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    Clinical Trial Results:
    A Multicenter Study of the Efficacy and Safety of the Human Anti-TNF Monoclonal Antibody Adalimumab as Maintenance Therapy in Subjects Requiring High Dose Corticosteroids for Active Non-infectious Intermediate Uveitis, Posterior Uveitis, or Panuveitis – Including a Sub-study in Japanese Patients

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2009-016095-68
    Trial protocol
    FR   ES   BE   PT   GB   NL   DE   DK   AT   IT   CZ   GR  
    Global end of trial date
    29 Aug 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Jul 2016
    First version publication date
    24 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M10-877
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01138657
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Abbvie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Information, Abbvie, 001 800-633-9110,
    Scientific contact
    Andrew Payne, AbbVie, andy.payne@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Aug 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Aug 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this study was to evaluate the efficacy and safety of adalimumab 80 mg loading dose followed by 40 mg dose given every other week (eow) subcutaneously (SC) starting at Week 1 compared with placebo as maintenance therapy in subjects requiring high dose corticosteroids for active non-infectious intermediate uveitis, posterior uveitis, or panuveitis.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, ICH guidelines, applicable regulations and guidelines governing clinical study conduct, and the ethical principles that have their origin in the Declaration of Helsinki and all applicable local regulations. The investigator or his/her representative explained the nature of the study to the subject, and answered all questions regarding the study. Prior to any study-related screening procedures being performed on the subject, the informed consent statement was reviewed and signed and dated by the subject, the person who administered the informed consent, and any other signatories according to local requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    10 Aug 2010
    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
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Japan: 16
    Country: Number of subjects enrolled
    Mexico: 4
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United States: 85
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    Czech Republic: 1
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 20
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Italy: 12
    Worldwide total number of subjects
    239
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    213
    From 65 to 84 years
    26
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study includes a Japan sub-study. 239 subjects with active non-infectious intermediate uveitis, posterior uveitis, or panuveitis were randomized worldwide, including 223 participants at 67 sites in Australia, Europe, Israel, Latin America, and North America (Main Study), and 16 participants randomized at 7 sites in Japan (Japan sub-study).

    Pre-assignment
    Screening details
    Subjects were randomized in a 1:1 ratio double-masked fashion using baseline immunosuppressant usage as the stratification factor. Subjects recruited in the Japan sub-study were randomized in a separate stratum with no stratification by baseline IMM usage. Study completion is defined as meeting treatment failure or reaching study Week 80.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo subcutaneous injection at Baseline followed by every other week (eow) dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered by subcutaneous injection

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper schedule in which all subjects continuing in the study were to discontinue prednisone no later than Week 15.

    Arm title
    Adalimumab
    Arm description
    Subjects received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.
    Arm type
    Experimental

    Investigational medicinal product name
    Adalimumab
    Investigational medicinal product code
    Other name
    Humira
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered SC as an 80 mg loading dose (2 syringes) at Baseline followed by a 40 mg dose eow starting at Week 1.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper schedule in which all subjects continuing in the study were to discontinue prednisone no later than Week 15.

    Number of subjects in period 1
    Placebo Adalimumab
    Started
    120
    119
    Enrolled in Main Study
    112
    111
    Enrolled in Japan Sub-study
    8 [1]
    8 [2]
    Completed
    112
    101
    Not completed
    8
    18
         Other
             3
             4
         Adverse event
             3
             10
         Lack of efficacy
             2
             1
         Lost to follow-up
             -
             3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only includes subjects who enrolled in Japan
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Only includes subjects who enrolled in Japan

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo subcutaneous injection at Baseline followed by every other week (eow) dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Reporting group title
    Adalimumab
    Reporting group description
    Subjects received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Reporting group values
    Placebo Adalimumab Total
    Number of subjects
    120 119 239
    Age categorical
    Units: Subjects
        < 40 years
    56 47 103
        40 - 64 years
    54 56 110
        ≥ 65 years
    10 16 26
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    43.19 ± 14.331 43.46 ± 15.458 -
    Gender categorical
    Units: Subjects
        Female
    73 66 139
        Male
    47 53 100
    Race
    Units: Subjects
        White
    91 89 180
        Black
    12 11 23
        Asian
    10 12 22
        American Indian/Alaskan Native
    1 0 1
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Other
    5 6 11
        Multi Race
    1 1 2
    Type of Uveitis
    Units: Subjects
        Intermediate
    24 25 49
        Posterior
    38 38 76
        Panuveitis
    58 56 114
    Diagnosis
    Units: Subjects
        Idiopathic
    50 40 90
        Birdshot Choroidopathy
    21 24 45
        Multifocal Choroiditis And Panuveitis
    5 8 13
        Vogt Koyanagi Harada
    14 12 26
        Sarcoid
    12 12 24
        Behcet's
    4 14 18
        Other
    14 9 23
    Eye Affected
    Units: Subjects
        Left
    5 6 11
        Right
    4 7 11
        Both
    111 106 217
    Duration of Uveitis
    Units: months
        arithmetic mean (standard deviation)
    58.56 ± 85.308 41.18 ± 53.53 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo subcutaneous injection at Baseline followed by every other week (eow) dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Reporting group title
    Adalimumab
    Reporting group description
    Subjects received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Subject analysis set title
    Main Study: Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects, excluding those enrolled in the Japan sub-study, received placebo subcutaneous injection at Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Subject analysis set title
    Main Study: Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects, excluding those enrolled in the Japan sub-study, received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses every other week (eow) starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Subject analysis set title
    Integrated Study (Main + Japan Sub-study): Placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects, including those enrolled in the Main Study and the Japan Sub-study, received placebo subcutaneous injection at Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Subject analysis set title
    integrated Study (Main + Japan Sub-study): Adalimumab
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Subjects, including those enrolled in the Main Study and the Japan Sub-study, received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Primary: Time to Treatment Failure on or After Week 6

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    End point title
    Time to Treatment Failure on or After Week 6
    End point description
    Time to treatment failure was analyzed using Kaplan-Meier methods. Treatment failures on or after Week 6 were counted as events. Dropouts for reasons other than treatment failure at any time during the study were censored at the drop out date. To be considered a treatment failure, ≥ 1 of these criteria had to be present in at least 1 eye: • New active, inflammatory chorioretinal or retinal vascular lesions relative to Baseline • Inability to achieve ≤ 0.5+ at Week 6 or a 2-step increase relative to best state achieved at all visits after Week 6 in anterior chamber cell grade or vitreous haze grade • Worsening of best corrected visual acuity by ≥ 15 letters relative to best state achieved. The primary analysis was performed in the intent-to-treat (ITT) population which included all randomized subjects recruited outside Japan; 6 subjects at 2 sites were excluded from the ITT due to incomplete efficacy source data and compliance issues. "99999" indicates values not estimable.
    End point type
    Primary
    End point timeframe
    From Baseline until end of study (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    107
    110
    115
    118
    Units: months
        median (inter-quartile range (Q1-Q3))
    3 (1.5 to 5.6)
    5.6 (3 to 99999)
    3 (1.5 to 5.6)
    4.8 (2.8 to 99999)
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The primary analysis of the primary endpoint was performed on Main Study data, excluding the Japanese sub-study. The statistical test was performed at a 2-sided significance level of 0.05. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment as factor.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.36
         upper limit
    0.7
    Notes
    [1] - Difference
    Statistical analysis title
    Additional Analysis – Integrated Study
    Statistical analysis description
    An additional analysis of the primary endpoint was performed using the Integrated Study data (Main Study + Japan sub-study). The statistical test was performed at a 2-sided significance level of 0.05. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment and race (Japanese versus non-Japanese) as factors.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    < 0.001
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.56
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.4
         upper limit
    0.76
    Notes
    [2] - Difference

    Secondary: Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in Anterior Chamber (AC) Cell Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    Slit lamp examinations were conducted at each visit to assess AC cell count. The number of AC cells observed within a 1 mm × 1 mm slit beam was used to determine the grade according to the Standardization of Uveitis Nomenclature (SUN) criteria: Grade 0 = < 1 cell Grade 0.5+ = 1-5 cells Grade 1+ = 6-15 cells Grade 2+ = 16-25 cells Grade 3+ = 26-50 cells Grade 4+ = > 50 cells. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used; subjects with no values after Week 6 were excluded.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6 and at the Final/Early Termination Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [3]
    101 [4]
    110 [5]
    109 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Left Eye
    0.59 ± 0.935
    0.35 ± 0.763
    0.56 ± 0.913
    0.35 ± 0.744
        Right Eye
    0.69 ± 1.067
    0.36 ± 0.746
    0.65 ± 1.039
    0.36 ± 0.727
    Notes
    [3] - Subjects with values at both timepoints
    [4] - Subjects with values at both timepoints
    [5] - Subjects with values at both timepoints
    [6] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.011 [8]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.51
         upper limit
    -0.07
    Notes
    [7] - Difference
    [8] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as factor adjusted for clustered observations (i.e., observations from each of the subject's eyes).
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.019 [10]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.46
         upper limit
    -0.04
    Notes
    [9] - Difference
    [10] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations (i.e., observations from each of the subject's eyes).

    Secondary: Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in Vitreous Haze (VH) Grade in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    Vitreous haze was measured using dilated indirect ophthalmoscopy (DIO) and assessed by the Investigator according to National Eye Institute (NEI) and SUN criteria: Grade 0: No evident vitreous haze; Grade 0.5+: Slight blurring of the optic disc margin because of the haze; normal striations and reflex of the nerve fiber layer cannot be visualized; Grade 1+: Permits a better definition of both the optic nerve head and the retinal vessels (compared to higher grades); Grade 2+: Permits better visualization of the retinal vessels (compared to higher grades); Grade 3+: Permits the observer to see the optic nerve head, but the borders are quite blurry; Grade 4+: Optic nerve head is obscured. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used; subjects with no values after Week 6 were excluded.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    103 [11]
    101 [12]
    111 [13]
    109 [14]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Left eye
    0.33 ± 0.666
    0.11 ± 0.559
    0.34 ± 0.675
    0.11 ± 0.547
        Right eye
    0.45 ± 0.781
    0.13 ± 0.648
    0.49 ± 0.815
    0.16 ± 0.648
    Notes
    [11] - Subjects with values at both time points
    [12] - Subjects with values at both time points
    [13] - Subjects with values at both time points
    [14] - Subjects with values at both time points
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    P-value
    < 0.001 [16]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.27
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    -0.11
    Notes
    [15] - Difference
    [16] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as factor adjusted for clustered observations.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    other [17]
    P-value
    < 0.001 [18]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.28
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.43
         upper limit
    -0.12
    Notes
    [17] - Difference
    [18] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations.

    Secondary: Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change In Logarithm of the Minimum Angle of Resolution (LogMAR) Best Corrected Visual Acuity (BCVA) In Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    Using corrective lenses based on that visit's refraction testing, subject's best corrected visual acuity was measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) logMAR chart. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used; subjects with no values after Week 6 were excluded.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    103 [19]
    101 [20]
    111 [21]
    109 [22]
    Units: logMAR
    arithmetic mean (standard deviation)
        Left eye
    0.12 ± 0.169
    0.07 ± 0.16
    0.11 ± 0.179
    0.07 ± 0.164
        Right eye
    0.13 ± 0.32
    0.04 ± 0.143
    0.13 ± 0.328
    0.05 ± 0.145
    Notes
    [19] - Subjects with values at both timepoints
    [20] - Subjects with values at both timepoints
    [21] - Subjects with values at both timepoints
    [22] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Adalimumab v Main Study: Placebo
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    other [23]
    P-value
    = 0.003 [24]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.11
         upper limit
    -0.02
    Notes
    [23] - Difference
    [24] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as factor adjusted for clustered observations.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    220
    Analysis specification
    Pre-specified
    Analysis type
    other [25]
    P-value
    = 0.008 [26]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -0.06
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    -0.02
    Notes
    [25] - Difference
    [26] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors adjusted for clustered observations.

    Secondary: Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6

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    End point title
    Time to Optical Coherence Tomography (OCT) Evidence of Macular Edema in At Least 1 Eye On or After Week 6
    End point description
    Optical coherence tomography was performed at every visit using 1 of 3 approved machines. Images were evaluated by a central reader. Macular edema was defined as cystoid macular edema. OCT evidence of macular edema on or after Week 6 was to be counted as an event. Dropouts due to reasons other than OCT evidence of macular edema were to be considered as censored observations at the time of dropping out. This endpoint was only analyzed in subjects without macular edema at Baseline. "99999" indicates values not estimable.
    End point type
    Secondary
    End point timeframe
    From Baseline until the Final Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    45 [27]
    55 [28]
    47 [29]
    57 [30]
    Units: months
        median (inter-quartile range (Q1-Q3))
    6.2 (1.4 to 99999)
    11.1 (2.6 to 15.9)
    3.7 (1.4 to 99999)
    9.2 (2.7 to 15.9)
    Notes
    [27] - Subjects without macular edema at Baseline
    [28] - Subjects without macular edema at Baseline
    [29] - Subjects without macular edema at Baseline
    [30] - Subjects without macular edema at Baseline
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment as factor.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    other [31]
    P-value
    = 0.231
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.39
         upper limit
    1.26
    Notes
    [31] - Difference
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%. The hazard ratio of adalimumab versus placebo was calculated using proportional hazards regression with treatment and race (Japanese versus non-Japanese) as factors.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    other [32]
    P-value
    = 0.191
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.38
         upper limit
    1.21
    Notes
    [32] - Difference

    Secondary: Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Percent Change in Central Retinal Thickness in Each Eye From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    Central retinal thickness was measured using OCT and assessed by a central reader. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used; subjects with no values after Week 6 were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6 and Final/Early Termination Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [33]
    101 [34]
    108 [35]
    109 [36]
    Units: percent change
    arithmetic mean (standard deviation)
        Left eye (n=100, 100, 107, 108)
    20.2 ± 52.01
    9.6 ± 29.76
    19 ± 50.57
    13.9 ± 53.95
        Right eye (n=102, 101, 108, 109)
    22 ± 62.48
    8.2 ± 25.78
    21.7 ± 60.75
    14.5 ± 57.05
    Notes
    [33] - Subjects with values at both timepoints
    [34] - Subjects with values at both timepoints
    [35] - Subjects with values at both timepoints
    [36] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [37]
    P-value
    = 0.02 [38]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -11.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.9
         upper limit
    -1.8
    Notes
    [37] - Difference
    [38] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and OCT machine as factors adjusted for clustered observations.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    integrated Study (Main + Japan Sub-study): Adalimumab v Integrated Study (Main + Japan Sub-study): Placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [39]
    P-value
    = 0.428 [40]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    -5.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.7
         upper limit
    7.5
    Notes
    [39] - Difference
    [40] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment, race (Japanese versus non-Japanese) and OCT machine as factors adjusted for clustered observations.

    Secondary: Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in Visual Functioning Questionnaire 25 (VFQ-25) Composite Score From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The overall composite score ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used; subjects with no values after Week 6 were excluded.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [41]
    101 [42]
    110 [43]
    109 [44]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -5.5 ± 11.968
    -1.3 ± 10.98
    -5.34 ± 11.899
    -1.68 ± 10.924
    Notes
    [41] - Subjects with values at both timepoints
    [42] - Subjects with values at both timepoints
    [43] - Subjects with values at both timepoints
    [44] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [45]
    P-value
    = 0.01 [46]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    4.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.02
         upper limit
    7.38
    Notes
    [45] - Difference
    [46] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as a factor.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    integrated Study (Main + Japan Sub-study): Adalimumab v Integrated Study (Main + Japan Sub-study): Placebo
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    other [47]
    P-value
    = 0.019 [48]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    3.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    6.71
    Notes
    [47] - Difference
    [48] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors.

    Secondary: Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in VFQ-25 Distance Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The distance vision subscore is calculated from the answers to 3 distance vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    From Baseline to Week 6 and at the Final/Early Termination Visit (up to 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [49]
    101 [50]
    110 [51]
    109 [52]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -5.64 ± 14.654
    -3.77 ± 13.414
    -5.72 ± 14.531
    -4.42 ± 13.871
    Notes
    [49] - Participants with values at both time points
    [50] - Participants with values at both time points
    [51] - Participants with values at both time points
    [52] - Participants with values at both time points
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [53]
    P-value
    = 0.346 [54]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    1.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.03
         upper limit
    5.75
    Notes
    [53] - Difference
    [54] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as a factor.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    other [55]
    P-value
    = 0.496 [56]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    1.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.47
         upper limit
    5.09
    Notes
    [55] - Difference
    [56] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors.

    Secondary: Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in VFQ-25 Near Vision Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The near vision subscore is calculated from the answers to 3 near vision-related questions and ranges from 0 to 100, where higher scores or increases in score indicate better vision-related functioning. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [57]
    101 [58]
    110 [59]
    109 [60]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -8.09 ± 17.754
    -2.97 ± 16.784
    -7.65 ± 17.808
    -3.52 ± 16.494
    Notes
    [57] - Subjects with values at both timepoints
    [58] - Subjects with values at both timepoints
    [59] - Subjects with values at both timepoints
    [60] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [61]
    P-value
    = 0.036 [62]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    5.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.34
         upper limit
    9.9
    Notes
    [61] - Difference
    [62] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as a factor.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    other [63]
    P-value
    = 0.077 [64]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    4.14
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.45
         upper limit
    8.72
    Notes
    [63] - Difference
    [64] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors.

    Secondary: Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit

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    End point title
    Change in VFQ-25 Ocular Pain Subscore From Best State Achieved Prior to Week 6 to the Final/Early Termination Visit
    End point description
    The National Eye Institute VFQ-25 is an ocular disease-specific survey that measures the influence of visual disability and visual symptoms on generic health domains such as emotional well-being and social functioning, in addition to task-oriented domains related to daily visual functioning. The VFQ-25 consists of a base set of 25 vision-targeted questions plus an additional single-item general health rating question. The ocular pain subscore is calculated from the answers to 2 eye pain questions and ranges from 0 to 100, where higher scores or increases in score indicate less pain. This endpoint was analyzed in the intent-to-treat population; last observation carried forward (LOCF) imputation was used.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6 and Final/Early Termination Visit (up 80 weeks)
    End point values
    Main Study: Placebo Main Study: Adalimumab Integrated Study (Main + Japan Sub-study): Placebo integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects analysed
    102 [65]
    101 [66]
    110 [67]
    109 [68]
    Units: units on a scale
        arithmetic mean (standard deviation)
    -12.62 ± 21.435
    -2.6 ± 15.342
    -12.39 ± 20.841
    -3.56 ± 16.056
    Notes
    [65] - Subjects with values at both timepoints
    [66] - Subjects with values at both timepoints
    [67] - Subjects with values at both timepoints
    [68] - Subjects with values at both timepoints
    Statistical analysis title
    Primary Analysis - Main Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Main Study: Placebo v Main Study: Adalimumab
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    other [69]
    P-value
    < 0.001 [70]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    10.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    4.86
         upper limit
    15.19
    Notes
    [69] - Difference
    [70] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment as a factor.
    Statistical analysis title
    Additional Analysis - Integrated Study
    Statistical analysis description
    The statistical test for the ranked secondary variables was carried out in hierarchical order at the significance level of 5%.
    Comparison groups
    Integrated Study (Main + Japan Sub-study): Placebo v integrated Study (Main + Japan Sub-study): Adalimumab
    Number of subjects included in analysis
    219
    Analysis specification
    Pre-specified
    Analysis type
    other [71]
    P-value
    < 0.001 [72]
    Method
    ANOVA
    Parameter type
    Mean Difference
    Point estimate
    8.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    3.88
         upper limit
    13.79
    Notes
    [71] - Difference
    [72] - From ANOVA of change from best state achieved prior to Week 6 to final/early termination visit with treatment and race (Japanese versus non-Japanese) as factors.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first study drug administration until 70 days following the last study drug administration or until rollover into the extension study. Median duration of treatment was 91 days in the placebo arm and 129 days in the adalimumab arm.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo subcutaneous injection at Baseline followed by eow dosing starting at Week 1 for up to 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Reporting group title
    Adalimumab
    Reporting group description
    Subjects received adalimumab 80 mg subcutaneous loading dose at Baseline followed by 40 mg doses eow starting at Week 1 for a maximum of 80 weeks or until treatment failure. Subjects continued to receive prednisone orally, 60 mg/day at study entry followed by a protocol-defined mandatory taper until Week 15.

    Serious adverse events
    Placebo Adalimumab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 120 (4.17%)
    16 / 119 (13.45%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Neovascularisation
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion Induced
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Carcinoid Tumour Of The Gastrointestinal Tract
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glioblastoma Multiforme
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist Fracture
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (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
    Demyelination
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Angle Closure Glaucoma
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis Acute
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Calculus Ureteric
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure Chronic
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Lupus-Like Syndrome
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid Overload
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis Viral
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pilonidal Cyst
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 120 (0.83%)
    0 / 119 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    1 / 119 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Adalimumab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 120 (50.83%)
    71 / 119 (59.66%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 120 (3.33%)
    7 / 119 (5.88%)
         occurrences all number
    5
    9
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 120 (13.33%)
    13 / 119 (10.92%)
         occurrences all number
    17
    21
    Paraesthesia
         subjects affected / exposed
    0 / 120 (0.00%)
    6 / 119 (5.04%)
         occurrences all number
    0
    6
    Eye disorders
    Cystoid Macular Oedema
         subjects affected / exposed
    6 / 120 (5.00%)
    3 / 119 (2.52%)
         occurrences all number
    6
    3
    Eye Pain
         subjects affected / exposed
    2 / 120 (1.67%)
    9 / 119 (7.56%)
         occurrences all number
    4
    10
    Uveitis
         subjects affected / exposed
    8 / 120 (6.67%)
    12 / 119 (10.08%)
         occurrences all number
    8
    13
    Vision Blurred
         subjects affected / exposed
    2 / 120 (1.67%)
    8 / 119 (6.72%)
         occurrences all number
    2
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 120 (5.83%)
    12 / 119 (10.08%)
         occurrences all number
    7
    12
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 120 (0.00%)
    6 / 119 (5.04%)
         occurrences all number
    0
    7
    Insomnia
         subjects affected / exposed
    8 / 120 (6.67%)
    9 / 119 (7.56%)
         occurrences all number
    8
    12
    Gastrointestinal disorders
    Dry Mouth
         subjects affected / exposed
    1 / 120 (0.83%)
    6 / 119 (5.04%)
         occurrences all number
    1
    6
    Nausea
         subjects affected / exposed
    7 / 120 (5.83%)
    6 / 119 (5.04%)
         occurrences all number
    8
    7
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    3 / 120 (2.50%)
    7 / 119 (5.88%)
         occurrences all number
    3
    8
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    12 / 120 (10.00%)
    10 / 119 (8.40%)
         occurrences all number
    14
    13
    Back Pain
         subjects affected / exposed
    3 / 120 (2.50%)
    9 / 119 (7.56%)
         occurrences all number
    3
    10
    Muscle Spasms
         subjects affected / exposed
    4 / 120 (3.33%)
    7 / 119 (5.88%)
         occurrences all number
    4
    8
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 120 (3.33%)
    7 / 119 (5.88%)
         occurrences all number
    5
    8
    Influenza
         subjects affected / exposed
    6 / 120 (5.00%)
    1 / 119 (0.84%)
         occurrences all number
    6
    1
    Nasopharyngitis
         subjects affected / exposed
    11 / 120 (9.17%)
    21 / 119 (17.65%)
         occurrences all number
    13
    27
    Urinary Tract Infection
         subjects affected / exposed
    0 / 120 (0.00%)
    6 / 119 (5.04%)
         occurrences all number
    0
    8

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2010
    Substantial changes included: ● Revised treatment failure parameters and efficacy variables where referenced throughout the document to reflect updated scientific approach and statistical analyses. ● Exclusion Criteria: changed BCVA worse than 20/400 to 20/200 and logMar from "> 1.34" to "> 1.0." ● Exclusion Criteria: added "All subjects with intermediate uveitis must have had a prior brain MRI at time of or after diagnosis of intermediate uveitis" to ensure that patients with intermediate uveitis do not have demyelinating disease such as multiple sclerosis, an appropriate diagnostic work up should include a brain MRI. ● Concomitant Therapy: added text regarding the use of topical or systemic corticosteroids.
    23 Apr 2010
    Substantial changes included: ● Revised the description of primary endpoint with regard to fundus visualization and to make editorial changes. ● Exclusion criteria: Added exclusion of subjects with severe vitreous haze that precludes visualization of the fundus to ensure the appropriate subject population is studied. ● Best Corrected Visual Acuity Testing: Removed the requirement that the individual performing refraction and BCVA testing not be the Principal Investigator nor the same person entering data on the eCRFs; there are no restrictions on who the BCVA examiners are for this study; however, they must be proficient in ETDRS refraction and ETDRS visual acuity measurement, and they must be certified by standardization vendor in both those study tasks. ● Study Procedures/Oral Prednisone Taper: Added text regarding oral prednisone taper to clarify that no deviations from the oral prednisone taper are allowed.
    10 Jun 2010
    Substantial changes included: ● Inclusion Criterion: Added "Subject with prior adequate response to corticosteroids (equivalent of prednisone up to 1 mg/kg/day)" to clarify the intent of Exclusion Criterion No. 2 which defines the appropriate subject population for this trial. ● Exclusion Criterion: Added Human T-Lymphotropic Virus Type 1 (HTLV-1), Whipple's disease, HZV (herpes zoster virus) as examples of potential infectious causes of uveitis. ● Exclusion Criterion: Revised to read "Subject has previous exposure to anti-TNF therapy and any biologic [including anti vascular endothelial growth factor (VEGF) therapy with a potential therapeutic impact on non-infectious uveitis" to provide clarification that prior anti VEGF therapy is also considered exclusionary for this clinical trial. ● Prohibited Therapy: Added "anti-VEGF therapy" and "periocular, intraocular or intravitreal injections" to clarify that anti-VEGF therapy, periocular, intraocular or intravitreal injections are not allowed during the study. ● Study Activities Table: Added Magnetic Resonance Imaging (MRI) to ensure the appropriate subject population is studied. ● Study Procedures: Indicated the correct order the eye exams are to be performed to ensure that the tests are done in the correct order to maximize the result of these procedures. ● Secondary Variables: Addition of change in Anterior Chamber (AC) cells to indicate that information collected on AC cell count/grade would not only be a component of the primary endpoint but also be evaluated as a secondary efficacy variable. ● Added Human Immunodeficiency Virus (HIV) testing Screening visit for Japanese subjects to satisfy local requirements in Japan.
    11 Feb 2011
    Substantial changes included: ● Inclusion Criteria and Study Procedures: - Added option to use QuantiFERON®-TB Gold for tuberculosis screening. - Added instruction that subjects with positive PPD and or QuantiFERON® TB Gold, history of active or latent tuberculosis [TB] or chest x-ray indicative of latent TB will be required to initiate and take at least 2 weeks of an ongoing course of prophylaxis prior to starting study therapy. ● Exclusion Criterion: - Changed to exclude subjects with 1 immunosuppressive therapy with dose increase within previous 28 days or who are on a dose outside of the allowed range listed and clarified that the dose of 1 allowable concomitant immunosuppressive therapy must be in the allowable range at Baseline. - Added text to exclude subjects with macular edema due to diabetic retinopathy. - Added Ozurdex® (dexamethasone implant) and intravitreal methotrexate (MTX) as prohibited therapy. - Added exclusion criterion that allows the prior use of intravitreal anti-VEGF therapy provided a 3 month washout period from Baseline is observed. - Added text to exclude use of marijuana in the previous 12 months. - Exclude hepatitis B surface antigen (HBsAg) positive subjects or subjects who are positive for either hepatitis surface antibodies (HBsAb) and/or core antibodies (HBcAb, Total), and HBV DNA PCR result that meets or exceeds detection sensitivity. ● Added requirement if at Week 52, a subject has a positive TB test subjects will undergo a standard Chest X-ray. ● Discontinuation of Individual Subjects: added dysplasia of the gastrointestinal tract, diagnosis of lupus like syndrome, multiple sclerosis or demyelinating disease and non-compliance with TB therapy.
    21 Mar 2011
    Substantial changes included: ● Added text to exclude use of systemic carbonic anhydrase inhibitor within 1 week prior to Screening visit and as prohibited therapy. ● Added instruction to evaluate subjects for treatment failure criteria at Unscheduled visits (as applicable) and complete Unscheduled visit activities per the investigator's clinical judgment. ● Added instruction to use the same fundus camera throughout the study per subject.
    24 Aug 2011
    Substantial changes included: ● Limited the maximum corticosteroid dose at study start to ≤ 60 mg/day. ● Removed allowance for subjects with positive TB tests except where a subject received a BCG vaccination or has a history of an ulcerative reaction to a PPD skin test. If the PPD test is positive, the QuantiFERON®-TB Gold test (or equivalent) must be performed. If the QuantiFERON®-TB Gold test (or equivalent) is negative, the subject is eligible. ● Changed BCVA score to < 34 letters. ● Added exclusion for those subjects who have had Retisert® (glucocorticosteroid implant) removed less than 90 days before Baseline or had complications related to the removal of the device. ● Changed exclusion of subjects with macular edema due to diabetic retinopathy to subjects with clinically significant macular edema due to diabetic retinopathy. ● Modified that both Fluorescent Treponemal Antibody (FTA) and Rapid Plasma Reagin (RPR) must be tested. If RPR or FTA is positive, the subject is excluded. ● Added criterion to exclude subjects with macular edema as the only sign of uveitis. ● Added criterion to exclude subjects with a history of scleritis. ● Added criterion to exclude subjects who require TB-prophylaxis. ● Added "Retisert® (glucocorticosteroid implant)" to list of prohibited medications. ● Changed secondary efficacy variable analysis to be percent change in central retinal thickness. ● Added hypotony to the list of uveitis related events.
    15 Mar 2012
    Substantial changes included: ● Revised language to include subjects with either negative PPD (< 5 mm of induration) or negative QuantiFERON®-TB Gold test (or Interferon-Gamma Release Assay [IGRA] equivalent) as eligible. ● Added that subjects with "previous" TB are also not eligible for this study. ● Reduced the number of letters a subject must read for BCVA to 20 letters. ● Added tacrolimus as an acceptable concomitant immunosuppressant ● Allow prior use of cyclophosphamide provided a 30 day washout prior to Baseline is observed. Added chlorambucil and cyclophosphamide to prohibited concomitant medication list. ● Reduced the washout period for intraocular or periocular corticosteroids to 30 days. ● Reduced intravitreal anti-VEGF therapy washout periods for Lucentis® (ranibizumab) or Avastin® (bevacizumab) to 45 days of the Baseline visit or for anti-VEGF Trap (Aflibercept) for 60 days of the Baseline visit. ● Allow refractive laser surgery, retinal laser photocoagulation or Nd:YAG capsulotomy (neodymium-doped yttrium aluminium garnet (YAG)) laser ≥ 30 days prior to Baseline visit. ● Removed Rapid Plasma Reagin testing. Syphillis testing will consist of Fluorescent Treponemal Antibody (FTA) testing only. ● Added that each vaccine administered to the subject should be listed as a concomitant medication on the Other Medications eCRF. Live vaccines may not be given concurrently while on study drug or for 70 days after the last dose of adalimumab. ● Changed reporting of uveitis-related events such that standard adverse reporting procedures apply for all adverse events regardless of the relationship to uveitis.
    21 Dec 2012
    Substantial changes included: ● Reordered ranking of secondary variables: The Anterior Chamber (AC) Cell grade and Vitreous Haze grade ranking were changed based on observed reasons for treatment failure in the blinded data. ● Removed interim analyses and reduced the total number of treatment failures to complete the study. ● Added language and new requirements regarding malignancy in patients who are 30 years old or younger. ● Adverse Event Reporting changed to require non-serious events of malignancy in subjects 30 or younger to be reported to Abbvie within 24 hours of site awareness.
    24 Jun 2013
    Substantial changes included: ● Added Rituxan® (rituximab) as prohibited therapy. ● Subjects with optic neuritis are exclusionary. ● Added Stelara® (ustekinumab), Benlysta® (belimumab), and corticosteroids with the exceptions of protocol specified prednisone taper and the protocol specified corticosteroid eye drop taper as prohibited medications.
    19 Nov 2013
    Substantial changes included: ● Increased overall sample size to 266 subjects (including 32 Japanese subjects) and increased the number of required treatment failures to 138 events and 19 events in subjects enrolled in Japan in order to maintain a power of 90%. ● Changed the definition of secondary endpoints to be able to include those subjects in the analysis that have a treatment failure at Week 6.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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