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    Clinical Trial Results:
    A Randomised Controlled Trial Assessing the Effectiveness, Safety and Cost-effectiveness of Methotrexate versus Ciclosporin in the Treatment of Severe Atopic Eczema in Children: The TREatment of Severe Atopic Eczema Trial (TREAT)

    Summary
    EudraCT number
    		 2015-002013-29
    Trial protocol
    		 GB   IE  
    Global end of trial date
    14 May 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2023
    First version publication date
    15 Dec 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    TREAT
    Additional study identifiers
    ISRCTN number
    		 ISRCTN15837754
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Carsten Flohr, Kings College London, 44 07806514078, carsten.flohr@kcl.ac.uk
    Scientific contact
    Carsten Flohr, Kings College London, 44 07806514078, carsten.flohr@kcl.ac.uk
    Sponsor organisation name
    Guy's and St Thomas NHS Foundation Trust
    Sponsor organisation address
    Great Maze Pond, London, United Kingdom, SE1 9RT
    Public contact
    Carsten Flohr, Guy's and St Thomas' Foundation NHS Trust, 44 07806514078, carsten.flohr@kcl.ac.uk
    Scientific contact
    Carsten Flohr, Guy's and St Thomas' Foundation NHS Trust, 44 07806514078, carsten.flohr@kcl.ac.uk
    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
    21 Apr 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 May 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    14 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    There are two co-primary endpoints: To assess the change in atopic ezcema severity between baseline visit and 12 weeks of treatment with Methotrexate or Ciclosporin treatment, using the 0SCORAD index and Time to first significant flare up during the 24 weeks after the end of treatment with either Methotrexate or Ciclosporin.
    Protection of trial subjects
    The drug dosing for MTX and CyA as well as the frequency of the study visits and safety assessments, including safety bloods, are in keeping with SmPC guidance and the American Academy of Dermatology guidelines for the use of systemic immuno-suppressive therapy in children and young people with severe atopic eczema. The trial was was overseen by the Trial Management Group, the Trial Steering Group and Independent Data and Safety Monitoring Committee.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Mar 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 98
    Country: Number of subjects enrolled
    Ireland: 5
    Worldwide total number of subjects
    103
    EEA total number of subjects
    5
    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)
    65
    Adolescents (12-17 years)
    38
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants will be identified by the clinical team at each centre via a search of the patient database/s either electronically or manually or clinic list review to find potentially eligible patients. At the routine clinic visit, the patient and/or parent/guardian will be asked whether they would be willing to participate in the study.

    Pre-assignment
    Screening details
    		 Participants will be identified by the clinical team at each centre via a search of the patient database/s either electronically or manually or clinic list review to find potentially eligible patients. At the routine clinic visit, the patient and/or parent/guardian will be asked whether they would be willing to participate in the study.

    Period 1
    Period 1 title
    Main Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    As the trial interventions are at different frequencies (daily vs once weekly), have rather different side effect profiles and since no placebo is used as part of the study, blinding of the local investigator and research nurse will not be possible. However, the assessor who will perform the severity assessments (o-SCORAD, EASI & IGA), will be blinded to the trial allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ciclosporin
    Arm description
    		 Patients should remain on the full treatment dose (4mg/kg/day for CyA) for the 12 weeks. After that, dose increases to a maximum of 5mg/kg/day or dose decreases are allowed, according to the treatment response.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ciclosporin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    2mg/kg (total: 4mg/kg/day) (rounded to the nearest whole capsule where applicable)

    Arm title
    		 Methotrexate
    Arm description
    		 Patients will start on an initial test dose (0.1/mg/kg/week) for MTX (week 0) and then continue on the full treatment dose (0.4mg/kg/week for MTX – maximum dose of 25mg/week) from the following week (week 1), providing there have not been any significant side effects and the results from the safety bloods are acceptable.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Subcutaneous use
    Dosage and administration details
    Initial dose of 0.1mg/kg/week, then 0.4mg/kg/week from week 1 (maximum 25mg/week)

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only the assessor in the trial was blinded.
    Number of subjects in period 1
    		Ciclosporin Methotrexate
    Started
    52
    51
    Completed
    47
    44
    Not completed
    5
    7
         Physician decision
    2
    4
         Consent withdrawn by subject
    3
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ciclosporin
    Reporting group description
    		 Patients should remain on the full treatment dose (4mg/kg/day for CyA) for the 12 weeks. After that, dose increases to a maximum of 5mg/kg/day or dose decreases are allowed, according to the treatment response.

    Reporting group title
    Methotrexate
    Reporting group description
    		 Patients will start on an initial test dose (0.1/mg/kg/week) for MTX (week 0) and then continue on the full treatment dose (0.4mg/kg/week for MTX – maximum dose of 25mg/week) from the following week (week 1), providing there have not been any significant side effects and the results from the safety bloods are acceptable.

    Reporting group values
    		 Ciclosporin Methotrexate Total
    Number of subjects
    		 52 51 103
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age in years
    Units: years
        arithmetic mean (standard deviation)
    		 10.34 ± 4.21 9.82 ± 4.01 -
    Gender categorical
    Sex
    Units: Subjects
        Female
    		 21 28 49
        Male
    		 31 23 54
    Ethnicity
    Ethnicity
    Units: Subjects
        White British
    		 27 27 54
        Black British
    		 6 4 10
        Indian
    		 2 3 5
        Mixed
    		 2 3 5
        Other White
    		 2 3 5
        Pakistani
    		 2 3 5
        Asian
    		 1 2 3
        Asian (Philippines)
    		 0 1 1
        Asian (Other)
    		 1 0 1
        Bangladeshi
    		 0 1 1
        Black African
    		 1 0 1
        Brazilian
    		 0 1 1
        British Bangladeshi
    		 0 1 1
        British Pakistani
    		 1 0 1
        Filipino
    		 1 0 1
        German, Czech
    		 1 0 1
        Latin American
    		 0 1 1
        Mixed White
    		 1 0 1
        South East Asian
    		 1 0 1
        Sri Lankan
    		 1 0 1
        White Irish
    		 1 0 1
        Chinese
    		 1 1 2
    IGA
    IGA
    Units: Subjects
        Mild
    		 0 1 1
        Moderate
    		 16 18 34
        Severe
    		 31 29 60
        Very Severe
    		 5 3 8
    Weight
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 38.12 ± 20.32 37.04 ± 18.08 -
    Height
    Height - n=51 for CyA group
    Units: cm
        arithmetic mean (standard deviation)
    		 137.82 ± 24.66 133.75 ± 22.62 -
    BMI
    BMI - n = 51 for CyA group
    Units: kg/m
        arithmetic mean (standard deviation)
    		 18.80 ± 4.16 19.30 ± 4.15 -
    EASI
    EASI does have units.
    Units: EASI
        arithmetic mean (standard deviation)
    		 28.97 ± 12.53 27.12 ± 11.62 -
    o-SCORAD
    o-SCORAD does not have units.
    Units: o-SCORAD
        arithmetic mean (standard deviation)
    		 48.34 ± 11.35 45.25 ± 9.60 -
    POEM
    POEM does not have units. There were 50 pts who had POEM at baseline in the CyA group and 49 in the MTX group.
    Units: POEM
        arithmetic mean (standard deviation)
    		 20.40 ± 5.26 20.84 ± 5.47 -
    DFI
    DFI doe not have units. 51 pts in the CyX group had a baseline value.
    Units: DFI
        arithmetic mean (standard deviation)
    		 15.24 ± 7.89 15.59 ± 7.67 -
    IDQoL - Dermatitis
    IDQoL-Dermatitis (under 4s only)does not have units. 3 pts in the CyA group and 5 pts in the MTX group reported this outcome.
    Units: IDQoL
        arithmetic mean (standard deviation)
    		 3 ± 0 2.80 ± 0.84 -
    IDQoL - Life Quality Index
    IDQoL - Life Quality Index (under 4s only) has no units. n-=3 in the CyA group and n=5 in the MTC group.
    Units: IDQoL
        arithmetic mean (standard deviation)
    		 16 ± 8.19 13 ± 7.91 -
    CDLQI
    CDLQI does not have any units. n=48 in the CyA group and n=47in the MTC group.
    Units: CDLQI
        arithmetic mean (standard deviation)
    		 14.67 ± 6.96 15.26 ± 6.57 -

    End points

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    End points reporting groups
    Reporting group title
    Ciclosporin
    Reporting group description
    		 Patients should remain on the full treatment dose (4mg/kg/day for CyA) for the 12 weeks. After that, dose increases to a maximum of 5mg/kg/day or dose decreases are allowed, according to the treatment response.

    Reporting group title
    Methotrexate
    Reporting group description
    		 Patients will start on an initial test dose (0.1/mg/kg/week) for MTX (week 0) and then continue on the full treatment dose (0.4mg/kg/week for MTX – maximum dose of 25mg/week) from the following week (week 1), providing there have not been any significant side effects and the results from the safety bloods are acceptable.

    Primary: O-SCORAD

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    End point title
    		 O-SCORAD
    End point description
    End point type
    Primary
    End point timeframe
    Change in atopic eczema severity between baseline and 12 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [1]
    51 [2]
    Units: O-SCORAD
        arithmetic mean (standard deviation)
    25.84 ± 10.79
    30.86 ± 12.14
    Notes
    [1] - Values at 12 weeks.
    [2] - Values at 12 weeks.
    Statistical analysis title
    		 Change in atopic eczema severity using o-SCORAD
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0131
    Method
    		 ANCOVA
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.69
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -10.81
         upper limit
    		 -0.57
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.25
    Statistical analysis title
    		 Sensitivity analysis
    Statistical analysis description
    Inclusion of centre as a random effect in a linear mixed model.
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0115
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.47
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -10.31
         upper limit
    		 -0.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.12

    Primary: Time to first significant Flare

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    End point title
    		 Time to first significant Flare
    End point description
    End point type
    Primary
    End point timeframe
    During the 24 weeks after treatment cessation
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52
    51
    Units: Events
        Flare
    25
    18
        No Flare
    27
    33
    Statistical analysis title
    		 Time to first significant flare
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1529 [3]
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.55
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 3.1
    Notes
    [3] - P-value based on log-rank test
    Statistical analysis title
    		 Sensitivity analysis 1
    Statistical analysis description
    The analysis will be carried out in the subset of those who completed 36 weeks treatment.
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1948
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    5.14
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 1.03
         upper limit
    		 25.62
    Statistical analysis title
    		 Sensitivity analysis 2
    Statistical analysis description
    Those who stopped trial treatment early but continued to take MTX or CyA begin the 24 week follow-up period from the end date of the con-med as recorded on the con-med form.
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1538
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.54
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 3.09

    Secondary: EASI

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    End point title
    		 EASI
    End point description
    End point type
    Secondary
    End point timeframe
    EASI was measured at baseline and Weeks 4, 8, 12,20, 28,36,48 and 60.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [4]
    51 [5]
    Units: EASI
    arithmetic mean (standard error)
        Week 12
    12.36 ± 0.86
    15.49 ± 0.87
        Week 36
    12.81 ± 0.82
    11.19 ± 0.84
        Week 48
    13.03 ± 0.93
    9.04 ± 0.94
        Week 60
    13.25 ± 1.09
    6.89 ± 1.10
    Notes
    [4] - Week 36 n=48 Week 48 n=47 Week 60 n=46
    [5] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 Linear Mixed Model for EASI
    Statistical analysis description
    Linear Mixed Model parameter estimates - EASI
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.27
         upper limit
    		 -2.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.4

    Secondary: IGA

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    End point title
    		 IGA
    End point description
    IGA does not have units.
    End point type
    Secondary
    End point timeframe
    IGA was measured at baseline and Weeks 4, 8, 12,20, 28,36,48 and 60.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52
    51
    Units: IGA
        arithmetic mean (standard deviation)
    1099.02 ± 290.37
    1043.16 ± 293.10
    Statistical analysis title
    		 IGA Area Under the Curve
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3785
    Method
    		 Area Under the Curve
    Confidence interval

    Secondary: O-SCORAD - Secondary

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    End point title
    		 O-SCORAD - Secondary
    End point description
    End point type
    Secondary
    End point timeframe
    O-SCORAD was measured at baseline and Weeks 4, 8, 12,20, 28,36,48 and 60.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [6]
    51 [7]
    Units: o-SCORAD
    arithmetic mean (standard error)
        Week 12
    26.53 ± 1.13
    31.32 ± 1.15
        Week 36
    27.09 ± 1.10
    25.64 ± 1.11
        Week 48
    27.37 ± 1.21
    22.80 ± 1.23
        Week 60
    27.64 ± 1.39
    19.96 ± 1.41
    Notes
    [6] - Week 36 n=48 Week 48 n=47 Week 60 n=46
    [7] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 Linear Mixed Model for O-SCORAD
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -7.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.5
         upper limit
    		 -4.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.82

    Secondary: POEM

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    End point title
    		 POEM
    End point description
    End point type
    Secondary
    End point timeframe
    All patients and/or parent/legal guardian will be asked to complete a diary during treatment and a separate diary during follow up.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    51
    51
    Units: POEM
    arithmetic mean (standard error)
        Week 12
    9.28 ± 0.72
    12.01 ± 0.72
        Week 36
    10.10 ± 0.72
    9.89 ± 0.72
        Week 48
    10.52 ± 0.73
    8.82 ± 0.73
        Week 60
    10.93 ± 0.75
    7.76 ± 0.75
    Statistical analysis title
    		 Linear Mixed Model parameter estimates – POEM
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -4.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.27
         upper limit
    		 -2.15
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.04
    Statistical analysis title
    		 POEM AUC results
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3773
    Method
    		 Area Under the Curve
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -375.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1214.61
         upper limit
    		 464.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    423.08

    Secondary: Number of parent-reported flares after treatment cessation

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    End point title
    		 Number of parent-reported flares after treatment cessation
    End point description
    The following analyses were restricted to those who completed more than 80% of each respective question within the participant diaries during the 24 weeks following treatment cessation.
    End point type
    Secondary
    End point timeframe
    Number of flares reported after treatment cessation.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    22
    26
    Units: Flares
        arithmetic mean (standard deviation)
    9.41 ± 5.40
    6.19 ± 4.22
    Statistical analysis title
    		 Mean number of patient/parent flares
    Statistical analysis description
    T-test comparing the mean number of patient/parent-reported flares between treatment groups following trial treatment cessation.
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0251
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 6.01

    Secondary: Number of participants who re-flared

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    End point title
    		 Number of participants who re-flared
    End point description
    End point type
    Secondary
    End point timeframe
    Number of participants who re-flared according to co-primary outcome 2 definition during the 24 weeks after treatment cessation.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52
    51
    Units: Re-flares
        Re-flare
    25
    18
        No re-flare
    27
    33
    Statistical analysis title
    		 Chi-square test comparing number of participants
    Statistical analysis description
    Chi-square test comparing number of participants who re-flared according to co-primary outcome 2 definition
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1884
    Method
    		 Chi-squared
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.77
         upper limit
    		 3.74

    Secondary: Proportion of participants achieving 50% improvement in the o-SCORAD index

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    End point title
    		 Proportion of participants achieving 50% improvement in the o-SCORAD index
    End point description
    End point type
    Secondary
    End point timeframe
    Proportion of participants achieving 50% improvement in the o-SCORAD index at 12, 36, 48, and 60 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [8]
    51 [9]
    Units: Participants
        Week 12
    25
    14
        Week 36
    27
    24
        Week 48
    16
    23
        Week 60
    22
    24
    Notes
    [8] - Week 12 n=52 Week 36 n=48 Week 48 n=47 Week 60 n=46
    [9] - Week 12 n=51 Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 Proportion of participants with 50% improvement
    Comparison groups
    Methotrexate v Ciclosporin
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [10]
    Method
    		 GLMM
    Parameter type
    		 Treatment Difference
    Point estimate
    1.47
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 2.34
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.44
    Notes
    [10] - P-value from the 50% improvement GLMM parameter estimates

    Secondary: Participants who withdraw from treatment because of AEs

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    End point title
    		 Participants who withdraw from treatment because of AEs
    End point description
    End point type
    Secondary
    End point timeframe
    Throughout the trial.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52
    51
    Units: Participants
        Withdrew
    4
    6
        Did not withdraw
    48
    45
    Statistical analysis title
    		 Withdraw from treatment because of AE
    Statistical analysis description
    Proportion of participants who withdraw from treatment because of AEs
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5256
    Method
    		 Fisher exact
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.17
         upper limit
    		 2.36

    Secondary: Quality of Life using CDLQI

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    End point title
    		 Quality of Life using CDLQI
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at Weeks 12, 36, 48 and 60.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    49 [11]
    49 [12]
    Units: CDLQI
    arithmetic mean (standard error)
        Week 12
    7.09 ± 0.76
    8.45 ± 0.76
        Week 36
    7.63 ± 0.58
    7.80 ± 0.59
        Week 48
    7.90 ± 0.61
    7.48 ± 0.62
        Week 60
    8.17 ± 0.70
    7.15 ± 0.72
    Notes
    [11] - Week 12 n=49 Week 36 n=48 Week 48 n=46 Week 60 n=47
    [12] - Week 12 n=49 Week 36 n=42 Week 48 n=41 Week 60 n=43
    Statistical analysis title
    		 CDLQI score
    Statistical analysis description
    Linear Mixed Model mean estimated differences CDLQI score
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    98
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1351
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.53
         upper limit
    		 0.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.31

    Secondary: IDQOL

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    End point title
    		 IDQOL
    End point description
    Due to the low numbers no formal statistical testing was carried out.
    End point type
    Secondary
    End point timeframe
    Measured at baseline, week 12, week 36, week 48 and Week 60
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    3 [13]
    9 [14]
    Units: IDQOL
    arithmetic mean (standard deviation)
        Week 12
    12.33 ± 5.51
    10.22 ± 4.84
        Week 36
    6.75 ± 8.18
    9.5 ± 6.66
        Week 48
    9.33 ± 3.51
    10.80 ± 6.53
        Week 60
    0 ± 0
    12.50 ± 0.71
    Notes
    [13] - Week 12 n=3 Week 36 n=4 Week 48 n=3 Week 60 n=0
    [14] - Week 12 n=9 Week 36 n=6 Week 48 n=5 Week 60 n=2
    No statistical analyses for this end point

    Secondary: DFI

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    End point title
    		 DFI
    End point description
    End point type
    Secondary
    End point timeframe
    Measured at baseline, Week 12, Week 36, Week 48 and Week 60.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    51 [15]
    51 [16]
    Units: DFI
    arithmetic mean (standard error)
        Week 12
    7.59 ± 0.88
    8.56 ± 0.88
        Week 36
    8.50 ± 0.73
    7.96 ± 0.73
        Week 48
    8.95 ± 0.75
    7.66 ± 0.76
        Week 60
    9.40 ± 0.83
    7.36 ± 0.85
    Notes
    [15] - Week 12 n=51 Week 36 n=48 Week 48 n=47 Week 60 n=47
    [16] - Week 12 n=51 Week 36 n=44 Week 48 n=44 Week 60 n=60
    Statistical analysis title
    		 Linear Mixed Model parameter estimates – DFI
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2369
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -1.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.57
         upper limit
    		 1.13
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.45

    Secondary: Association between FLG carriage and treatment response (EASI)

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    End point title
    		 Association between FLG carriage and treatment response (EASI)
    End point description
    End point type
    Secondary
    End point timeframe
    FLG measured at 12 , 36 and 60 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    46 [17]
    43 [18]
    Units: EASI
        arithmetic mean (standard error)
    27.42 ± 12.27
    23.46 ± 10.09
    Notes
    [17] - For EASI at week 12 n=46 For EASI at week 36 n=43 For EASI at week 60 n=42 result is for baseline
    [18] - For EASI at week 12 n=43 For EASI at week 36 n=39 For EASI at week 60 n=37 result is for baseline
    Statistical analysis title
    		 Linear model estimates for EASI score at 12 weeks
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.075
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -0.644
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.354
         upper limit
    		 0.067
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.357
    Statistical analysis title
    		 Linear model estimates for EASI score at 36 weeks
    Statistical analysis description
    This analysis has 82 patients included
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.572
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Diffe
    Point estimate
    0.205
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.515
         upper limit
    		 0.925
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.362
    Notes
    [19] - A total of 82 participants were included in this analysis.
    Statistical analysis title
    		 Linear model estimates for EASI score at 60 weeks
    Statistical analysis description
    There were 79 patients included in this analysis
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [20]
    P-value
    		 = 0.041
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment difference
    Point estimate
    0.877
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.037
         upper limit
    		 1.718
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.422
    Notes
    [20] - A total of 79 participants included in this analysis.

    Secondary: Association between FLG carriage and treatment response (OSCORAD)

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    End point title
    		 Association between FLG carriage and treatment response (OSCORAD)
    End point description
    End point type
    Secondary
    End point timeframe
    Analysis performed at 12,36 and 60 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    46 [21]
    43 [22]
    Units: OSCORAD
        arithmetic mean (standard deviation)
    46.83 ± 11.97
    42.77 ± 9.42
    Notes
    [21] - results are for Yes in CYA at baseline
    [22] - results are for Yes in MTX at baseline
    Statistical analysis title
    		 Linear model estimate for O-SCORAD at 12 weeks
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.049
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -6.838
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.631
         upper limit
    		 -0.046
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.416
    Statistical analysis title
    		 Linear model estimate for O-SCORAD at 36 weeks
    Statistical analysis description
    There are 82 patients in this analysis
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.586
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    1.922
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.067
         upper limit
    		 8.91
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.51
    Statistical analysis title
    		 Linear model estimate for O-SCORAD at 60 weeks
    Statistical analysis description
    There are 79 patients included in this analysis
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    8.827
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.287
         upper limit
    		 16.366
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.784

    Post-hoc: Proportion of participants achieving at least 50% improvement in EASI 50

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    End point title
    		 Proportion of participants achieving at least 50% improvement in EASI 50
    End point description
    End point type
    Post-hoc
    End point timeframe
    Proportion of participants achieving at least 50% improvement in EASI score at 12, 16, 36, 48 and 60 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [23]
    51 [24]
    Units: Patients
        Week 12
    35
    27
        Week36
    34
    40
        Week 48
    23
    35
        Week 60
    32
    34
    Notes
    [23] - Week 36 n=48 Week 48 n=47 Week 60 n= 46
    [24] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 50% improvement in EASI - GLMM parameter estimates
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0044
    Method
    		 GLMM
    Parameter type
    		 Treatment Difference
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.36
         upper limit
    		 1.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.4

    Post-hoc: Proportion of participants achieving at least 50% improvement in EASI 75

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    End point title
    		 Proportion of participants achieving at least 50% improvement in EASI 75
    End point description
    End point type
    Post-hoc
    End point timeframe
    Proportion of participants achieving at least 75% improvement in EASI score at 12, 16, 36, 48 and 60 weeks.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [25]
    51 [26]
    Units: Patients
        Week 12
    23
    10
        Week 36
    20
    21
        Week 48
    14
    21
        Week 60
    16
    21
    Notes
    [25] - Week 36 n=48 Week 48 n=47 Week 60 n=46
    [26] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 75% improvement in EASI - GLMM parameter estimates
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0003
    Method
    		 GLMM
    Parameter type
    		 Treatment Difference
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.7
         upper limit
    		 2.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.41

    Post-hoc: Proportion of participants achieving at least 50% improvement in EASI 90

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    End point title
    		 Proportion of participants achieving at least 50% improvement in EASI 90
    End point description
    End point type
    Post-hoc
    End point timeframe
    Proportion of participants achieving at least 90% improvement in EASI score at 12, 16, 36, 48 and 60 weeks
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [27]
    51 [28]
    Units: Patients
        Week 12
    4
    1
        Week 36
    5
    9
        Week 48
    3
    7
        Week 60
    2
    7
    Notes
    [27] - Week 36 n=48 Week 48 n=47 Week 60 n=46
    [28] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    Statistical analysis title
    		 90% improvement in EASI - GLMM parameter estimates
    Comparison groups
    Methotrexate v Ciclosporin
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0011
    Method
    		 GLMM
    Parameter type
    		 Treatment Difference
    Point estimate
    2.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 3.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.69

    Post-hoc: O-SCORAD-75

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    End point title
    		 O-SCORAD-75
    End point description
    End point type
    Post-hoc
    End point timeframe
    Proportion of participants achieving at least 75% improvement in O-SCORAD score at 12, 16, 36, 48 and 60 weeks.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [29]
    51 [30]
    Units: Patients
        Week 12
    6
    1
        Week 36
    3
    6
        Week 48
    3
    7
        Week 60
    6
    1
    Notes
    [29] - Week 36 n=47 Week 48 n=46 Week 60 n=52
    [30] - Week 36 n=45 Week 48 n=44 Week 60 n=51
    Statistical analysis title
    		 75% improvement in O-SCORAD - GLMM parameter estim
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    103
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0307
    Method
    		 GLMM
    Parameter type
    		 Treatment difference
    Point estimate
    1.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.16
         upper limit
    		 3.31
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.8

    Post-hoc: O-SCORAD-90

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    End point title
    		 O-SCORAD-90
    End point description
    End point type
    Post-hoc
    End point timeframe
    Proportion of participants achieving at least 90% improvement in O-SCORAD score at 12, 16, 36, 48 and 60 weeks.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    52 [31]
    51 [32]
    Units: Patients
        Week 12
    0
    0
        Week 36
    1
    2
        Week 48
    0
    1
        Week 60
    0
    1
    Notes
    [31] - Week 36 n=48 Week 48 n=47 Week 60 n=46
    [32] - Week 36 n=46 Week 48 n=45 Week 60 n=44
    No statistical analyses for this end point

    Post-hoc: EASI sensitivity analysis

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    End point title
    		 EASI sensitivity analysis
    End point description
    EASI, excluding those who restarted a systemic treatment
    End point type
    Post-hoc
    End point timeframe
    EASI Collected at as described in protocol.
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    51 [33]
    50 [34]
    Units: EASI
    arithmetic mean (standard error)
        Week 12
    12.30 ± 0.89
    15.43 ± 0.90
        Week 36
    12.83 ± 0.90
    10.97 ± 0.90
        Week 48
    13.10 ± 1.05
    8.74 ± 1.03
        Week 60
    13.36 ± 1.25
    6.51 ± 1.22
    Notes
    [33] - Week 36 n=44 Week 48 n=35 Week 60 n=28
    [34] - Week 36 n=44 Week 48 n=37 Week 60 n=32
    Statistical analysis title
    		 Linear Mixed Model parameter estimates – EASI,
    Statistical analysis description
    Linear Mixed Model parameter estimates – EASI, excluding those who restarted a systemic treatment
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    101
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -5.64
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.51
         upper limit
    		 -2.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.46

    Post-hoc: o-SCORAD sensitivity analysis

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    End point title
    		 o-SCORAD sensitivity analysis
    End point description
    End point type
    Post-hoc
    End point timeframe
    o-SCORAD collected at
    End point values
    		 Ciclosporin Methotrexate
    Number of subjects analysed
    51 [35]
    50 [36]
    Units: o-SCORAD
    arithmetic mean (standard error)
        Week 12
    26.44 ± 1.17
    31.32 ± 1.18
        Week 36
    26.76 ± 1.18
    25.27 ± 1.18
        Week 48
    26.91 ± 1.34
    22.25 ± 1.32
        Week 60
    27.07 ± 1.57
    19.23 ± 1.54
    Notes
    [35] - Week 36 n=44 Week 48 n=35 Week 60 n=28
    [36] - Week 36 n= 44 Week 48 n=37 Week 60 n=32
    Statistical analysis title
    		 Linear Mixed Model parameter estimates – o-SCORAD
    Statistical analysis description
    Linear Mixed Model mean estimated differences in o-SCORAD score, excluding those who restarted a systemic treatment
    Comparison groups
    Ciclosporin v Methotrexate
    Number of subjects included in analysis
    101
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Mixed models analysis
    Parameter type
    		 Treatment Difference
    Point estimate
    -8.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.76
         upper limit
    		 -4.35
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.88

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15
    Reporting groups
    Reporting group title
    Ciclosporin
    Reporting group description
    		 Patients should remain on the full treatment dose (4mg/kg/day for CyA) for the 12 weeks. After that, dose increases to a maximum of 5mg/kg/day or dose decreases are allowed, according to the treatment response.

    Reporting group title
    Methotrexate
    Reporting group description
    		 Patients will start on an initial test dose (0.1/mg/kg/week) for MTX (week 0) and then continue on the full treatment dose (0.4mg/kg/week for MTX – maximum dose of 25mg/week) from the following week (week 1), providing there have not been any significant side effects and the results from the safety bloods are acceptable.

    Serious adverse events
    		 Ciclosporin Methotrexate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 51 (9.80%)
    7 / 51 (13.73%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deafness bilateral
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 51 (3.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Eczema herpeticum
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral tonsillitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shingles
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ciclosporin Methotrexate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    48 / 51 (94.12%)
    47 / 51 (92.16%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 51 (5.88%)
    12 / 51 (23.53%)
         occurrences all number
    4
    35
    Pyrexia
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 51 (9.80%)
         occurrences all number
    6
    7
    Feeling cold
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    3
    Chest pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Influenza like illness
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Malaise
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Chest discomfort
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Feeling hot
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Pallor
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Seasonal allergy
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    Food allergy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Menstruation irregular
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Balanoposthitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Menstruation delayed
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Testicular swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 51 (9.80%)
    6 / 51 (11.76%)
         occurrences all number
    6
    7
    Oropharyngeal pain
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 51 (7.84%)
         occurrences all number
    6
    6
    Rhinorrhoea
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 51 (3.92%)
         occurrences all number
    3
    2
    Wheezing
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 51 (7.84%)
         occurrences all number
    0
    5
    Asthma
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 51 (5.88%)
         occurrences all number
    1
    3
    Epistaxis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Productive cough
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    Dyspnoea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Mood swings
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 51 (3.92%)
         occurrences all number
    1
    13
    Mood altered
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    3
    2
    Enuresis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    4
    Insomnia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    3
    Irritability
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Stress
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Glomerular filtration rate abnormal
         subjects affected / exposed
    14 / 51 (27.45%)
    8 / 51 (15.69%)
         occurrences all number
    17
    14
    Neutrophil count decreased
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 51 (3.92%)
         occurrences all number
    3
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 51 (5.88%)
         occurrences all number
    1
    5
    Blood creatine increased
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 51 (3.92%)
         occurrences all number
    2
    4
    Lymphocyte count decreased
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 51 (3.92%)
         occurrences all number
    3
    3
    Liver function test abnormal
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    4
    Haemoglobin decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    3
    Weight decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    Haematocrit decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase abnormal
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Blood alkaline phosphatase decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood creatine decreased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood pressure increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Blood sodium increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood urea increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Lymphocyte count increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Mean cell volume abnormal
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Platelet count increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Red blood cell count decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Foot fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Immunisation anxiety related reaction
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Sunburn
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    14 / 51 (27.45%)
    11 / 51 (21.57%)
         occurrences all number
    24
    27
    Dizziness
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Lethargy
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    6
    Syncope
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Cluster headache
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    2
    Burning sensation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 51 (5.88%)
         occurrences all number
    0
    4
    Hypoacusis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    0
    Eye disorders
    Eye discharge
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Vision blurred
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Eye irritation
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Eye swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Eyelid oedema
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Eyelid pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Ocular hyperaemia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 51 (17.65%)
    22 / 51 (43.14%)
         occurrences all number
    12
    35
    Abdominal pain upper
         subjects affected / exposed
    9 / 51 (17.65%)
    22 / 51 (43.14%)
         occurrences all number
    12
    35
    Abdominal pain
         subjects affected / exposed
    7 / 51 (13.73%)
    22 / 51 (43.14%)
         occurrences all number
    10
    35
    Vomiting
         subjects affected / exposed
    9 / 51 (17.65%)
    9 / 51 (17.65%)
         occurrences all number
    13
    11
    Diarrhoea
         subjects affected / exposed
    8 / 51 (15.69%)
    7 / 51 (13.73%)
         occurrences all number
    10
    8
    Mouth ulceration
         subjects affected / exposed
    0 / 51 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    0
    12
    Abdominal distension
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Dyspepsia
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Faeces discoloured
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Lip swelling
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain lower
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Aphthous ulcer
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Duodenogastric reflux
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Frequent bowel movements
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Gingival pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Lip pain
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Retching
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    22 / 51 (43.14%)
    15 / 51 (29.41%)
         occurrences all number
    45
    19
    Pruritus
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 51 (3.92%)
         occurrences all number
    4
    4
    rash
         subjects affected / exposed
    4 / 51 (7.84%)
    2 / 51 (3.92%)
         occurrences all number
    4
    2
    Alopecia
         subjects affected / exposed
    4 / 51 (7.84%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Acne
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Urticaria
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Blister
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Dermatitis atopic
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Renal and urinary disorders
    Micturition urgency
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Polyuria
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 51 (0.00%)
         occurrences all number
    3
    0
    Back pain
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Pain in extremity
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Arthralgia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 51 (13.73%)
    9 / 51 (17.65%)
         occurrences all number
    8
    9
    Eczema infected
         subjects affected / exposed
    6 / 51 (11.76%)
    6 / 51 (11.76%)
         occurrences all number
    8
    8
    Lower respiratory tract infection
         subjects affected / exposed
    5 / 51 (9.80%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 51 (5.88%)
         occurrences all number
    4
    3
    Molluscum contagiosum
         subjects affected / exposed
    3 / 51 (5.88%)
    3 / 51 (5.88%)
         occurrences all number
    3
    3
    Viral infection
         subjects affected / exposed
    0 / 51 (0.00%)
    6 / 51 (11.76%)
         occurrences all number
    0
    6
    Folliculitis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Skin infection
         subjects affected / exposed
    2 / 51 (3.92%)
    3 / 51 (5.88%)
         occurrences all number
    2
    3
    Tonsillitis
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 51 (1.96%)
         occurrences all number
    4
    1
    Herpes simplex
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Oral herpes
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 51 (3.92%)
         occurrences all number
    2
    2
    Staphylococcal infection
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 51 (1.96%)
         occurrences all number
    3
    1
    Ear infection
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 51 (3.92%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Herpes zoster
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Rhinitis
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 51 (1.96%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    2
    Conjunctivitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Localised infection
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Sinusitis
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 51 (1.96%)
         occurrences all number
    1
    1
    Varicella
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 51 (3.92%)
         occurrences all number
    0
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    2
    0
    Body tinea
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Campylobacter infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Croup infectious
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Eczema herpeticum
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Erythema infectiosum
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Furuncle
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Gingivitis
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Helicobacter infection
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Infected bite
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Lice infestation
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Rash pustular
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Staphylococcal skin infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Varicella zoster virus infection
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1
    Viral rash
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Vulvitis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 51 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 51 (5.88%)
    8 / 51 (15.69%)
         occurrences all number
    4
    11
    Iron deficiency
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 51 (1.96%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Oct 2015
    page 2 & 7 – change from Senior Lecturer to Reader for Dr Carsten Flohr page 22 – change to exclusion criteria 7 to include males and to say that an acceptable method of contraception must be used for 6 months after the last dose of study drug page 23 – addition of the following to the exclusion criteria: - Receiving treatment with medicines that are substrates for the multidrug efflux transporter P-glycoprotein or the organic anion transporter proteins (OATP) for which elevated plasma concentrations are associated with serious and/or life-threatening events; this includes bosentan, dabigatran etexilate and aliskiren. - Receiving treatment with products containing Hypericum perforatum (St. John's wort) - Receiving oral treatment with tacrolimus - Receiving oral treatment with everolimus and sirolimus - Receiving oral treatment with lercanidipine page 26 – section 6.5.2 has been amended to say that patients who develop an unacceptable toxicity based on the investigator’s judgement will be withdrawn. page 31 – text added to explain the dosing regimen for methotrexate page 34-36 – Details have been added to section 7.7.2 to describe any medications that are not permitted and any precautions that are required to be taken with regards to administration of concomitant medications.
    23 Oct 2015
    Page 2 – addition of qualifications for Carsten Flohr and Ashley Jones. Page 5 – title altered to ‘Professor’ for Leonie Taams Page 11 – Progressive Multifocal Leukoencephalopathy (PML), Tuberculosis (TB) and Thiopurine Methyltransferase (TPMT) added to Glossary Page 15 – schematic of study design altered to reflect new schedule and figures for recruitment corrected Page 16-17 – Further details added on why we are comparing ciclosporin with methotrexate. Page 18-20 – Further detail on risk:benefit ratio of trial interventions added Page 24 – Exclusion to reflect abnormal chest x-ray added to the exclusion criteria Page 27 – Details on steps in place to ensure blinding is maintained added Page 29 – Details added on the drug dosing for the trial Investigational Medicinal Products and information regarding chest x-rays required for patients with a risk of TB Page 31 – Information on when occasional monitoring of ciclosporin is recommended added Page 32-33 – Further details on precautions to be taken when prescribing and dispensing methotrexate added Page 34 – ‘New or worsening unexplained dyspnoea or cough’ added to the monitoring parameters for Methotrexate Page 36 – Information added with regards to avoiding ibuprofen whilst taking methotrexate and management of this if it occurs. Page 39 – window added for week 1 and 2. Page 40 – Table of study procedures altered to reflect new schedule. Page 41-45 – Visit summary altered to reflect new schedule Page 45 – Details on what is recorded in patient diary added Page 45 – Procedures for assessing safety updated to reflect new schedule Page 46 – Details on what is recorded in patient diary added Page 46 – ‘intervention vs control’ changed to ‘MTX vs CyA’ Page 59 – Patient information leaflets changed to patient information sheets
    17 Oct 2016
    - Minor clarifications and corrections - Clarification and further information added to eligibility criteria - Clarification to consent and screening process - Clarification of sample collection - Further detail added regarding treatment regimes - Addition of pregnancy CRF - Clarification of AE and SAE reporting period - Visit summary amended to reflect new summary -
    29 Jun 2017
    - Addition of pregnancy test during the baseline visit to confirm patient eligibility at the point of randomisation - Addition of POEM baseline questionnaire used to capture POEM data at baseline visit only - Addition of adverse event reporting procedures for patients discontinued from trial treatment but remain to be treated by their clinician on one of the trial interventions - Clarification of safety reporting - Addition of adverse event reporting procedures for patients discontinued from trial treatment but remain to be treated by their clinician on one of the trial interventions
    18 Feb 2019
    - Text added to refine co-primary outcome - Text added to refine the secondary endpoints - Addition of text highlighting importance of eligibility - Detail added to clarify collection of data for patients who discontinue trial treatment - Further detail added to the monitoring parameter table, to allow for temporary interruption to MTX - Text added to indicate which hospital collects tape striping and mechanistic samples. - Reference to Creatinine, Cystatin C, and urine NAG as being safety bloods removed - Additional text added to allow research nurses to contact patients in order to collect missing health resource use data. Addition of GP questionnaire to collect health resource use data. - Text added to refine the analysis of the co primary outcome

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37722926
    http://www.ncbi.nlm.nih.gov/pubmed/29727479
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