%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    1 / 563 (0.18%)
    0 / 595 (0.00%)
         occurrences all number
    4
    0
    0
    0
    2
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    10 / 602 (1.66%)
    1 / 196 (0.51%)
    4 / 68 (5.88%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    5 / 563 (0.89%)
    1 / 595 (0.17%)
         occurrences all number
    11
    1
    4
    0
    0
    0
    5
    1
    Oropharyngeal pain
         subjects affected / exposed
    10 / 602 (1.66%)
    1 / 196 (0.51%)
    1 / 68 (1.47%)
    0 / 76 (0.00%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    10 / 563 (1.78%)
    0 / 595 (0.00%)
         occurrences all number
    11
    1
    1
    0
    2
    0
    10
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 602 (4.65%)
    10 / 196 (5.10%)
    6 / 68 (8.82%)
    2 / 76 (2.63%)
    3 / 35 (8.57%)
    0 / 29 (0.00%)
    22 / 563 (3.91%)
    1 / 595 (0.17%)
         occurrences all number
    50
    16
    12
    2
    6
    0
    29
    1
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    16 / 602 (2.66%)
    3 / 196 (1.53%)
    3 / 68 (4.41%)
    1 / 76 (1.32%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    13 / 563 (2.31%)
    2 / 595 (0.34%)
         occurrences all number
    16
    4
    3
    1
    2
    0
    14
    2
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    24 / 602 (3.99%)
    0 / 196 (0.00%)
    5 / 68 (7.35%)
    7 / 76 (9.21%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    28 / 563 (4.97%)
    0 / 595 (0.00%)
         occurrences all number
    47
    0
    13
    21
    1
    0
    60
    0
    Skin and subcutaneous tissue disorders
    Dermatitis atopic
         subjects affected / exposed
    152 / 602 (25.25%)
    75 / 196 (38.27%)
    11 / 68 (16.18%)
    14 / 76 (18.42%)
    13 / 35 (37.14%)
    6 / 29 (20.69%)
    123 / 563 (21.85%)
    10 / 595 (1.68%)
         occurrences all number
    198
    123
    14
    22
    18
    10
    201
    12
    Pruritus
         subjects affected / exposed
    32 / 602 (5.32%)
    10 / 196 (5.10%)
    2 / 68 (2.94%)
    4 / 76 (5.26%)
    1 / 35 (2.86%)
    2 / 29 (6.90%)
    20 / 563 (3.55%)
    0 / 595 (0.00%)
         occurrences all number
    41
    15
    2
    5
    1
    2
    27
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 602 (0.83%)
    2 / 196 (1.02%)
    3 / 68 (4.41%)
    4 / 76 (5.26%)
    0 / 35 (0.00%)
    1 / 29 (3.45%)
    18 / 563 (3.20%)
    0 / 595 (0.00%)
         occurrences all number
    5
    2
    3
    4
    0
    1
    19
    0
    Tendonitis
         subjects affected / exposed
    3 / 602 (0.50%)
    0 / 196 (0.00%)
    0 / 68 (0.00%)
    0 / 76 (0.00%)
    0 / 35 (0.00%)
    2 / 29 (6.90%)
    6 / 563 (1.07%)
    0 / 595 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    2
    6
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    11 / 602 (1.83%)
    4 / 196 (2.04%)
    3 / 68 (4.41%)
    7 / 76 (9.21%)
    2 / 35 (5.71%)
    1 / 29 (3.45%)
    14 / 563 (2.49%)
    1 / 595 (0.17%)
         occurrences all number
    12
    4
    3
    8
    2
    1
    15
    1
    Conjunctivitis
         subjects affected / exposed
    43 / 602 (7.14%)
    4 / 196 (2.04%)
    3 / 68 (4.41%)
    4 / 76 (5.26%)
    0 / 35 (0.00%)
    0 / 29 (0.00%)
    41 / 563 (7.28%)
    4 / 595 (0.67%)
         occurrences all number
    50
    4
    3
    6
    0
    0
    52
    4
    Influenza
         subjects affected / exposed
    18 / 602 (2.99%)
    5 / 196 (2.55%)
    4 / 68 (5.88%)
    3 / 76 (3.95%)
    1 / 35 (2.86%)
    0 / 29 (0.00%)
    7 / 563 (1.24%)
    2 / 595 (0.34%)
         occurrences all number
    18
    5
    5
    3
    1
    0
    7
    2
    Nasopharyngitis
         subjects affected / exposed
    15 / 602 (2.49%)
    2 / 196 (1.02%)
    0 / 68 (0.00%)
    3 / 76 (3.95%)
    2 / 35 (5.71%)
    0 / 29 (0.00%)
    5 / 563 (0.89%)
    1 / 595 (0.17%)
         occurrences all number
    16
    2
    0
    3
    2
    0
    5
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    139 / 602 (23.09%)
    41 / 196 (20.92%)
    14 / 68 (20.59%)
    18 / 76 (23.68%)
    4 / 35 (11.43%)
    2 / 29 (6.90%)
    143 / 563 (25.40%)
    12 / 595 (2.02%)
         occurrences all number
    172
    54
    17
    26
    5
    4
    201
    12

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2017
    The reason for the amendment was due to a request for changes from the Health Authorities in Europe after their review of the protocol. The main amendments are listed below. 1) It was clarified that all subjects in the trial will have a safety follow-up visit (end of trial visit) 16 weeks after last injection of IMP (investigational medicinal product), including those that are offered participation in the long-term extension trial conducted under a separate protocol (LP0162 1337). This was to ensure that safety follow-up information was collected for all subjects enrolled in this trial, and to ensure that a safety evaluation could be made based on data collected after IMP had been discontinued. Furthermore, the evaluation of anti-drug antibodies was considered to be most reliable when samples are taken in the absence of IMP. 2) 2 additional blood samples (PK and anti drug antibodies) were added at Week 4 to better monitor potential development of immunogenicity. 3) The transfer criteria to open-label treatment was changed to keep subjects who entered maintenance treatment with IGA 0/1 in maintenance treatment until they have a sustained 2 step change in IGA (IGA of 0 becoming ≥2; IGA of 1 becoming ≥3). 4) The exclusion criteria regarding receipt of any marketed (i.e. immunoglobulin, anti-IgE) or investigational biologic agent was updated with dupilumab since it was then approved in USA. 5) Infusion reactions were deleted from the risk list since they are not relevant for this trial. Malignancies and interference with reproductive function were added to align with the Investigator’s Brochure. 6) It was clarified that subjects who permanently discontinue IMP prior to Week 16 should also be assessed at the nominal Week 16 visit. This was to allow sensitivity analyses of primary endpoints and secondary endpoints in the initial treatment period. 7) The procedure for emergency unblinding of the individual subject’s treatment was clarified.
    12 Dec 2017
    The reason for the amendment is due to a request for changes from the Health Authorities in the US after their review of the protocol. The main amendments are listed below. 1) Several 'other endpoints' were included to the trial objectives and endpoints to allow for an evaluation of the efficacy of tralokinumab over time on severity and extent of AD, itch, and health-related quality of life compared with placebo. Additional endpoints were included to evaluate the patient-reported outcomes and health care resource utilisation. 2) Clarification that transfer to open-label requires a persistent worsening of disease observed over 3 consecutive visits in the maintenance period was included. 3) Clarification of how Worst Daily Pruritus NRS at baseline will be calculated was included. 4) Clarification that female subjects of childbearing potential must have used a highly effective form of birth control for at least 1 month prior to baseline was included. 5) Clarification that the small biomarker panel may include more than 7 biomarkers. 6) Clarification that AE reporting starts at screening, not baseline was included. 7) For all randomised subjects the reasons for permanent discontinuation of IMP and for leaving the trial will be presented.
    14 Aug 2018
    The main reason for the amendment was that a new anti-drug antibody (ADA) assay had been developed with improved tralokinumab tolerance. It meant that the presence or absence of anti-drug antibodies (ADA) could be determined in serum samples with tralokinumab present. Previously, this was not possible and therefore ADA sampling at the end of the 14-week off-treatment safety follow-up was originally required for the ADA evaluation. Thus, the new ADA assay would allow eligible subjects who have completed the treatment periods of trial LP0162 1325 to continue into the long-term extension trial (conducted under a separate protocol [LP0162 1337, ECZTEND]) without completing the safety follow-up period in the present trial. These subjects would have their safety follow-up period after end-of-treatment in the long-term extension trial.

    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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