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    Clinical Trial Results:
    A 48 weeks study of three different dose regimens of BI 655066 administered subcutaneously in patients with moderate to severe chronic plaque psoriasis (randomised, dose-ranging, active-comparator-controlled (ustekinumab), double-blind within dose groups of BI 655066)

    Summary
    EudraCT number
    2012-004384-48
    Trial protocol
    FI   SE   DE   NO  
    Global end of trial date
    31 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Aug 2016
    First version publication date
    14 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1311.2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02054481
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.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
    15 Sep 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Nov 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The overall purpose of this trial is to assess clinical efficacy and safety of different subcutaneous doses of BI 655066 in adult patients with chronic plaque psoriasis in order to select doses for further clinical trials.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.
    Background therapy
    -
    Evidence for comparator
    Ustekinumab (Stelara®) administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.
    Actual start date of recruitment
    26 Feb 2014
    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
    Sweden: 6
    Country: Number of subjects enrolled
    United States: 120
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    Finland: 4
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Norway: 7
    Worldwide total number of subjects
    231
    EEA total number of subjects
    74
    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)
    210
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Assessor, Subject
    Blinding implementation details
    The different dose groups of BI 655066 were double-blind. Patients, investigators, and efficacy assessors were blinded to treatment. Stelara® was open-label to investigators and blinded to patients and efficacy assessors.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BI 655066 18 mg
    Arm description
    18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 655066 18 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    18 mg BI 655066 administered by subcutaneous injection at Week 0.

    Investigational medicinal product name
    Placebo matching BI 655066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Two placebo matching BI 655066 injections administered each at Weeks 0, 4 and 16.

    Arm title
    BI 655066 90 mg
    Arm description
    90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 655066 90 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    90 mg BI 655066 administered by subcutaneous injection at Weeks 0, 4 and 16.

    Investigational medicinal product name
    Placebo matching BI 655066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    2 placebo matching BI 655066 injections administered at Weeks 0 and 1 placebo matching BI 655066 injection at Weeks 4 and 16.

    Arm title
    BI 655066 180 mg
    Arm description
    180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed by 180 mg BI 655066 administered as two injections at Weeks 4 and 16.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 655066 180 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    180 mg BI 655066 administered by subcutaneous injection as two injections at Weeks 0, 4 and 16.

    Investigational medicinal product name
    Placebo matching BI 655066
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching BI 655066 injection administered at Week 0.

    Arm title
    Stelara®
    Arm description
    Stelara® administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.
    Arm type
    Active comparator

    Investigational medicinal product name
    Stelara®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Stelara® 45 mg or 90 mg was administered by subcutaneous injection at Weeks 0, 4 and 16.

    Investigational medicinal product name
    Saline injection
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Saline injection was done at Weeks 0, 4 and 16. 2 injections at Week 0 and 1 injection at Weeks 4 and 16.

    Number of subjects in period 1 [1]
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara®
    Started
    43
    41
    42
    40
    Completed
    39
    39
    40
    39
    Not completed
    4
    2
    2
    1
         Other reasoon
    2
    1
    2
    -
         Adverse event, non-fatal
    1
    1
    -
    1
         Lost to follow-up
    1
    -
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 655066 18 mg
    Reporting group description
    18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

    Reporting group title
    BI 655066 90 mg
    Reporting group description
    90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.

    Reporting group title
    BI 655066 180 mg
    Reporting group description
    180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed by 180 mg BI 655066 administered as two injections at Weeks 4 and 16.

    Reporting group title
    Stelara®
    Reporting group description
    Stelara® administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.

    Reporting group values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® Total
    Number of subjects
    43 41 42 40 166
    Age categorical
    Units: Subjects
    Age Continuous
    Safety Set (SAF) which Included all randomised patients who received at least 1 dose of trial medication and was based on the first treatment received.
    Units: Years
        arithmetic mean (standard deviation)
    44.1 ± 14.2 49.3 ± 13.3 44.9 ± 14 45.4 ± 12.1 -
    Gender, Male/Female
    Units: Participants
        Female
    20 11 13 13 57
        Male
    23 30 29 27 109

    End points

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    End points reporting groups
    Reporting group title
    BI 655066 18 mg
    Reporting group description
    18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

    Reporting group title
    BI 655066 90 mg
    Reporting group description
    90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.

    Reporting group title
    BI 655066 180 mg
    Reporting group description
    180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed by 180 mg BI 655066 administered as two injections at Weeks 4 and 16.

    Reporting group title
    Stelara®
    Reporting group description
    Stelara® administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.

    Subject analysis set title
    BI 655066 90+180 mg
    Subject analysis set type
    Full analysis
    Subject analysis set description
    90 mg BI 655066 or 180 mg BI 655066 administered by subcutaneous injection at Weeks 0, 4 and 16, plus matching placebos.

    Primary: Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12

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    End point title
    Achievement of ≥90% reduction from baseline PASI score (PASI90) at Week 12
    End point description
    Percentage of participants who achieved ≥90% reduction from baseline in Psoriasis Area and Severity Index score (PASI90) at Week 12. PASI score ranges from 0 (best) to 72 (worst). Full Analysis Set (FAS): Which included all randomised patients who received at least 1 dose of trial medication and was based on the randomised treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [1]
    41 [2]
    42 [3]
    40 [4]
    83 [5]
    Units: Percentage of participants
        number (confidence interval 95%)
    32.6 (19.1 to 48.5)
    73.2 (57.1 to 85.8)
    81 (65.9 to 91.4)
    40 (24.9 to 56.7)
    77.1 (66.6 to 85.6)
    Notes
    [1] - FAS
    [2] - FAS
    [3] - FAS
    [4] - FAS
    [5] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more Tumour Necrosis Factor (TNF) antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [6]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    36.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    19
         upper limit
    53.8
    Notes
    [6] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24

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    End point title
    Achievement of ≥75% reduction from baseline in PASI score (PASI75) at Weeks 12 and 24
    End point description
    Percentage of participants who achieved ≥75% reduction from baseline in Psoriasis Area and Severity Index score (PASI75) at Weeks 12 and 24. PASI score ranges from 0 (best) to 72 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12 and Week 24
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [7]
    41 [8]
    42 [9]
    40
    83 [10]
    Units: Percentage of participants
    number (confidence interval 95%)
        Week 12
    67.4 (51.5 to 80.9)
    97.6 (87.1 to 99.9)
    90.5 (77.4 to 97.3)
    77.5 (61.5 to 89.2)
    94 (86.5 to 98)
        Week 24
    55.8 (39.9 to 70.9)
    92.7 (80.1 to 98.5)
    92.9 (80.5 to 98.5)
    70 (53.5 to 83.4)
    92.8 (84.9 to 97.3)
    Notes
    [7] - FAS
    [8] - FAS
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    Statistical Analysis 1 (Week 12)
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0355 [11]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    14.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    28.2
    Notes
    [11] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.
    Statistical analysis title
    Statistical analysis 2 (Week 24)
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0062 [12]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    21.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    6
         upper limit
    36.2
    Notes
    [12] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12

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    End point title
    Achievement of 100% reduction from baseline in PASI score (PASI100) at Week 12
    End point description
    Percentage of participants who achieved 100% reduction from baseline in Psoriasis Area and Severity Index score (PASI100) at Week 12. PASI score ranges from 0 (best) to 72 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [13]
    41 [14]
    42 [15]
    40
    83 [16]
    Units: Percentage of participants
        number (confidence interval 95%)
    14 (5.3 to 27.9)
    41.5 (26.3 to 57.9)
    50 (34.2 to 65.8)
    17.5 (7.3 to 32.8)
    45.8 (34.8 to 57.1)
    Notes
    [13] - FAS
    [14] - FAS
    [15] - FAS
    [16] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0008 [17]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    27.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    11.3
         upper limit
    42.9
    Notes
    [17] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12

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    End point title
    Achievement of ≥50% reduction from baseline in PASI score (PASI50) at Week 12
    End point description
    Percentage of participants who achieved ≥50% reduction from baseline in Psoriasis Area and Severity Index score (PASI50) at Week 12. PASI score ranges from 0 (best) to 72 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [18]
    41 [19]
    42 [20]
    40
    83 [21]
    Units: Percentage of participants
        number (confidence interval 95%)
    93 (80.9 to 98.5)
    100 (91.4 to 100)
    95.2 (83.8 to 99.4)
    87.5 (73.2 to 95.8)
    97.6 (91.6 to 99.7)
    Notes
    [18] - FAS
    [19] - FAS
    [20] - FAS
    [21] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0706 [22]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    10.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.8
         upper limit
    21.1
    Notes
    [22] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Achievement of PASI90 at Week 24

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    End point title
    Achievement of PASI90 at Week 24
    End point description
    Percentage of participants who achieved PASI90 at Week 24. PASI score ranges from 0 (best) to 72 (worst).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [23]
    41 [24]
    42 [25]
    40 [26]
    83 [27]
    Units: Percentage of participants
        number (confidence interval 95%)
    30.2 (17.2 to 46.1)
    65.9 (49.4 to 79.9)
    85.7 (71.5 to 94.6)
    55 (38.5 to 70.7)
    75.9 (65.3 to 84.6)
    Notes
    [23] - FAS
    [24] - FAS
    [25] - FAS
    [26] - FAS
    [27] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03 [28]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    19.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.9
         upper limit
    37.7
    Notes
    [28] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Percentage change in PASI score from baseline at Week 12

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    End point title
    Percentage change in PASI score from baseline at Week 12
    End point description
    Percentage change in Psoriasis Area and Severity Index (PASI) from baseline at Week 12. PASI score ranges from 0 (best) to 72 (worst).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    39 [29]
    41 [30]
    41 [31]
    37 [32]
    82 [33]
    Units: Percentage of PASI score
        arithmetic mean (standard deviation)
    -79.7 ± 19.5
    -93.4 ± 7.7
    -90.7 ± 23.1
    -82.1 ± 19.5
    -92.1 ± 17.1
    Notes
    [29] - FAS
    [30] - FAS
    [31] - FAS
    [32] - FAS
    [33] - FAS
    No statistical analyses for this end point

    Secondary: Achievement of sPGA clear or almost clear at Week 12

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    End point title
    Achievement of sPGA clear or almost clear at Week 12
    End point description
    Percentage of participants who achieved static Physician Global Assessment (sPGA) clear or almost clear at Week 12. sPGA is assessed on a six-point scale from 0 (clear) to 5 (severe).
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [34]
    41 [35]
    42 [36]
    40
    83 [37]
    Units: Percentage of participants
        number (confidence interval 95%)
    62.8 (46.7 to 77)
    90.2 (76.9 to 97.3)
    90.5 (77.4 to 97.3)
    67.5 (50.9 to 81.4)
    90.4 (81.9 to 95.7)
    Notes
    [34] - FAS
    [35] - FAS
    [36] - FAS
    [37] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    The difference in proportion responding between BI 90+180 mg and Stelara® was estimated and tested using the Cochran-Mantel-Haenszel (CMH) risk difference estimate stratified by the randomisation factors of weight (≤100 kg vs. >100 kg) and prior exposure to 2 or more TNF antagonists with discontinuation due to lack of efficacy, with weights proposed by Greenland/Robins. Difference calculated as BI 90+180 mg minus Stelara®.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0072 [38]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Mean difference (net)
    Point estimate
    21.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    5.7
         upper limit
    36.6
    Notes
    [38] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Secondary: Time to loss of PASI50 response

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    End point title
    Time to loss of PASI50 response
    End point description
    Time to loss of PASI50 response. 99999: Summary statistics were not calculable due to low number of patients with events.
    End point type
    Secondary
    End point timeframe
    From first drug administration until end of follow-up period, up to 48 weeks.
    End point values
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara® BI 655066 90+180 mg
    Number of subjects analysed
    43 [39]
    41 [40]
    42 [41]
    40 [42]
    83 [43]
    Units: Days
        median (confidence interval 95%)
    253 (212 to 285)
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    338 (253 to 99999)
    99999 (99999 to 99999)
    Notes
    [39] - FAS
    [40] - FAS
    [41] - FAS
    [42] - FAS
    [43] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    BI 655066 treatment groups BI 90 mg + 180 mg were tested vs. Stelara® using a stratified Kaplan-Meier estimate and the log-rank test.
    Comparison groups
    Stelara® v BI 655066 90+180 mg
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [44]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.1844
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    0.4
    Notes
    [44] - Pairwise comparisons of all doses and treatments were conducted using the same CMH methods; 95% confidence intervals (CI) as well as nominal p-values of the comparison of doses were provided. There were no adjustments for multiplicity.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first drug administration until 15 weeks after the last drug administration, up to 231 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    BI 655066 18 mg
    Reporting group description
    18 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed by two placebo matching BI 655066 injections each at Weeks 4 and 16.

    Reporting group title
    BI 655066 90 mg
    Reporting group description
    90 mg BI 655066 administered by subcutaneous injection plus two placebo matching BI 655066 injections at Week 0, followed 90 mg BI 655066 plus one placebo matching BI 655066 injection at Weeks 4 and 16.

    Reporting group title
    BI 655066 180 mg
    Reporting group description
    180 mg BI 655066 administered by subcutaneous injection as two injections plus a placebo matching BI 655066 injection at Week 0, followed 180 mg BI 655066 administered as two injections at Weeks 4 and 16.

    Reporting group title
    Stelara®
    Reporting group description
    Stelara® administered by subcutaneous injection plus two saline injections at Week 0, Stelara® injection plus one saline injection at Weeks 4 and 16. Stelara® dose was 45 mg for patients with body weight ≤100 kg at randomisation or 90 mg for patients with body weight >100 kg at randomisation.

    Serious adverse events
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 43 (11.63%)
    6 / 41 (14.63%)
    0 / 42 (0.00%)
    3 / 40 (7.50%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abortion induced
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland neoplasm
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy to arthropod bite
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema multiforme
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 41 (0.00%)
    0 / 42 (0.00%)
    1 / 40 (2.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BI 655066 18 mg BI 655066 90 mg BI 655066 180 mg Stelara®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 43 (76.74%)
    32 / 41 (78.05%)
    29 / 42 (69.05%)
    29 / 40 (72.50%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 43 (11.63%)
    2 / 41 (4.88%)
    3 / 42 (7.14%)
    4 / 40 (10.00%)
         occurrences all number
    6
    2
    3
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 41 (2.44%)
    3 / 42 (7.14%)
    1 / 40 (2.50%)
         occurrences all number
    1
    1
    3
    1
    Psoriasis
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 41 (2.44%)
    0 / 42 (0.00%)
    3 / 40 (7.50%)
         occurrences all number
    3
    1
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 41 (4.88%)
    3 / 42 (7.14%)
    2 / 40 (5.00%)
         occurrences all number
    2
    2
    3
    2
    Back pain
         subjects affected / exposed
    2 / 43 (4.65%)
    4 / 41 (9.76%)
    1 / 42 (2.38%)
    1 / 40 (2.50%)
         occurrences all number
    2
    4
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 41 (2.44%)
    3 / 42 (7.14%)
    3 / 40 (7.50%)
         occurrences all number
    0
    1
    3
    3
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    3 / 43 (6.98%)
    1 / 41 (2.44%)
    1 / 42 (2.38%)
    0 / 40 (0.00%)
         occurrences all number
    3
    1
    1
    0
    Gastroenteritis
         subjects affected / exposed
    1 / 43 (2.33%)
    4 / 41 (9.76%)
    0 / 42 (0.00%)
    0 / 40 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    15 / 43 (34.88%)
    14 / 41 (34.15%)
    11 / 42 (26.19%)
    5 / 40 (12.50%)
         occurrences all number
    19
    20
    17
    6
    Rhinitis
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    1 / 40 (2.50%)
         occurrences all number
    0
    4
    1
    1
    Sinusitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 41 (0.00%)
    1 / 42 (2.38%)
    4 / 40 (10.00%)
         occurrences all number
    1
    0
    1
    4
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 43 (0.00%)
    3 / 41 (7.32%)
    1 / 42 (2.38%)
    1 / 40 (2.50%)
         occurrences all number
    0
    3
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Mar 2014
    Global protocol amendment 1 introduced the following key changes: 1. The inclusion criterion 8 was modified to add having vasectomized sexual partner(s) as an acceptable option of contraception for female patients. 2. Rules for blinding/unblinding of the trial team, investigators, efficacy assessors, and patients were specified. Unblinding of the trial bioanalyst and bioanalytical laboratory to support PK/ADA sample bioanalysis was introduced and blinded data reviews of PK/ADA results by the trial team were specified. 3. A restriction on the use of moisturizers/emollients containing retinoids and the use of tanning beds was introduced. Their use was not allowed as it could ameliorate psoriasis disease activity. 4. It was specified that body temperature could be measured orally or tympanically. The same BP recording instrument was to be used if possible. 5. Procedures for re-screening of patients in exceptional cases were introduced. 6. Further details on the procedure of obtaining skin biopsies were added.
    25 Jun 2014
    Global protocol amendment 2 allowed for a pre-randomisation call to the IRT for logistical reasons.
    03 Jul 2014
    Global protocol amendment 3 introduced the following key changes: 1. Rules for roll-over to the open-label extension study 1311.13 were specified 2. Exclusion criterion 4 was specified with regards to latent and active tuberculosis. Patients with latent or active TB were to continue to be excluded from the trial, but in case of a positive QuantiFERON test and documentation of adequately treated infection with no signs and symptoms of currently ongoing active or latent TB infection, the patients could have been included. 3. Exclusion criterion 11, concerning prior participation in another trial, was modified to be consistent with the restricted medication rules.

    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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