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    Clinical Trial Results:
    Randomised Control Trial of the Clinical Effectiveness, Safety and Cost Effectiveness of Adalimumab in Combination with Methotrexate for the Treatment of Juvenile Idiopathic Arthritis Associated Uveitis.

    Summary
    EudraCT number
    2010-021141-41
    Trial protocol
    GB  
    Global end of trial date
    14 Dec 2016

    Results information
    Results version number
    v2(current)
    This version publication date
    04 May 2019
    First version publication date
    23 Mar 2018
    Other versions
    v1
    Version creation reason
    • Changes to summary attachments
    During site closedown for the trial, data were identified for participants that had not been sent to CTRC by sites and subsequently were not present in the database at the time of data lock. The impact was assessed by the statistics team who confirmed the omitted data would have minimal impact on the trial results so therefore the database was not unlocked. This event was not considered a serious breach. Full details are described within the attached file note. The report has not changed.
    Summary report(s)
    Baseline Data
    Supplementary Material - Open Label Phase Results
    File note

    Trial information

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    Trial identification
    Sponsor protocol code
    CH/2008/3061
    Additional study identifiers
    ISRCTN number
    ISRCTN10065623
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Funding reference numbers: HTA 90/51/01; ARUK 19612
    Sponsors
    Sponsor organisation name
    University Hospitals Bristol NHS Foundation Trust
    Sponsor organisation address
    UH Bristol Education Centre, Level 3, Upper Maudlin Street, Bristol, United Kingdom, BS2 8AE
    Public contact
    Ashley Jones, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk
    Scientific contact
    Ashley Jones, Clinical Trials Research Centre, University of Liverpool, +44 151 795 8751, ctrcqa@liverpool.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-000366-PIP12-02
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare how effective the use of adalimumab, in combination with methotrexate versus methotrexate alone with regard to controlling disease activity in refractory uveitis associated with juvenile idiopathic arthritis. Please note: As stated in the protocol, the formal end of trial is defined as the date of final database lock which was on 02/08/17.
    Protection of trial subjects
    The first dose of IMP was administered by the research / clinical team looking after the patient. All participants or a family member were invited to self-administer the study treatment after the first dose and taught as such to do this under procedures in place within each participating centre for teaching this. The first dose they administered was also be under supervision of the clinical team, who ensured they are confident and able to carry out all parts of the procedure appropriately and accurately. This would allow patients to then have their remaining trial treatment in the familiar surroundings of their home to reduce distress. If they did not want to do this, then arrangements were put in place on an individual basis for ensuring trial medication is administered as prescribed. Study visits and study assessments were set around routine clinical care to minimise the inconvenience for patients and families, travel expenses were provided for visits outside of routine care that were specific for SYCAMORE.
    Background therapy
    All subjects to receive a stable dose of methotrexate
    Evidence for comparator
    Methotrexate (MTX) is well established as the first-line disease modifying agent in the management of JIA. MTX is also thought to be effective for JIA-associated uveitis in children with moderate-to-severe uveitis, but there have been no prospective randomised placebo-controlled trials of MTX or steroid regimens in JIA-associated uveitis. Adalimumab is a fully human monoclonal antibody engineered by gene technology that uses site-directed mutagenesis to enhance its binding efficiency to tumor necrosis factor (TNF). It does not contain nonhuman or artificial protein sequences. There are no prospective studies of efficacy and safety of anti-TNF agents in JIA-associated uveitis. In the randomised controlled trial of adalimumab in JIA that demonstrated safety and efficacy, the most commonly reported adverse events were infections and injection-site reactions. Serious adverse events considered possibly related to study drug by the investigator occurred in 14 patients.
    Actual start date of recruitment
    21 Oct 2011
    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: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    69
    Adolescents (12-17 years)
    21
    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
    The trial took place in 17 United Kingdom centres; 14 of these centres randomised at least one participant. The first patient was randomised on the 27th October 2011 and the last patient was randomised on the 31st March 2015.

    Pre-assignment
    Screening details
    There was a total of 332 patients assessed for eligibility from 519 screenings (patients could be screened on multiple occasions). 130 (39%) were eligible and 90 were consented and were randomised.

    Pre-assignment period milestones
    Number of subjects started
    90
    Number of subjects completed
    90

    Period 1
    Period 1 title
    Blinded Phase
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    This trial was placebo-controlled and all study assessments were carried out by health professionals, parents/carers and patients without knowledge of treatment allocation. The placebo solution for the injection was a clear, colourless solution presented in a single-use vial for the injection in volumes of 0.8mL. The packaging of the kit of adalimumab and placebo were identical. Each kit consisted of two vials of adalimumab or placebo in an outer carton.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab (blinded phase)
    Arm description
    Adalimumab subcutaneous injection every 2 weeks for 18 months. Participants in the adalimumab group who were still on treatment at the point of the TSC decision to unblind subsequently took part in an open-label phase of the trial. Placebo participants moved straight to follow-up. See attached summary for the results of any analyses including the open-label phase data.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    20mg for participants weighing <30kg; 40mg for participants weighing ≥ 30kg

    Arm title
    Placebo (blinded phase)
    Arm description
    Placebo subcutaneous injection every 2 weeks for 18 months
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo subcutaneous injection every 2 weeks for 18 months

    Number of subjects in period 1
    Adalimumab (blinded phase) Placebo (blinded phase)
    Started
    60
    30
    Completed
    58
    29
    Not completed
    2
    1
         Consent withdrawn by subject
    2
    1
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Adalimumab (follow-up)
    Arm description
    The original trial design included an 18 month treatment period followed by an 18 month follow-up period. If the patient was deemed to be classified as a treatment failure or discontinued their allocated treatment (either before or at 18 months) they were to enter into the follow-up period of the trial. During this follow-up period, patients were to be assessed at 3, 6, 9, 12, 15 and 18 months post treatment cessation. A later change to the study protocol (see More Information: Substantial Protocol Amendments section) allowed the follow-up period to be reduced from 18 months to 6 months. The assessments were then carried out at two follow-up visits at 3 months and 6 months post treatment cessation.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Placebo (follow-up)
    Arm description
    See above.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Adalimumab (follow-up) Placebo (follow-up)
    Started
    58
    29
    Completed
    58
    29

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adalimumab (blinded phase)
    Reporting group description
    Adalimumab subcutaneous injection every 2 weeks for 18 months. Participants in the adalimumab group who were still on treatment at the point of the TSC decision to unblind subsequently took part in an open-label phase of the trial. Placebo participants moved straight to follow-up. See attached summary for the results of any analyses including the open-label phase data.

    Reporting group title
    Placebo (blinded phase)
    Reporting group description
    Placebo subcutaneous injection every 2 weeks for 18 months

    Reporting group values
    Adalimumab (blinded phase) Placebo (blinded phase) Total
    Number of subjects
    60 30 90
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    46 23 69
        Adolescents (12-17 years)
    14 7 21
        Adults (18-64 years)
    0 0 0
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Age at randomisation
    Units: years
        arithmetic mean (standard deviation)
    9.07 ± 3.94 8.56 ± 3.79 -
    Gender categorical
    Gender
    Units: Subjects
        Female
    47 23 70
        Male
    13 7 20
    Number of study eyes
    Units: Subjects
        Unilateral
    43 22 65
        Bilateral
    17 8 25
    Weight (kg)
    Units: Subjects
        <30kg
    33 17 50
        >=30kg
    26 13 39
        Unobtainable
    1 0 1
    Type of JIA (Internation League of Associations for Rheumatology (ILAR) classification)
    Units: Subjects
        Extended oligoarthritis
    14 7 21
        Persistent oligoarthritis
    36 17 53
        Polyarthritis RF negative
    8 4 12
        Polyarthritis RF positive
    1 1 2
        Psoriatic arthritis
    1 1 2
    Anti-nuclear antibody
    Units: Subjects
        Negative
    24 10 34
        Positive
    33 15 48
        Not carried out
    3 5 8
    Double-stranded deoxyribonucleic acid
    Units: Subjects
        Negative
    47 22 69
        Positive
    3 2 5
        Not carried out
    10 6 16
    Rheumatoid factor
    Units: Subjects
        Negative
    46 20 66
        Positive
    1 3 4
        Not carried out
    13 7 20
    Disease duration
    6 adalimumab and 4 placebo participants had unobtainable disease duration.
    Units: years
        arithmetic mean (standard deviation)
    5.58 ± 3.69 4.81 ± 3.19 -
    Physician global assessment of disease activity
    2 adalimumab and 1 placebo participants had unobtainable physician global assessment of disease activity.
    Units: Physician global assessment
        arithmetic mean (standard deviation)
    0.76 ± 1.48 0.83 ± 1.09 -
    Active joint count [all joints]
    Units: Active joints
        arithmetic mean (standard deviation)
    0.57 ± 2.03 1.1 ± 2.23 -
    Swollen joint count [all joints]
    Units: Swollen joints
        arithmetic mean (standard deviation)
    0.55 ± 1.66 1 ± 1.55 -

    End points

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    End points reporting groups
    Reporting group title
    Adalimumab (blinded phase)
    Reporting group description
    Adalimumab subcutaneous injection every 2 weeks for 18 months. Participants in the adalimumab group who were still on treatment at the point of the TSC decision to unblind subsequently took part in an open-label phase of the trial. Placebo participants moved straight to follow-up. See attached summary for the results of any analyses including the open-label phase data.

    Reporting group title
    Placebo (blinded phase)
    Reporting group description
    Placebo subcutaneous injection every 2 weeks for 18 months
    Reporting group title
    Adalimumab (follow-up)
    Reporting group description
    The original trial design included an 18 month treatment period followed by an 18 month follow-up period. If the patient was deemed to be classified as a treatment failure or discontinued their allocated treatment (either before or at 18 months) they were to enter into the follow-up period of the trial. During this follow-up period, patients were to be assessed at 3, 6, 9, 12, 15 and 18 months post treatment cessation. A later change to the study protocol (see More Information: Substantial Protocol Amendments section) allowed the follow-up period to be reduced from 18 months to 6 months. The assessments were then carried out at two follow-up visits at 3 months and 6 months post treatment cessation.

    Reporting group title
    Placebo (follow-up)
    Reporting group description
    See above.

    Primary: Blinded Phase: Time to treatment failure

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    End point title
    Blinded Phase: Time to treatment failure
    End point description
    Treatment failure was classified as occurrence of one of the following: 1) Anterior segment inflammatory score grade (SUN criteria) following at least 3 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria, or any of the concomitant medications not allowed. 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks Full details on the treatment failure criteria can be found within the protocol.
    End point type
    Primary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Treatment Failures
        Failed treatment
    14
    17
        Censored
    46
    13
    Attachments
    Untitled (Filename: Blinded Phase - Primary Outcome.pdf)
    Statistical analysis title
    Time to treatment failure
    Comparison groups
    Placebo (blinded phase) v Adalimumab (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Logrank
    Parameter type
    Cox proportional hazard
    Point estimate
    0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.12
         upper limit
    0.51

    Secondary: Blinded phase: Number of participants failing treatment

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    End point title
    Blinded phase: Number of participants failing treatment
    End point description
    Treatment failure was classified as occurrence of one of the following: 1) Anterior segment inflammatory score grade (SUN criteria) following at least 3 months of therapy. 2) Use of Concomitant Medications: At any time, requirement to use concomitant medications in manner out with pre-defined acceptable criteria, or any of the concomitant medications not allowed. 3) Intermittent or continuous suspension of study treatment (adalimumab/placebo) for a cumulative period longer than 4 weeks Full details on the treatment failure criteria can be found within the protocol.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Treatment Failures
        Failed treatment
    14
    17
        Did not fail treatment
    46
    13
    Statistical analysis title
    Number of participants failing treatment
    Comparison groups
    Placebo (blinded phase) v Adalimumab (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    Chi-squared
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    0.72

    Secondary: Blinded phase: Total oral corticosteroid dose

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    End point title
    Blinded phase: Total oral corticosteroid dose
    End point description
    The total dose is calculated by summing the daily doses and standardised to per patient years.
    End point type
    Secondary
    End point timeframe
    Participants are assessed from randomisation until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    5 [1]
    1 [2]
    Units: miligrams per patient year
    number (not applicable)
        Total dose per patient years
    804.31
    3767.74
    Notes
    [1] - 5 participants were taking oral corticosteroids at randomisation.
    [2] - 1 participant was taking oral corticosteroids at randomisation.
    Statistical analysis title
    Total oral corticosteroid dose
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Poisson regression
    Parameter type
    Rate ratio
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.23

    Secondary: Blinded phase: Reduction in systemic corticosteroid dose from entry dose to 0mg

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    End point title
    Blinded phase: Reduction in systemic corticosteroid dose from entry dose to 0mg
    End point description
    Reduction in systemic corticosteroid dose from entry dose to 0mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at randomisation. The planned analysis was a competing risks time-to-event model. No comparative analysis was able to be performed due to the fact that statistical algorithm did not converge.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    5 [3]
    1 [4]
    Units: Events
        Reduced dose
    3
    1
        Censored
    2
    0
    Notes
    [3] - 5 participants were prescribed systemic corticosteroids >0mg at baseline.
    [4] - 1 participant was prescribed systemic corticosteroids >0mg at baseline.
    No statistical analyses for this end point

    Secondary: Blinded phase: Rate of systemic corticosteroid dose from entry dose

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    End point title
    Blinded phase: Rate of systemic corticosteroid dose from entry dose
    End point description
    The total dose is calculated by summing the daily doses and standardised to per patient years.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    5 [5]
    1 [6]
    Units: miligrams per patient years
    number (not applicable)
        Total dose per patient years
    804.31
    3767.74
    Notes
    [5] - 5 participants were taking systemic corticosteroids at randomisation.
    [6] - 1 participant was taking systemic corticosteroids at randomisation.
    Statistical analysis title
    Rate of systemic corticosteroids from entry dose
    Comparison groups
    Placebo (blinded phase) v Adalimumab (blinded phase)
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Poisson regression
    Parameter type
    Rate ratio
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    0.23

    Secondary: Blinded phase: Time to reduction to <2 drops in topical corticosteroids

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    End point title
    Blinded phase: Time to reduction to <2 drops in topical corticosteroids
    End point description
    Time to reduction to < 2 drops for those patients already on >= 2 drops at randomisation.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    45 [7]
    18 [8]
    Units: Events
        Reduced drops
    24
    3
        Censored
    21
    15
    Notes
    [7] - 45 participants were on ≥ 2 drops per day at baseline.
    [8] - 18 participants were on ≥ 2 drops per day at baseline.
    Statistical analysis title
    Time to reduction to <2 drops
    Statistical analysis description
    This was a competing risks analysis, accounting for the time to treatment failure.
    Comparison groups
    Placebo (blinded phase) v Adalimumab (blinded phase)
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Fine and Gray
    Parameter type
    Hazard ratio (HR)
    Point estimate
    3.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.18
         upper limit
    25.2

    Secondary: Blinded phase: Need for pulsed corticosteroid

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    End point title
    Blinded phase: Need for pulsed corticosteroid
    End point description
    Need for pulsed corticosteroid.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Needed pulsed corticosteroids
    2
    1
        Did not need pulsed corticosteroids
    58
    29
    Statistical analysis title
    Need for pulsed corticosteroid
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.99
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.09
         upper limit
    10.59

    Secondary: Blinded phase: Optic and Ocular: Number of participants with disease flares following a minimum of 3 months of disease control

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with disease flares following a minimum of 3 months of disease control
    End point description
    Disease control is when a patient has a score of “0” for the field “AC cells (SUN)” for 3 months (12 weeks ± 7 days i.e. at least 11 weeks) from randomisation within each eligible eye and has had at least one topical treatment during this time. Disease flares are defined as an increase in the “AC cells (SUN)” score at two consecutive visits at least 4 weeks apart. Two analyses were performed for this outcome: 3 months disease control and a flare in at least one eye, and 3 months disease control in both eyes and a flare in at least one eye. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Disease flare
    5
    1
        No disease flare
    55
    29
    Statistical analysis title
    Disease flares following 3 months disease control
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.31
         upper limit
    20.45

    Secondary: Blinded phase: Optic and Ocular: Number of participants with disease flares within the first 3 months of the study

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with disease flares within the first 3 months of the study
    End point description
    Disease flare is defined by worsening based on SUN criteria. Two analyses were due to be performed for this outcome: disease flare in at least one eye, and disease flare in both eyes. No participants who had a flare were eligible on both eyes and therefore the second analysis was not possible.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Disease flare
    0
    3
        No disease flare
    60
    27
    Statistical analysis title
    Disease flare within first 3 months
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    1.36

    Secondary: Blinded phase: Optic and Ocular: Visual acuity as measured by age-appropriate LogMAR assessment

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    End point title
    Blinded phase: Optic and Ocular: Visual acuity as measured by age-appropriate LogMAR assessment
    End point description
    Change in assessment over time. Summary tables showing the number of assessments at each time point have been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: LogMAR
    arithmetic mean (standard deviation)
        Best-case: Baseline
    0.04 ± 0.15
    0.06 ± 0.12
        Best-case: 1 month
    0.03 ± 0.17
    0.02 ± 0.16
        Best-case: 2 months
    0.02 ± 0.17
    0.05 ± 0.18
        Best-case: 3 months
    0.00 ± 0.16
    0.01 ± 0.11
        Best-case: 6 months
    0.02 ± 0.20
    0.05 ± 0.16
        Best-case: 9 months
    -0.01 ± 0.14
    0.00 ± 0.17
        Best-case: 12 months
    -0.01 ± 0.14
    0.03 ± 0.14
        Best-case: 15 months
    0.00 ± 0.14
    0.00 ± 0.26
        Best-case: 18 months
    0.02 ± 0.13
    0.02 ± 0.21
        Worst-case: Baseline
    0.05 ± 0.16
    0.08 ± 0.12
        Worst-case: 1 month
    0.04 ± 0.18
    0.06 ± 0.17
        Worst-case: 2 months
    0.04 ± 0.19
    0.06 ± 0.18
        Worst-case: 3 months
    0.02 ± 0.20
    0.03 ± 0.12
        Worst-case: 6 months
    0.03 ± 0.20
    0.07 ± 0.19
        Worst-case: 9 months
    -0.01 ± 0.14
    0.04 ± 0.20
        Worst-case: 12 months
    0.00 ± 0.14
    0.08 ± 0.17
        Worst-case: 15 months
    0.00 ± 0.13
    0.00 ± 0.26
        Worst-case: 18 months
    0.04 ± 0.11
    0.02 ± 0.21
    Attachments
    Untitled (Filename: Blinded Phase - LogMAR.pdf)
    Statistical analysis title
    Joint Modelling for LogMAR (best-case)
    Statistical analysis description
    Joint modelling of LogMAR estimating longitudinal treatment effects adjusted for dropout due to treatment failure. In this analysis, when only one eye was involved the single LogMAR value was used. When there were two eyes involved, the best LogMAR measurement was used (the minimum of the 2 values).
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.51
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.02
    Statistical analysis title
    Joint Modelling for LogMAR (worst-case)
    Statistical analysis description
    Joint modelling of LogMAR estimating longitudinal treatment effects adjusted for dropout due to treatment failure. In this analysis, when only one eye was involved the single LogMAR value was used. When there were two eyes involved, the worst LogMAR measurement was used (the maximum of the 2 values).
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.07
         upper limit
    0.02

    Secondary: Blinded phase: Optic and Ocular: Number of participants with resolution of associated optic nerve

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with resolution of associated optic nerve
    End point description
    Assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) where available. Two analyses were due to be performed for this outcome: resolution in at least 1 eye, and resolution in both eyes. There were no participants who had associated optic nerve at baseline or developed this during the course of the study in the placebo group. It was, therefore, not possible to carry out either of the planned statistical tests of these data.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    4 [9]
    0 [10]
    Units: Events
        Resolved
    2
        Not resolved
    2
    Notes
    [9] - There were 4 participants who had associated optic nerve at baseline or developed it later.
    [10] - There were 0 participants who had associated optic nerve at baseline or developed it later.
    No statistical analyses for this end point

    Secondary: Blinded phase: Optic and Ocular: Number of participants with resolution of macular oedema

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with resolution of macular oedema
    End point description
    Assessed by slit lamp biomicroscopy or optical coherence tomography (OCT) where available. Two analyses were performed for this outcome: resolution in at least 1 eye, and resolution in both eyes. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    4 [11]
    2 [12]
    Units: Events
        Resolved
    3
    0
        Not resolved
    1
    2
    Attachments
    Untitled (Filename: Blinded Phase - Macular Oedema.pdf)
    Notes
    [11] - There were 4 participants who had MO at baseline or developed it later.
    [12] - There were 2 participants who had MO at baseline or developed it later.
    Statistical analysis title
    Resolution of macular oedema
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.4
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    74.52

    Secondary: Blinded phase: Optic and Ocular: Number of participants with disease control for 3 months

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with disease control for 3 months
    End point description
    Disease control is defined as zero cells, with topical treatment for 3 months. Two analyses were performed for this outcome: disease control in at least 1 eye, and disease control in both eyes. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Disease control
    23
    2
        No disease control
    37
    28
    Attachments
    Untitled (Filename: Blinded Phase - Number of participants with disease control for 3 months.pdf)
    Statistical analysis title
    Disease control for 3 months
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    5.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.45
         upper limit
    22.78

    Secondary: Blinded phase: Optic and Ocular: Number of participants with disease control for 6 months

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    End point title
    Blinded phase: Optic and Ocular: Number of participants with disease control for 6 months
    End point description
    Disease control is defined as zero cells, with topical treatment for 6 months. Two analyses were performed for this outcome: disease control in at least 1 eye, and disease control in both eyes. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Disease control
    17
    1
        No disease control
    43
    29
    Attachments
    Untitled (Filename: Blinded Phase - Number of participants with disease control for 6 months.pdf)
    Statistical analysis title
    Disease control 6 months
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    8.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.19
         upper limit
    60.87

    Secondary: Blinded phase: Optic and Ocular: Number of participants entering disease remission for 3 months

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    End point title
    Blinded phase: Optic and Ocular: Number of participants entering disease remission for 3 months
    End point description
    Disease remission is defined as zero cells without topical treatment for 3 months. Two analyses were performed for this outcome: disease remission in at least 1 eye, and disease remission in both eyes. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Remission
    15
    1
        No remission
    45
    29
    Statistical analysis title
    Disease remission for 3 months
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.02
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.04
         upper limit
    54.12

    Secondary: Blinded phase: Optic and Ocular: Number of participants entering disease remission for 6 months

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    End point title
    Blinded phase: Optic and Ocular: Number of participants entering disease remission for 6 months
    End point description
    Disease remission is defined as zero cells without topical treatment for 6 months. Two analyses were performed for this outcome: disease remission in at least 1 eye, and disease remission in both eyes. The latter has been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Remission
    13
    0
        No remission
    47
    30
    Attachments
    Untitled (Filename: Blinded Phase - Number of participants with disease remission for 6 months.pdf)
    Statistical analysis title
    Disease remission 6 months
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    13.72
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.84
         upper limit
    223.26

    Secondary: Blinded phase: Optic and Ocular: Duration of sustaining inactive disease

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    End point title
    Blinded phase: Optic and Ocular: Duration of sustaining inactive disease
    End point description
    Inactive disease is defined as zero cells with or without topical treatment.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Days
        least squares mean (standard error)
    180.91 ± 16.81
    16.36 ± 23.79
    Statistical analysis title
    Duration of inactive disease
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    164.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    104.41
         upper limit
    224.69

    Secondary: Blinded phase: Quality of life assessments: Childhood Health Questionnaire (CHQ)

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    End point title
    Blinded phase: Quality of life assessments: Childhood Health Questionnaire (CHQ)
    End point description
    The CHQ consists of two scores: Physical score (PhS) Psychosocial score (PsS) Summary tables showing the number of assessments at each time point have been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    53 [13]
    22 [14]
    Units: CHQ
    arithmetic mean (standard deviation)
        PhS: Baseline
    43.20 ± 11.84
    40.48 ± 16.36
        PhS: 1 month
    45.54 ± 11.29
    44.73 ± 12.10
        PhS: 2 months
    47.54 ± 10.69
    43.65 ± 15.56
        PhS: 3 months
    46.50 ± 13.13
    47.35 ± 7.97
        PhS: 6 months
    47.16 ± 11.84
    41.95 ± 15.79
        PhS: 9 months
    47.50 ± 11.26
    45.20 ± 14.77
        PhS: 12 months
    47.29 ± 13.06
    53.09 ± 4.79
        PhS: 15 months
    42.85 ± 15.88
    55.75 ± 2.48
        PhS: 18 months
    45.92 ± 12.06
    53.77 ± 9.71
        PsS: Baseline
    51.17 ± 9.53
    49.48 ± 7.55
        PsS: 1 month
    51.06 ± 10.36
    50.01 ± 10.27
        PsS: 2 months
    53.02 ± 10.00
    50.20 ± 10.75
        PsS: 3 months
    54.12 ± 9.02
    54.21 ± 8.57
        PsS: 6 months
    53.94 ± 9.79
    49.68 ± 11.56
        PsS: 9 months
    55.82 ± 6.84
    50.26 ± 13.72
        PsS: 12 months
    54.08 ± 9.22
    54.18 ± 8.83
        PsS: 15 months
    53.56 ± 7.76
    53.27 ± 11.83
        PsS: 18 months
    53.58 ± 11.71
    47.25 ± 18.64
    Attachments
    Untitled (Filename: Blinded Phase - CHQ.pdf)
    Notes
    [13] - 53 had a baseline measurement.
    [14] - 22 had a baseline assessment.
    Statistical analysis title
    CHQ: Psychosocial subscale (PsS)
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout due to treatment failure.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.15
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    2.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.44
         upper limit
    5.4
    Statistical analysis title
    CHQ: Physical subscale (PhS)
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout due to treatment failure.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    75
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.55
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    1.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.41
         upper limit
    5.05

    Secondary: Blinded phase: Quality of life assessments: Childhood Health Assessment Questionnaire (CHAQ)

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    End point title
    Blinded phase: Quality of life assessments: Childhood Health Assessment Questionnaire (CHAQ)
    End point description
    The overall index is calculated by summing the overall scores for each of the categories in the CHAQ and dividing by the number of categories answered. This will give a score between 0 and 3. Summary tables showing the number of assessments at each time point have been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    59 [15]
    28 [16]
    Units: CHAQ
    arithmetic mean (standard deviation)
        Baseline
    0.52 ± 0.64
    0.48 ± 0.49
        1 month
    0.41 ± 0.56
    0.60 ± 0.55
        2 months
    0.38 ± 0.53
    0.54 ± 0.59
        3 months
    0.36 ± 0.58
    0.37 ± 0.47
        6 months
    0.36 ± 0.61
    0.46 ± 0.63
        9 months
    0.35 ± 0.63
    0.36 ± 0.57
        12 months
    0.33 ± 0.60
    0.09 ± 0.15
        15 months
    0.43 ± 0.58
    0.03 ± 0.04
        18 months
    0.30 ± 0.48
    0.03 ± 0.05
    Attachments
    Untitled (Filename: Blinded Phase - CHAQ.pdf)
    Notes
    [15] - 59 had a baseline assessment.
    [16] - 28 had a baseline assessment.
    Statistical analysis title
    CHAQ
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout due to treatment failure.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.09
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.31
         upper limit
    0.02

    Secondary: Blinded phase: American College of Rheaumatology (ACR) score

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    End point title
    Blinded phase: American College of Rheaumatology (ACR) score
    End point description
    The 6 paediatric core set criteria assessed at each study visit are:  Physician global assessment of disease activity (10 cm visual analogue scale).  Parent/patient assessment of overall well-being (10 cm visual analogue scale).  Functional ability (Childhood Health Assessment Questionnaire, CHAQ).  Number of joints with active arthritis.  Number of joints with limited range of movement.  Erythrocyte sedimentation rate. Summary tables showing the number of assessments at each time point have been uploaded as a supplementary file. The ACR Paediatric 30, 50, 70, 90 and 100 levels are defined as 30%, 50%, 70%, 90% and 100% improvement, respectively, in a minimum of three variables in the core set with worsening of one variable by no more than 30% as defined in the ACR criteria. The frequencies below show the number of participants who achieved each ACR level.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    46 [17]
    25 [18]
    Units: ACR frequency
    number (not applicable)
        ACR30: 1 month
    12
    7
        ACR30: 2 months
    16
    8
        ACR30: 3 months
    16
    6
        ACR30: 6 months
    13
    3
        ACR30: 9 months
    10
    1
        ACR30: 12 months
    12
    2
        ACR30: 15 months
    8
    1
        ACR30: 18 months
    9
    1
        ACR50: 1 month
    7
    7
        ACR50: 2 months
    10
    7
        ACR50: 3 months
    13
    5
        ACR50: 6 months
    11
    3
        ACR50: 9 months
    9
    1
        ACR50: 12 months
    10
    2
        ACR50: 15 months
    6
    1
        ACR50: 18 months
    8
    1
        ACR70: 1 month
    2
    5
        ACR70: 2 months
    5
    3
        ACR70: 3 months
    9
    3
        ACR70: 6 months
    9
    3
        ACR70: 9 months
    7
    1
        ACR70: 12 months
    5
    1
        ACR70: 15 months
    5
    1
        ACR70: 18 months
    5
    1
        ACR90: 1 month
    2
    1
        ACR90: 2 months
    3
    1
        ACR90: 3 months
    7
    2
        ACR90: 6 months
    6
    2
        ACR90: 9 months
    7
    1
        ACR90: 12 months
    5
    1
        ACR90: 15 months
    4
    1
        ACR90: 18 months
    3
    1
        ACR100: 1 month
    1
    0
        ACR100: 2 months
    1
    1
        ACR100: 3 months
    2
    1
        ACR100: 6 months
    2
    1
        ACR100: 9 months
    5
    0
        ACR100: 12 months
    3
    0
        ACR100: 15 months
    1
    0
        ACR100: 18 months
    1
    0
    Attachments
    Untitled (Filename: Blinded Phase - ACR.pdf)
    Notes
    [17] - There were 46 participants with a result at 1 month; see supp. tables for totals at later timepoints
    [18] - There were 25 participants with a result at 1 month; see supp. tables for totals at later timepoints
    Statistical analysis title
    ACR30
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.98
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.37
         upper limit
    1.59
    Statistical analysis title
    ACR50
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.37
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.15
         upper limit
    0.77
    Statistical analysis title
    ACR70
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.08
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.7
         upper limit
    0.46
    Statistical analysis title
    ACR90
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.72
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.22
         upper limit
    1.39
    Statistical analysis title
    ACR100
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.65
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.32
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.85
         upper limit
    1.17

    Secondary: Blinded phase: Number of participants undergoing disease flares

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    End point title
    Blinded phase: Number of participants undergoing disease flares
    End point description
    For this secondary outcome, ‘disease flare’ refers to a flare of arthritis rather than the eye. The definition of ‘disease flare’ is a worsening of 30% or more in 3 or more of the 6 variables of the JIA core set , with no more than one variable improving by 30% or more.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Disease flare
    0
    3
        No disease flare
    60
    27
    Statistical analysis title
    Disease flare
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.004
         upper limit
    1.36

    Secondary: Blinded phase: Number of participants with minimum disease activity

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    End point title
    Blinded phase: Number of participants with minimum disease activity
    End point description
    Minimum disease activity is defined for those with Oligoarthritis and Polyarthritis.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    59 [19]
    29 [20]
    Units: Events
        Minimum disease activity
    19
    4
        No minimum disease activity
    40
    25
    Notes
    [19] - There were 59 participants with Oligoarticular JIA or Polyarticular JIA.
    [20] - There were 29 participants with Oligoarticular JIA or Polyarticular JIA.
    Statistical analysis title
    Minimum disease activity
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08
    Method
    Chi-squared
    Parameter type
    Risk ratio (RR)
    Point estimate
    2.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.87
         upper limit
    6.24

    Secondary: Blinded phase: Number of participants requiring change in biologic and/or DMARD therapy for arthritis due to failure to respond

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    End point title
    Blinded phase: Number of participants requiring change in biologic and/or DMARD therapy for arthritis due to failure to respond
    End point description
    DMARDs are disease-modifying anti-rheumatic drugs.
    End point type
    Secondary
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Events
        Change in therapy
    2
    1
        No change in therapy
    58
    29
    Statistical analysis title
    Number of participants requiring change in DMARDs
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.99
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.2
         upper limit
    5.09

    Secondary: Blinded phase: Participants score of the Juvenile Arthritis Disease Activity Score (JADAS)

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    End point title
    Blinded phase: Participants score of the Juvenile Arthritis Disease Activity Score (JADAS)
    End point description
    The JADAS is comprised of four components: -physician global assessment of disease activity,  -parent/patient global assessment of well-being,  -active joint count, in 27, 71 or 10 joints,  -erythrocyte sedimentation rate (ESR). The JADAS is calculated as a sum of scores giving global scores of 0-57, 0-101 and 0-40 for the JADAS-27, JADAS-71 and JADAS-10 respectively. Summary tables showing the number of assessments at each time point have been uploaded as a supplementary file.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: JADAS
    arithmetic mean (standard deviation)
        JADAS10: Baseline
    3.48 ± 4.20
    4.51 ± 5.61
        JADAS10: 1 month
    2.03 ± 2.31
    3.12 ± 3.84
        JADAS10: 2 months
    1.62 ± 2.29
    3.72 ± 5.76
        JADAS10: 3 months
    1.54 ± 2.13
    3.56 ± 4.64
        JADAS10: 6 months
    1.78 ± 2.44
    3.02 ± 3.80
        JADAS10: 9 months
    1.12 ± 1.51
    1.42 ± 1.24
        JADAS10: 12 months
    1.46 ± 2.35
    0.20 ± 0.26
        JADAS10: 15 months
    1.07 ± 1.28
    1.33 ± 0.97
        JADAS10: 18 months
    1.62 ± 1.94
    1.50 ± 1.31
        JADAS27: Baseline
    3.29 ± 3.89
    3.65 ± 4.41
        JADAS27: 1 month
    1.92 ± 1.94
    2.59 ± 2.71
        JADAS27: 2 months
    1.62 ± 2.29
    3.43 ± 5.40
        JADAS27: 3 months
    1.49 ± 1.97
    3.25 ± 4.04
        JADAS27: 6 months
    1.73 ± 2.34
    3.02 ± 3.80
        JADAS27: 9 months
    1.12 ± 1.51
    1.42 ± 1.24
        JADAS27: 12 months
    1.46 ± 2.35
    0.20 ± 0.26
        JADAS27: 15 months
    1.02 ± 1.24
    1.33 ± 0.97
        JADAS27: 18 months
    1.62 ± 1.94
    1.50 ± 1.31
        JADAS71: Baseline
    3.54 ± 4.43
    4.24 ± 5.95
        JADAS71: 1 month
    2.03 ± 2.31
    3.29 ± 4.38
        JADAS71: 2 months
    1.62 ± 2.29
    3.72 ± 5.76
        JADAS71: 3 months
    1.54 ± 2.13
    3.79 ± 5.23
        JADAS71: 6 months
    1.78 ± 2.44
    3.02 ± 3.80
        JADAS71: 9 months
    1.12 ± 1.51
    1.42 ± 1.24
        JADAS71: 12 months
    1.46 ± 2.35
    0.20 ± 0.26
        JADAS71: 15 months
    1.07 ± 1.28
    1.33 ± 0.97
        JADAS71: 18 months
    1.62 ± 1.94
    1.50 ± 1.31
    Attachments
    Untitled (Filename: Blinded Phase - JADAS.pdf)
    Statistical analysis title
    JADAS10
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0.01
    Statistical analysis title
    JADAS27
    Statistical analysis description
    Joint modelling for estimating longitudinal treatment effects adjusted for dropout.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.08
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.34
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.76
         upper limit
    0.03
    Statistical analysis title
    JADAS71
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.78
         upper limit
    0.004

    Secondary: Blinded phase: Compliance according to participant diaries

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    End point title
    Blinded phase: Compliance according to participant diaries
    End point description
    Treatment diaries were used to estimate participant compliance by dividing the number of doses recorded as taken in the treatment diary by the expected number of doses the participant should have taken (according to the time the participant was on treatment). No formal statistical analysis was undertaken.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -withdrawal -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: percent
    number (not applicable)
        Compliance
    84
    74
    No statistical analyses for this end point

    Secondary: Blinded phase: Compliance according to accountability logs

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    End point title
    Blinded phase: Compliance according to accountability logs
    End point description
    Accountability logs were used to provide another estimate of adalimumab and placebo compliance by dividing the sum of the number of vials returned used and the number of missing vials, by the number of vials issued.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -withdrawal -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: percent
    number (not applicable)
        Compliance
    94
    90
    No statistical analyses for this end point

    Secondary: Blinded phase: Laboratory parameters

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    End point title
    Blinded phase: Laboratory parameters
    End point description
    The parameters reported on for haematological assessments are:  -Heamatocrit  -Haemoglobin  -Red blood cell count  -White blood cell count  -Neutrophils  -Lymphocytes  -Monocytes  -Basophils  -Eosinophils  -Platelet count  -Erythrocyte sedimentation rate  -Plasma viscosity (only done if ESR not available The parameters reported on for biochemical assessments are:  -C- Reactive protein (CRP)  -Urea  -Creatinine  -Sodium  -Potassium  -Calcium  -Inorganic phosphate  -Glucose  -Chloride  -Bicarbonate  -Total bilirubin  -Alanine aminotransferase (ALT)  -Aspartate aminotransferase (AST) The parameters reported on for urinalysis are:  -Protein  -Glucose  -Blood  -Leukocyte esterase  -Specific gravity  -pH Supplementary tables summarising the data have been uploaded.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: See supplementary tables.
    60
    30
    Attachments
    Untitled (Filename: Blinded Phase - Laboratory Parameters.pdf)
    No statistical analyses for this end point

    Secondary: Blinded phase: Incremental cost-effectiveness and cost utility

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    End point title
    Blinded phase: Incremental cost-effectiveness and cost utility
    End point description
    End point type
    Secondary
    End point timeframe
    This analysis is reported separately by Health Economists at the Universtiy of Bangor. See HTA report for full details upon publication.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    60
    30
    Units: Unit costs
    60
    30
    No statistical analyses for this end point

    Secondary: Follow-up phase: Use of corticosteroids over duration of study period (blinded, open label and follow up phase)

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    End point title
    Follow-up phase: Use of corticosteroids over duration of study period (blinded, open label and follow up phase)
    End point description
    The total dose is calculated separately for the treatment phase and follow ­up period, by summing the daily doses of each oral treatment on the Concomitant Medication Form taken during each period. The total dose for each time­ period of interest (treatment, follow ­up and whole trial) should be summed across each treatment arm and standardised to per patient years for that treatment. This is calculated by dividing the total oral dose in each arm by the cumulative years all patients in the corresponding arm are on treatment for.
    End point type
    Secondary
    End point timeframe
    Duration of study period (blinded, open-label and follow-up phase).
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    5 [21]
    1 [22]
    Units: miligrams per patient year
    number (not applicable)
        Total dose per patient years
    790.27
    3767.74
    Notes
    [21] - 5 participants were taking oral corticosteroids at randomisation.
    [22] - 1 participant was taking oral corticosteroids at randomisation.
    Statistical analysis title
    Total oral corticosteroid dose
    Comparison groups
    Adalimumab (follow-up) v Placebo (follow-up)
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Poisson regression
    Parameter type
    Rate ratio
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.23

    Secondary: Follow-up phase: Reduction in systemic corticosteroid dose from entry dose to 0mg

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    End point title
    Follow-up phase: Reduction in systemic corticosteroid dose from entry dose to 0mg
    End point description
    Reduction in systemic corticosteroid dose from entry dose to 0mg from randomisation to end of trial. It was not possible to undertake this analysis due to the fact that the statistical algorithm did not converge.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation to the end of the trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    5 [23]
    1 [24]
    Units: Events
        Reduced dose
    5
    1
        Censored
    0
    0
    Notes
    [23] - At baseline 5 participants were prescribed systemic corticosteroids >0mg.
    [24] - At baseline 1 participant was prescribed systemic corticosteroids >0mg.
    No statistical analyses for this end point

    Secondary: Follow-up phase: Reduction in systemic corticosteroid dose from entry dose to <5mg

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    End point title
    Follow-up phase: Reduction in systemic corticosteroid dose from entry dose to <5mg
    End point description
    Reduction in systemic corticosteroid dose from entry dose to less than 5mg from randomisation to end of trial. It was not possible to undertake the analysis as the statistical algorithm did not converge.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation to the end of the trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    2 [25]
    1 [26]
    Units: Events
        Reduced dose
    2
    1
        Censored
    0
    0
    Notes
    [25] - At baseline 2 participants were prescribed systemic corticosteroids >=5mg.
    [26] - At baseline 1 participant was prescribed systemic corticosteroids >=5mg.
    No statistical analyses for this end point

    Secondary: Follow-up phase: Time to reduction to <2 drops in topical corticosteroids

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    End point title
    Follow-up phase: Time to reduction to <2 drops in topical corticosteroids
    End point description
    See blinded phase for full description of end-point.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation to the end of the trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    45 [27]
    18 [28]
    Units: Events
        Reduced drops
    27
    3
        Censored
    18
    15
    Notes
    [27] - There were 45 participants who were on >=2 drops at baseline.
    [28] - There were 18 participants who were on >=2 drops at baseline.
    Statistical analysis title
    Time to reduction to <2 drops
    Statistical analysis description
    This was a competing risks analysis, accounting for the time to treatment failure.
    Comparison groups
    Adalimumab (follow-up) v Placebo (follow-up)
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    Fine and Gray
    Parameter type
    Hazard ratio (HR)
    Point estimate
    4.74
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.41
         upper limit
    16

    Secondary: Follow-up phase: Need for pulsed corticosteroid

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    End point title
    Follow-up phase: Need for pulsed corticosteroid
    End point description
    See blinded phase for full description of end-point.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation to the end of trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    58
    29
    Units: Events
        Needed pulsed corticosteroids
    4
    1
        Did not need pulsed corticosteroids
    54
    28
    Statistical analysis title
    Need for pulsed corticosteroids
    Comparison groups
    Placebo (follow-up) v Adalimumab (follow-up)
    Number of subjects included in analysis
    87
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.66
    Method
    Fisher exact
    Parameter type
    Risk ratio (RR)
    Point estimate
    2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.23
         upper limit
    17.12

    Secondary: Follow-up phase: Laboratory parameters

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    End point title
    Follow-up phase: Laboratory parameters
    End point description
    Supplementary tables summarising the data have been uploaded.
    End point type
    Secondary
    End point timeframe
    Participants were followed up for a maximum of 18 months post treatment.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    58
    29
    Units: See supplementary tables.
    58
    29
    Attachments
    Untitled (Filename: Follow-up Phase - Laboratory Parameters.pdf)
    No statistical analyses for this end point

    Secondary: Blinded phase: Reduction in systemic corticosteroid dose from entry dose to <5mg

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    End point title
    Blinded phase: Reduction in systemic corticosteroid dose from entry dose to <5mg
    End point description
    Reduction in systemic corticosteroid dose from entry dose to <5mg will be analysed for a subset of patients, as not everyone will be taking systemic corticosteroids at randomisation.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    2 [29]
    1 [30]
    Units: Events
        Reduced dose
    1
    1
        Censored
    1
    0
    Notes
    [29] - 2 participants were prescribed systemic corticosteroids >=5mg at baseline.
    [30] - 1 participant was prescribed systemic corticosteroids >=5mg at baseline.
    No statistical analyses for this end point

    Secondary: Follow-up phase: Rate of systemic corticosteroid dose from entry dose

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    End point title
    Follow-up phase: Rate of systemic corticosteroid dose from entry dose
    End point description
    The total dose is calculated by summing the daily doses and standardised to per patient years.
    End point type
    Secondary
    End point timeframe
    Participants were assessed from randomisation to end of trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    5 [31]
    1 [32]
    Units: miligrams per patient year
    number (not applicable)
        Total dose per patient years
    790.27
    3767.74
    Notes
    [31] - 5 participants were taking oral corticosteroids at randomisation.
    [32] - 1 participant was taking oral corticosteroids at randomisation.
    Statistical analysis title
    Rate of systemic corticosteroid dose
    Comparison groups
    Placebo (follow-up) v Adalimumab (follow-up)
    Number of subjects included in analysis
    6
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Poisson regression
    Parameter type
    Rate ratio
    Point estimate
    0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.19
         upper limit
    0.23

    Post-hoc: Blinded phase: Time to reduction to 0 drops in topical corticosteroids

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    End point title
    Blinded phase: Time to reduction to 0 drops in topical corticosteroids
    End point description
    This outcome is the time to reduction to 0 drops for those patients already on >0 drop at randomisation.
    End point type
    Post-hoc
    End point timeframe
    Participants were assessed for treatment failure from randomisation up until: -time of treatment failure -completion of 18 months of treatment -unblinding following TSC decision, whichever occurred first.
    End point values
    Adalimumab (blinded phase) Placebo (blinded phase)
    Number of subjects analysed
    49 [33]
    25 [34]
    Units: Events
    number (not applicable)
        Events
    25
    4
        Censored
    24
    21
    Notes
    [33] - 49 participants were on >0 drops at randomisation.
    [34] - 25 participants were on >0 drops at randomisation.
    Statistical analysis title
    Time to reduction to 0 drops
    Statistical analysis description
    This was a competing risks analysis, accounting for the time to treatment failure.
    Comparison groups
    Adalimumab (blinded phase) v Placebo (blinded phase)
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.01
    Method
    Fine and Gray
    Parameter type
    Hazard ratio (HR)
    Point estimate
    4.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.4
         upper limit
    11.5

    Post-hoc: Follow-up phase: Time to reduction to 0 drops in topical corticosteroid

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    End point title
    Follow-up phase: Time to reduction to 0 drops in topical corticosteroid
    End point description
    This outcome is the time to reduction to 0 drops for those patients already on >0 drops at randomisation.
    End point type
    Post-hoc
    End point timeframe
    Participants were assessed from randomisation to the end of the trial.
    End point values
    Adalimumab (follow-up) Placebo (follow-up)
    Number of subjects analysed
    49 [35]
    25 [36]
    Units: Events
        Reduced drops
    30
    4
        Censored
    19
    21
    Notes
    [35] - 49 participants were on >= 0 drops per day at baseline.
    [36] - 25 participants were on >= 0 drops per day at baseline.
    Statistical analysis title
    Time to reduction to 0 drops
    Comparison groups
    Adalimumab (follow-up) v Placebo (follow-up)
    Number of subjects included in analysis
    74
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0022
    Method
    Fine and Gray
    Parameter type
    Hazard ratio (HR)
    Point estimate
    5.24
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.82
         upper limit
    15.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected up to 30 days following treatment cessation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Adalimumab
    Reporting group description
    Adalimumab subcutaneous injection every 2 weeks for 18 months.

    Reporting group title
    Placebo
    Reporting group description
    Placebo subcutaneous injection every 2 weeks for 18 months

    Serious adverse events
    Adalimumab Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 60 (23.33%)
    2 / 30 (6.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Antiviral prophylaxis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testes exploration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Anterior chamber flare
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cataract
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uveitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Food poisoning
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Joint swelling
    Additional description: This SAE occurred during follow-up and outside the reporting timelines as stated in the SYCAMORE protocol.
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (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
    Cellulitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected bite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scarlet fever
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal infection
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Adalimumab Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 60 (100.00%)
    26 / 30 (86.67%)
    Surgical and medical procedures
    Tonsillectomy
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    5 / 60 (8.33%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    Immune system disorders
    Immunisation reaction
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Crying
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Drug intolerance
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Feeling hot
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Hangover
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Influenza like illness
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Injection site bruising
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Injection site erythema
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 30 (3.33%)
         occurrences all number
    4
    1
    Injection site mass
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    8
    0
    Injection site pain
         subjects affected / exposed
    5 / 60 (8.33%)
    2 / 30 (6.67%)
         occurrences all number
    15
    5
    Injection site pruritus
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Injection site reaction
         subjects affected / exposed
    8 / 60 (13.33%)
    0 / 30 (0.00%)
         occurrences all number
    40
    0
    Injection site swelling
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    9
    1
    Injection site vesicles
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Pyrexia
         subjects affected / exposed
    15 / 60 (25.00%)
    3 / 30 (10.00%)
         occurrences all number
    39
    6
    Swelling
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Agitation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Emotional distress
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Irritability
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    7
    0
    Pruritus genital
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Vaginal lesion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Arthropod bite
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    2
    Arthropod sting
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Bite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Contusion
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Fall
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Injury
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Joint dislocation
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    2
    Joint injury
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Laceration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Ligament sprain
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Upper limb fracture
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Foreign body
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 60 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    11
    1
    Aspartate aminotransferase abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 30 (3.33%)
         occurrences all number
    6
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Blood glucose abnormal
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blood potassium increased
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    C-reactive protein abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Haematocrit abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Intraocular pressure increased
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    7
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Red blood cell count abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Red blood cell sedimentation rate abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Rubulavirus test positive
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Urine protein/creatinine ratio abnormal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Vitamin D decreased
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Adenoidal disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Asthma
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    2
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    22 / 60 (36.67%)
    3 / 30 (10.00%)
         occurrences all number
    32
    3
    Dyspnoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    5
    0
    Nasal congestion
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nasal discomfort
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    19 / 60 (31.67%)
    2 / 30 (6.67%)
         occurrences all number
    43
    3
    Productive cough
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Sinus congestion
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Snoring
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Increased tendency to bruise
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Neutropenia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 60 (25.00%)
    4 / 30 (13.33%)
         occurrences all number
    26
    10
    Hypoaesthesia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Hyposmia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Migraine
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Paraesthesia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Psychomotor hyperactivity
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Eye discharge
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye inflammation
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Eye swelling
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Eyelid oedema
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Glaucoma
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Iridocyclitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Iris disorder
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Photopsia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Uveitis
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    4
    4
    Vision blurred
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Visual impairment
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Constipation
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    3
    Dental caries
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    7 / 60 (11.67%)
    1 / 30 (3.33%)
         occurrences all number
    11
    1
    Dyspepsia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Haematochezia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    6 / 60 (10.00%)
    2 / 30 (6.67%)
         occurrences all number
    10
    2
    Stomatitis
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Vomiting
         subjects affected / exposed
    19 / 60 (31.67%)
    6 / 30 (20.00%)
         occurrences all number
    43
    8
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Dermatitis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ingrowing nail
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Night sweats
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 30 (6.67%)
         occurrences all number
    6
    2
    Rash papular
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Swelling face
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 60 (21.67%)
    2 / 30 (6.67%)
         occurrences all number
    25
    3
    Arthritis
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Back pain
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Joint stiffness
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Joint swelling
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Juvenile idiopathic arthritis
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    2
    Pain in extremity
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Pain in jaw
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Dehydration
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Candida infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Cestode infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    3 / 60 (5.00%)
    0 / 30 (0.00%)
         occurrences all number
    3
    0
    Conjunctivitis viral
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Ear infection
         subjects affected / exposed
    7 / 60 (11.67%)
    2 / 30 (6.67%)
         occurrences all number
    8
    2
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Eye infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Herpes simplex
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    6
    0
    Herpes zoster
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Impetigo
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    5
    1
    Infected bite
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Influenza
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Localised infection
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Lower respiratory tract infection
         subjects affected / exposed
    8 / 60 (13.33%)
    2 / 30 (6.67%)
         occurrences all number
    9
    4
    Molluscum contagiosum
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    17 / 60 (28.33%)
    8 / 30 (26.67%)
         occurrences all number
    29
    10
    Oral herpes
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Otitis media
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 30 (3.33%)
         occurrences all number
    1
    1
    Paronychia
         subjects affected / exposed
    3 / 60 (5.00%)
    1 / 30 (3.33%)
         occurrences all number
    3
    1
    Pharyngitis
         subjects affected / exposed
    4 / 60 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    4
    0
    Pneumonia
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 30 (3.33%)
         occurrences all number
    2
    1
    Rubella
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Skin infection
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Staphylococcal infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Streptococcal infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Tonsillitis
         subjects affected / exposed
    13 / 60 (21.67%)
    0 / 30 (0.00%)
         occurrences all number
    24
    0
    Tonsillitis streptococcal
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 30 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 60 (8.33%)
    1 / 30 (3.33%)
         occurrences all number
    8
    1
    Urethritis
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 30 (3.33%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    10 / 60 (16.67%)
    3 / 30 (10.00%)
         occurrences all number
    13
    4
    Varicella
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 30 (0.00%)
         occurrences all number
    2
    0
    Viral infection
         subjects affected / exposed
    11 / 60 (18.33%)
    1 / 30 (3.33%)
         occurrences all number
    15
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Sep 2011
    The first amendment to the protocol made corrections to typographical errors in the original protocol.
    30 Sep 2011
    The second amendment added clarification to the Tissue Bank section, clarification to the primary endpoint section and introduction of endpoint for intermittent or continuous suspension of adalimumab/placebo, clarification that patients cannot have previously received adalimumab, addition of two further exclusion criteria points relating to intra-ocular pressure, removal of limit on how many times patients can be screened, addition of window for adalimumab/placebo injections, clarification of topical treatment after 3 months trial treatment, change to dose range of allowed methotrexate to 10-20mg/m2 and clarification of treatment timelines and visit windows.
    25 Apr 2013
    The third amendment to the protocol made changes to the monthly visit windows to allow a window of 7 days, clarified in the table of assessments that CSRI questionnaire is completed at baseline only, changed the timeline for tuberculosis assessment from 4 weeks to 12 weeks prior to baseline and clarified that haematological and biochemical samples taken at screening can be used for the baseline visit.
    25 Sep 2013
    The fourth amendment to the protocol reduced the sample size from 154 to 114 and the duration of follow up post treatment from 18 months to 6 months, changed the assessment of reduction of vision from number of letters to LogMAR units, clarification to inclusion and exclusion criteria, addition of systemic acetazolamide as medication not permitted, removal of the collection of human anti-human antibody samples, window for methotrexate administration added, change to the collection of routine patient-level information and costing systems (PLICS) data and clarification on definition of end of trial added.
    11 Aug 2014
    The fifth amendment to the protocol added text to say that the IDSMC may request an interim analysis of the primary outcome.
    11 Aug 2014
    The sixth change to the protocol clarified that patients are classed as withdrawals and not treatment failures if they miss more than 4 weeks of methotrexate treatment, added further clarification that haematological and biochemical blood results can be used for baseline if taken at screening only if assessment was completed within the previous 15 days, clarification added to Tissue Bank samples to state that 3 months sample should be taken at the very next opportunity if not taken at 3 months and that the 18 months samples should be taken if patient ends treatment early.
    17 Apr 2015
    The seventh change to the protocol stated that the blinded phase of the trial has been stopped, all patients on adalimumab will continue to be treated but patients on placebo will stop treatment and proceed to follow up.
    14 Jul 2016
    The eighth change to the protocol clarified that JADAS was a secondary outcome and SAE reporting procedures.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    17 Apr 2015
    Following the results of an interim analysis, the IDSMC recommended that recruitment to SYCAMORE stop and the allocations of patients who were currently in the trial be unblinded. They recommended that patients who were on placebo stop taking the allocated treatment and enter the 6 month follow-up period of the trial (treatment of these patients was then at the discretion of the treating clinician). Patients who were on adalimumab were to continue on their allocated treatment as per protocol in an ‘open label’ fashion. Following completion of this ‘open label’ period, adalimumab patients entered the 6 month follow-up period. The IDSMC recommended that the results of the double blind period be made publically available. On the 17th April 2015, following the IDSMC recommendation, the TSC made the decision to unblind the trial.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    N/A

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28445659
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