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    Clinical Trial Results:
    A Randomised, Blinded, Active-Controlled Study to Compare FKB327 Efficacy and Safety with the Comparator Humira® in Rheumatoid Arthritis Patients Inadequately Controlled on Methotrexate.

    Summary
    EudraCT number
    2014-000109-11
    Trial protocol
    DE   CZ   BG   ES  
    Global end of trial date
    12 Jul 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Jul 2017
    First version publication date
    20 Jul 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    FKB327-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02260791
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND Number: 116471
    Sponsors
    Sponsor organisation name
    FUJIFILM KYOWA KIRIN BIOLOGICS Co., Ltd.
    Sponsor organisation address
    1-6-1 Ohtemachi, Chiyoda-ku, Tokyo, Japan, 100-8185
    Public contact
    Clinical-Trials@fk-b.com, Clinical Trial Information, Fujifilm Kyowa Kirin Biologics Co., Ltd., EU Branch, +44 1896 668 173, Clinical-Trials@fk-b.com
    Scientific contact
    Clinical-Trials@fk-b.com, Clinical Trial Information, Fujifilm Kyowa Kirin Biologics Co., Ltd., EU Branch, +44 1896 668 173, Clinical-Trials@fk-b.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
    12 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: • To assess the efficacy of FKB327 compared with Humira®, when each was administered in combination with methotrexate (MTX). Secondary: • To compare the safety profiles of FKB327 and Humira, each in combination with MTX treatment. • To assess the efficacy profiles of FKB327 and Humira over time, including initial onset of effect. • To compare the proportions of patients on FKB327 and Humira, who develop anti-drug antibodies (ADAs) and to summarise the distribution of the level of ADA activity between patients on FKB327 and Humira. • To compare the steady state pharmacokinetics (PK) of FKB327 and Humira administered by multiple dosing in patients with rheumatoid arthritis (RA) receiving concomitant treatment with MTX.
    Protection of trial subjects
    The study was performed in compliance with European Union (EU) Directives 2001/20/EC and 2005/28/EC, the Declaration of Helsinki (South Africa Revision, 1996), Good Manufacturing Practice (GMP), and Good Clinical Practice (GCP). The study was designed in accordance with the EU guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues (EMA/CHMP/BMWP/403543/2010) and other relevant guidelines for similar biological medicinal products. Participants were given as long as they wished to read the patient information and informed consent form (ICF), and to ask as many questions as they wanted. Each participant had an opportunity to discuss the study in private with a fully registered physician who was familiar with the study. The physician observed the participant's signature, then countersigned the consent form. The participant gave consent freely and in writing. During the study participants were monitored closely. In addition, the investigator and sponsor formally reviewed safety results at agreed intervals. Participants could be withdrawn from the study if that was in their best interest and the study physician ensured that participants received any medical treatment that they needed.
    Background therapy
    Methotrexate (MTX) represents the conventional disease modifying anti-rheumatic drug (DMARD) of choice for Rheumatoid Arthritis (RA) treatment and is thought to act by decreasing the activity of the immune system. Clinical studies with the originator product, Humira, in RA were conducted both in combination with MTX and as monotherapy. In this study concomitant folate therapy was used to counter the known adverse effects of MTX treatment. In line with clinical practice, stable background doses of oral steroids and non-steroidal anti-inflammatory drugs (NSAIDs) were permitted during this study although they were not compulsory.
    Evidence for comparator
    Adalimumab is a recombinant human monoclonal antibody against human Tumor Necrosis Factor (TNF)-α. It neutralises the biological activity of TNF-α by blocking its interaction with TNF-α cell surface receptors. TNF-α is a naturally occurring cytokine produced by many different cell types, including macrophages, mast cells and T cells. High concentrations of TNF-α lead to inflammation and injury, and TNF-α has been implicated as an important pro-inflammatory cytokine involved in the pathogenesis of numerous autoimmune diseases, such as RA, psoriasis (Ps), Crohn’s disease (CD) and ulcerative colitis (UC). Adalimumab was first approved for the treatment of RA in September 2003 in the European Union (EU), and was subsequently launched globally under the brand name Humira. Humira is currently indicated in the EU in the adult population for RA, Ps, Psoriatic Arthritis (PsA), Ankylosing spondylitis (AS), axial spondyloarthritis (without radiographic evidence of AS), CD, UC, hidradenitis suppurativa (HS) and non-infectious uveitis. Approved indications in the paediatric population are polyarticular juvenile idiopathic arthritis in children from 2 years of age, active enthesitis-related arthritis from 6 years of age, severe chronic plaque psoriasis from 4 years of age, moderately to severe active CD from 6 years of age and moderate to severe HS in adolescents from 12 years of age.
    Actual start date of recruitment
    05 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 134
    Country: Number of subjects enrolled
    Romania: 28
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    Bulgaria: 14
    Country: Number of subjects enrolled
    Czech Republic: 67
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Chile: 41
    Country: Number of subjects enrolled
    Peru: 100
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    Ukraine: 114
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    728
    EEA total number of subjects
    279
    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)
    601
    From 65 to 84 years
    125
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    1. Men or women aged ≥18 years 2. RA, diagnosed to revised ACR criteria (2010) at least 3 months 3. Active RA, as confirmed by ≥6 tender and ≥6 swollen joint counts out of 68/66, respectively 4. CRP level ≥10 mg/L 5. Taking MTX for at least 3 months 6. A stable dose ≥4 weeks if taking oral steroids or NSAIDs 7. Pregnancy test negative

    Pre-assignment
    Screening details
    Patients were to be randomised in a 1:1 ratio to receive either FKB327 40 mg eow or Humira 40 mg eow using the following stratification factors: prior biological treatment for RA (yes/no) and Screening disease activity (DAS28-CRP ≤5.1/>5.1).

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Patients will be randomised to receive either FKB327 40 mg eow or Humira 40 mg eow in a 1:1 ratio. A blinded kit containing a single dose of either FKB327 or Humira was supplied by the Sponsor. The person preparing the injection (pharmacist or other suitably qualified member of staff not otherwise involved in the study) was unblinded once the treatment kit was opened.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    FKB327
    Arm description
    Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow).
    Arm type
    Experimental

    Investigational medicinal product name
    FKB327
    Investigational medicinal product code
    FKB327
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow)

    Arm title
    Humira
    Arm description
    Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow).
    Arm type
    Active comparator

    Investigational medicinal product name
    Humira
    Investigational medicinal product code
    Humira
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow).

    Number of subjects in period 1
    FKB327 Humira
    Started
    366
    362
    Completed
    333
    328
    Not completed
    33
    34
         Other
    7
    7
         Lack of efficacy
    2
    1
         Adverse event, serious fatal
    1
    -
         Adverse event, non-fatal
    13
    9
         Screen failure
    -
    1
         Consent withdrawn by subject
    10
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    FKB327
    Reporting group description
    Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow).

    Reporting group title
    Humira
    Reporting group description
    Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow).

    Reporting group values
    FKB327 Humira Total
    Number of subjects
    366 362 728
    Age categorical
    Units: Subjects
        In utero
    0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0
        Newborns (0-27 days)
    0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    302 299 601
        From 65-84 years
    63 62 125
        85 years and over
    1 1 2
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    53 (18 to 85) 53.6 (21 to 93) -
    Gender categorical
    Units: Subjects
        Female
    281 284 565
        Male
    85 78 163
    Race
    Units: Subjects
        American Indian or Alaska Native
    1 1 2
        Asian
    1 1 2
        Black or African American
    2 4 6
        White
    311 308 619
        Other
    51 48 99
    Subject analysis sets

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set was defined as the set of patients who received at least 1 dose of randomised treatment. The Safety Analysis Set was used for all safety analyses. Patient safety data were analysed according to treatment actually received.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. The FAS was used for the primary efficacy analysis and other efficacy endpoints and analyses. Patients were analysed according to the randomised treatment in the primary analysis.

    Subject analysis set title
    Per-Protocol Analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per-protocol Analysis Set (PPAS) was defined as the set of patients in the FAS that had not deviated sufficiently from the protocol as to impact on the primary efficacy endpoint.

    Subject analysis set title
    Pharmacokinetic analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The Pharmacokinetic Analysis Set (PKAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and had at least 1 serum adalimumab concentration result after receiving randomised treatment.

    Subject analysis sets values
    Safety analysis set Full Analysis Set Per-Protocol Analysis set Pharmacokinetic analysis set
    Number of subjects
    728
    721
    639
    722
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    601
    596
    541
    597
        From 65-84 years
    125
    123
    96
    123
        85 years and over
    2
    2
    2
    2
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    53.3 (18 to 93)
    53.3 (18 to 93)
    52.8 (18 to 93)
    53.3 (18 to 93)
    Gender categorical
    Units: Subjects
        Female
    565
    560
    501
    560
        Male
    163
    161
    138
    162
    Race
    Units: Subjects
        American Indian or Alaska Native
    2
    2
    2
    2
        Asian
    2
    2
    2
    2
        Black or African American
    6
    6
    6
    6
        White
    619
    614
    550
    615
        Other
    99
    97
    79
    97

    End points

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    End points reporting groups
    Reporting group title
    FKB327
    Reporting group description
    Patients were administered subcutaneous (sc) FKB327 40 mg every other week (eow).

    Reporting group title
    Humira
    Reporting group description
    Patients were administered subcutaneous (sc) Humira 40 mg every other week (eow).

    Subject analysis set title
    Safety analysis set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set was defined as the set of patients who received at least 1 dose of randomised treatment. The Safety Analysis Set was used for all safety analyses. Patient safety data were analysed according to treatment actually received.

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set (FAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and who had at least 1 evaluable primary efficacy measurement after their first dose of randomised treatment. The FAS was used for the primary efficacy analysis and other efficacy endpoints and analyses. Patients were analysed according to the randomised treatment in the primary analysis.

    Subject analysis set title
    Per-Protocol Analysis set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per-protocol Analysis Set (PPAS) was defined as the set of patients in the FAS that had not deviated sufficiently from the protocol as to impact on the primary efficacy endpoint.

    Subject analysis set title
    Pharmacokinetic analysis set
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The Pharmacokinetic Analysis Set (PKAS) was defined as the set of patients who received at least 1 dose of the randomised treatment and had at least 1 serum adalimumab concentration result after receiving randomised treatment.

    Primary: Percentage of Participants with an American College of Rheumatology (ACR) 20 Response at Week 24

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    End point title
    Percentage of Participants with an American College of Rheumatology (ACR) 20 Response at Week 24
    End point description
    The primary efficacy endpoint is the ACR20 response rate at Week 24. An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. • Acute phase reactant (CRP) • Patient global assessment of disease activity • Physician global assessment of disease activity • Patient pain scale • Disability/functional questionnaire (patient completed Health Assessment Questionnaire Disability Index [HAQ-DI])
    End point type
    Primary
    End point timeframe
    Week 24.
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Percentage of participants
        arithmetic mean (confidence interval 95%)
    74.4 (69.6 to 78.8)
    75.7 (70.9 to 80.1)
    Statistical analysis title
    Analysis of ACR20 Response Rate at Week 24
    Statistical analysis description
    The primary hypothesis to be tested was that FKB327 is biosimilar to Humira. The difference and its 95% CI for primary endpoint between FKB327 and Humira were estimated. If the 95% CI fell entirely between pre-specified equivalence margin (+-13%), then FKB327 was considered equivalent to Humira.
    Comparison groups
    FKB327 v Humira
    Number of subjects included in analysis
    721
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Risk difference (RD)
    Point estimate
    -1.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.6
         upper limit
    5

    Secondary: Disease Activity Score 28 (DAS28) based on C-reactive protein (DAS28-CRP) score

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    End point title
    Disease Activity Score 28 (DAS28) based on C-reactive protein (DAS28-CRP) score
    End point description
    The DAS28 assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad). The DAS28-CRP is a number on a scale from 0 to 10 indicating the current activity of the patient’s RA.
    End point type
    Secondary
    End point timeframe
    DAS28-CRP scores from Baseline, Weeks 2, 4, 8, 12, 16, 20, and 24.
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline (n = 362, 358)
    6.05 ± 0.913
    6.06 ± 0.852
        Week 2 (n = 361, 351)
    4.92 ± 1.07
    4.86 ± 1.203
        Week 4 (n = 357, 348)
    4.44 ± 1.317
    4.43 ± 1.383
        Week 8 (n = 348, 345)
    4.11 ± 1.295
    4.09 ± 1.397
        Week 12 (n = 351, 340)
    3.81 ± 1.32
    3.85 ± 1.339
        Week 16 (n = 350, 341)
    3.68 ± 1.304
    3.67 ± 1.419
        Week 20 (n = 344, 336)
    3.58 ± 1.329
    3.57 ± 1.388
        Week 24 (n = 340, 339)
    3.47 ± 1.298
    3.47 ± 1.336
    Statistical analysis title
    Analysis of DAS28-CRP at Week 24
    Statistical analysis description
    The key secondary hypothesis involved equivalence of the difference between FKB327 and Humira in DAS28-CRP at Week 24. Based on the repeated measures analysis model, the difference and its 95% CI in the least-squares means (LSMs) for DAS28-CRP at Week 24 between FKB327 and Humira were estimated. If the 95% CI fell entirely between the pre-specified margin (+- 0.6), then FKB327 was considered equivalent to Humira.
    Comparison groups
    FKB327 v Humira
    Number of subjects included in analysis
    721
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    Method
    Parameter type
    Difference in least square mean
    Point estimate
    0.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.16
         upper limit
    0.18

    Secondary: ACR20 response rates over time

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    End point title
    ACR20 response rates over time
    End point description
    An ACR20 response meant that the patient achieved a 20% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. •Acute phase reactant (CRP). •Patient global assessment of disease activity. •Physician global assessment of disease activity. •Patient pain scale. •Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index [HAQ-DI]).
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 8, 12, 16, 20, and 24.
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Responders %
    number (confidence interval 95%)
        Week 2 (n = 362, 352)
    37.3 (32.3 to 42.5)
    31 (26.2 to 36.1)
        Week 4 (n = 359, 349)
    51 (45.7 to 56.3)
    52.4 (47.1 to 57.8)
        Week 8 (n = 353, 347)
    64.6 (59.4 to 69.6)
    67.7 (62.5 to 72.6)
        Week 12 (n = 351, 342)
    69.2 (64.1 to 74)
    72.2 (67.2 to 76.9)
        Week 16 (n = 350, 342)
    74.6 (69.7 to 79.1)
    74.9 (69.9 to 79.4)
        Week 20 (n = 345, 338)
    78 (73.2 to 82.2)
    77.8 (73 to 82.1)
        Week 24 (n = 341, 338)
    77.1 (72.3 to 81.5)
    79.3 (74.6 to 83.5)
    No statistical analyses for this end point

    Secondary: ACR50 response rates over time

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    End point title
    ACR50 response rates over time
    End point description
    An ACR50 response meant that the patient achieved a 50% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. •Acute phase reactant (CRP). •Patient global assessment of disease activity. •Physician global assessment of disease activity. •Patient pain scale. •Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index [HAQ-DI]).
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 8, 12, 16, 20, and 24.
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Responders %
    number (confidence interval 95%)
        Week 2 (n = 362, 352)
    5 (3 to 7.7)
    8.8 (6.1 to 12.3)
        Week 4 (n = 359, 349)
    17.3 (13.5 to 21.6)
    17.8 (13.9 to 22.2)
        Week 8 (n = 353, 346)
    28.9 (24.2 to 33.9)
    30.9 (26.1 to 36.1)
        Week 12 (n = 351, 342)
    37.6 (32.5 to 42.9)
    35.1 (30 to 40.4)
        Week 16 (n = 350, 342)
    39.4 (34.3 to 44.8)
    44.7 (39.4 to 50.2)
        Week 20 (n = 345, 339)
    45.5 (40.2 to 50.9)
    46 (40.6 to 51.5)
        Week 24 (n = 341, 338)
    49 (43.6 to 54.4)
    49.4 (44 to 54.9)
    No statistical analyses for this end point

    Secondary: ACR70 response rates over time

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    End point title
    ACR70 response rates over time
    End point description
    An ACR70 response meant that the patient achieved a 70% improvement in Tender Joint Count and Swollen Joint Count and in at least 3 of the other 5 Core Data Set elements listed below. •Acute phase reactant (CRP). •Patient global assessment of disease activity. •Physician global assessment of disease activity. •Patient pain scale. •Disability/functional questionnaire (patient completed Health AssessmentQuestionnaire Disability Index [HAQ-DI]).
    End point type
    Secondary
    End point timeframe
    Weeks 2, 4, 8, 12, 16, 20, and 24.
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Responders %
    number (confidence interval 95%)
        Week 2 (n = 362, 352)
    0.3 (0 to 1.5)
    2.3 (1 to 4.4)
        Week 4 (n = 359, 349)
    4.5 (2.6 to 7.1)
    6.9 (4.5 to 10.1)
        Week 8 (n = 353, 347)
    11.3 (8.2 to 15.1)
    10.7 (7.6 to 14.4)
        Week 12 (n = 351, 342)
    15.4 (11.8 to 19.6)
    13.2 (9.8 to 17.2)
        Week 16 (n = 350, 342)
    17.4 (13.6 to 21.8)
    19 (15 to 23.6)
        Week 20 (n = 345, 339)
    20.9 (16.7 to 25.5)
    23.6 (19.2 to 28.5)
        Week 24 (n = 342, 338)
    21.3 (17.1 to 26.1)
    25.1 (20.6 to 30.1)
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (swollen joint count)

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    End point title
    Individual ACR core set variables (swollen joint count)
    End point description
    Counts of swollen joints from amongst 68/66 selected joints were to be performed by a trained and qualified joint assessor using standardised techniques recommended by the European League Against Rheumatism (EULAR).
    End point type
    Secondary
    End point timeframe
    Base line to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Count
    arithmetic mean (standard deviation)
        Baseline (n = 363, 358)
    16.3 ± 9.1
    16 ± 8.96
        Week 24 (n = 342, 339)
    3.8 ± 6.04
    3.5 ± 5.23
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (tender joint count)

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    End point title
    Individual ACR core set variables (tender joint count)
    End point description
    Counts of tender from amongst 68/66 selected joints were to be performed by a trained and qualified joint assessor as scheduled using standardised techniques recommended by the European League Against Rheumatism (EULAR).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Count
    arithmetic mean (standard deviation)
        Baseline (n = 363, 358)
    26.2 ± 14.49
    25.9 ± 14.52
        Week 24 (n = 342, 339)
    8.5 ± 10.56
    8.1 ± 9.36
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (C-Reactive Protein)

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    End point title
    Individual ACR core set variables (C-Reactive Protein)
    End point description
    Analysis of serum C-Reactive Protein (CRP) concentrations for inclusion in the ACR20/50/70 and DAS28-CRP scores was performed by a central laboratory.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Count
    arithmetic mean (standard deviation)
        Baseline (n= 362, 358)
    25.12 ± 26.746
    26.73 ± 28.534
        Week 24 (n = 340, 340)
    10.98 ± 16.819
    11.78 ± 18.528
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (patient's assessment of disease activity)

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    End point title
    Individual ACR core set variables (patient's assessment of disease activity)
    End point description
    Patient global assessment of disease activity visual analogue scale (VAS; ranging from very well to extremely bad) was assessed on 100-point scales. This VAS was to be completed by the patient themselves and results were recorded on an ePRO tablet device.
    End point type
    Secondary
    End point timeframe
    Base line to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 363, 358)
    68 ± 17.98
    68.2 ± 18.18
        Week 24 (n = 342, 339)
    35.2 ± 24.04
    33.2 ± 23.4
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (physician's assessment of disease activity)

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    End point title
    Individual ACR core set variables (physician's assessment of disease activity)
    End point description
    Physician global assessment of disease activity visual analogue scale (VAS; ranging from very low to very high) was assessed on 100-point scales. This VAS was to be completed by the physician themselves and results were recorded on an ePRO tablet device.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 362, 358)
    68.4 ± 14.58
    66.2 ± 15.48
        Week 24 (n = 342, 338)
    21.5 ± 17.29
    21.5 ± 16.97
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (patient's assessment of pain)

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    End point title
    Individual ACR core set variables (patient's assessment of pain)
    End point description
    Patient assessment of pain was assessed on 100-point scales. This VAS were to be completed by the patient themselves and results were recorded on an ePRO tablet device.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 363, 358)
    66.8 ± 18.71
    67.7 ± 18.56
        Week 24 (n = 342, 338)
    34.7 ± 23.86
    33.6 ± 23.86
    No statistical analyses for this end point

    Secondary: Individual ACR core set variables (Health Assessment Questionnaire Disability Index [HAQ-DI]) over time)

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    End point title
    Individual ACR core set variables (Health Assessment Questionnaire Disability Index [HAQ-DI]) over time)
    End point description
    The HAQ-DI is a 20-question, self-administered instrument that measures the patient’s functional ability on a 4-level difficulty scale (0 to 3, with 0 representing normal or no difficulty, and 3 representing inability to perform). Eight categories of functioning are included: dressing, rising, eating, walking, hygiene, reach, grip, and usual activities. The HAQ-DI questionnaire was to be completed on the ePRO device by the patient themselves.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 363, 358)
    1.78 ± 0.544
    1.8 ± 0.538
        Week 24 (n = 342, 338)
    1.21 ± 0.696
    1.26 ± 0.719
    No statistical analyses for this end point

    Secondary: Change in DAS28-CRP score over time

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    End point title
    Change in DAS28-CRP score over time
    End point description
    The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28 assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum CRP, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 362, 358)
    6.05 ± 0.913
    6.06 ± 0.852
        Week 24 (n = 340, 339)
    3.47 ± 1.298
    3.47 ± 1.336
    No statistical analyses for this end point

    Secondary: DAS28 score based on erythrocyte sedimentation rate (DAS28-ESR)

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    End point title
    DAS28 score based on erythrocyte sedimentation rate (DAS28-ESR)
    End point description
    The DAS28 score is a combined index that has been developed to measure the disease activity in patients with RA and has been extensively validated for its use in clinical studies. The DAS28-ESR assessment involved evaluating the number of tender (TJC) and swollen (SJC) joints (out of 28 specified joints), serum ESR, and patient global assessment of disease activity (VAS from 0 to 100, very well to extremely bad).
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    363
    358
    Units: Score
    arithmetic mean (standard deviation)
        Baseline (n = 361, 355)
    6.52 ± 0.941
    6.56 ± 0.902
        Week 24 (n = 342, 338)
    3.82 ± 1.384
    3.85 ± 1.371
    No statistical analyses for this end point

    Secondary: Proportion of patients developing Anti Drug Antibodies (ADAs)

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    End point title
    Proportion of patients developing Anti Drug Antibodies (ADAs)
    End point description
    Blood samples for the assessment of ADA activity were to be collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12, and 24.
    End point type
    Secondary
    End point timeframe
    Baseline to last sampling day
    End point values
    FKB327 Humira
    Number of subjects analysed
    366
    362
    Units: percentage %
    number (not applicable)
        Baseline (Positive)
    4.4
    5.5
        Baseline (Negative)
    95.4
    94.2
        Baseline (Missing)
    0.3
    0.3
        Last sampling day (Positive)
    61.7
    59.1
        Last sampling day (Negative)
    38.3
    40.9
    No statistical analyses for this end point

    Secondary: Trough adalimumab concentration

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    End point title
    Trough adalimumab concentration
    End point description
    Blood samples for the quantification of adalimumab concentration in serum were to be collected at Baseline (Week 0), prior to dosing at Weeks 2, 4, 12 and 20, and Week 24. Samples were to be taken prior to dosing (trough samples). Concentrations of MTX were not assessed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    FKB327 Humira
    Number of subjects analysed
    364
    358
    Units: ng/ml
    number (confidence interval 95%)
        Week 2
    2434.6 (2321.4 to 2553.2)
    2089.1 (1990.9 to 2192.2)
        Week 4
    3450.6 (3223.2 to 3694.1)
    2932.1 (2737 to 3141.1)
        Week 12
    4316.3 (3919.6 to 4753.2)
    3851.5 (3493.9 to 4245.7)
        Week 20
    4369.8 (3892.3 to 4905.9)
    3873 (3445.9 to 4353)
        Week 24
    4126 (3645.1 to 4670.4)
    3758.2 (3316.8 to 4258.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Patients were carefully monitored for AEs from signing of informed consent until Week 24 (for patients who will enter the open-label extension), Week 26 (for patients who did not enter the open-label extension), or the Early Termination visit.
    Adverse event reporting additional description
    SAEs were followed until resolution, the Investigator confirmed the event was unlikely to resolve or the patient was recorded as lost to follow-up.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    FKB327
    Reporting group description
    -

    Reporting group title
    Humira
    Reporting group description
    -

    Serious adverse events
    FKB327 Humira
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 366 (4.10%)
    19 / 362 (5.25%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         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
    Hip fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoma
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uterine leiomyoma
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infiltration
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Amyloidosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Anal fistula
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Lichen sclerosus
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 366 (0.82%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    1 / 366 (0.27%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 366 (0.00%)
    2 / 362 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Latent tuberculosis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         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
    0 / 366 (0.00%)
    1 / 362 (0.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 366 (0.27%)
    0 / 362 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    FKB327 Humira
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 366 (7.10%)
    29 / 362 (8.01%)
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    26 / 366 (7.10%)
    29 / 362 (8.01%)
         occurrences all number
    26
    29

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Sep 2014
    Global Amendment 1 incorporated comments received from the European Union Voluntary Harmonisation Procedure (VHP) reviewer and the US Food and Drug Administration (FDA) which, taken together, could potentially affect patient safety and the integrity of the data.
    05 Jun 2015
    Global Amendment 2; following interactions with regulatory authorities, a change was made to the margins used to assess equivalence based on the primary endpoint. This change necessitated an increase in the study sample size. Additionally, during the course of preparing study related documentation a number of non-substantial changes were identified which were also incorporated into this global amendment.
    09 Jul 2015
    Global Amendment 3; a potential safety issue concerning the comparator treatment arm only, which may affect handling of the study drug for site staff and current and future patients enrolled on the study protocol, was identified. The product information for the comparator treatment contains information on a potential safety risk for people with allergies to rubber or latex as the needle cover on the product contains dry natural rubber. All participating research sites were informed of appropriate steps to take to minimize any potential risks. These steps were not taken with regard to any specific known adverse event for any patient enrolled on the study, but rather due to the potential of an allergic reaction. The study protocol was amended to include this information.

    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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