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    Clinical Trial Results:
    A randomized, double-blind, parallel-group Phase III study to demonstrate equivalent efficacy and to compare safety & immunogenicity of GP2015 and Enbrel® (EU authorized) in patients with moderate to severe, active rheumatoid arthritis

    Summary
    EudraCT number
    		 2012-002009-23
    Trial protocol
    		 HU   CZ   LT   EE   GB   SK   LV   PL   DE   BG   ES  
    Global end of trial date
    12 Jun 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Jun 2018
    First version publication date
    27 Jun 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CGP15-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02638259
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    HEXAL AG / Sandoz
    Sponsor organisation address
    Indistriestr. 25, Holzkirchen, Germany, 83607
    Public contact
    Sandoz Biopharma Clinical Development - Strategic Planning, Sandoz, 49 0049080244760, biopharma.clinicaltrials@sandoz.com
    Scientific contact
    Sandoz Biopharma Clinical Development - Strategic Planning, Sandoz, 49 0049080244760, biopharma.clinicaltrials@sandoz.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 Jun 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jun 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate equivalence of change in DAS28-CRP score from Baseline to Week 24 between patients treated with GP2015 and patients treated with Enbrel.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Nov 2015
    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
    Slovakia: 8
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    United States: 49
    Country: Number of subjects enrolled
    Bulgaria: 22
    Country: Number of subjects enrolled
    Czech Republic: 31
    Country: Number of subjects enrolled
    Estonia: 46
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Latvia: 8
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Mexico: 9
    Country: Number of subjects enrolled
    Poland: 92
    Country: Number of subjects enrolled
    Russian Federation: 22
    Country: Number of subjects enrolled
    Serbia: 22
    Worldwide total number of subjects
    376
    EEA total number of subjects
    274
    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)
    300
    From 65 to 84 years
    76
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 GP2015 : 181 patients completed TP1 and 175 entered TP2. 6 stopped prior to entering TP2 : 3 due to Eligibility, 2 withdrew consent and 1 due to IP delay TP2 Enbrel GP2015 : 172 patients completed TP1 and 166 entered TP2. 6 stopped prior TP2 : 4 due to Eligibility, 1 withdrew consent and 1 due to adverse event

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 376
    Number of subjects completed
    		 376

    Period 1
    Period 1 title
    Treatment Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50mg GP2015
    Arm description
    		 Group 1 received treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continued treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50 mg subcutaneous injection once weekly

    Arm title
    		 50mg EU-authorized Enbrel
    Arm description
    		 Group 2 received treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response were switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Enbrel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50 mg subcutaneous injection once weekly

    Number of subjects in period 1
    		50mg GP2015 50mg EU-authorized Enbrel
    Started
    186
    190
    Completed
    181
    172
    Not completed
    5
    18
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    4
    6
         Adverse event, non-fatal
    1
    5
         Withdrawn per sponsor decision
    -
    2
         Lack of efficacy
    -
    1
         Protocol deviation
    -
    3
    Period 2
    Period 2 title
    Treatment Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 50mg GP2015
    Arm description
    		 Group 1 received treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continued treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etanercept
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50 mg subcutaneous injection once weekly

    Arm title
    		 50mg EU-authorized Enbrel
    Arm description
    		 Group 2 will receive treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response will be switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator
    Arm type
    		 treatment period 2 : GP2015

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		50mg GP2015 50mg EU-authorized Enbrel
    Started
    175
    166
    Completed
    169
    155
    Not completed
    6
    11
         Consent withdrawn by subject
    1
    7
         Adverse event, non-fatal
    5
    4
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Numbers are correct : TP2 GP2015 : 181 patients completed TP1 and 175 started TP2 ( 3 did not enter TP2 due to Eligibility, 2 withdrew consent and 1 due to IP delay) TP2 Enbrel GP2015 : 172 patients completed TP1 and 175 started TP2 ( 4 due to Eligibility, 1 withdrew consent and 1 due to adverse event)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    50mg GP2015
    Reporting group description
    		 Group 1 received treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continued treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator

    Reporting group title
    50mg EU-authorized Enbrel
    Reporting group description
    		 Group 2 received treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response were switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator

    Reporting group values
    		 50mg GP2015 50mg EU-authorized Enbrel Total
    Number of subjects
    		 186 190 376
    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)
    		 148 152 300
        From 65-84 years
    		 38 38 76
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ( 11.22 ) 53.1 ( 12.70 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 158 150 308
        Male
    		 28 40 68
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 1 1 2
        Asian
    		 0 3 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 5 1 6
        White
    		 180 185 365
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Region of Enrollment
    Units: Subjects
        Hungary|
    		 7 12 19
        United States|
    		 23 26 49
        Czechia|
    		 16 15 31
        United Kingdom|
    		 3 4 7
        Spain|
    		 5 5 10
        Russia|
    		 12 10 22
        Latvia|
    		 6 2 8
        Poland|
    		 44 48 92
        Italy|
    		 1 0 1
        Mexico|
    		 4 5 9
        Slovakia|
    		 3 5 8
        Bulgaria|
    		 11 11 22
        Lithuania|
    		 9 12 21
        Serbia|
    		 12 10 22
        Germany|
    		 4 5 9
        Estonia|
    		 26 20 46

    End points

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    End points reporting groups
    Reporting group title
    50mg GP2015
    Reporting group description
    		 Group 1 received treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continued treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator

    Reporting group title
    50mg EU-authorized Enbrel
    Reporting group description
    		 Group 2 received treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response were switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator
    Reporting group title
    50mg GP2015
    Reporting group description
    		 Group 1 received treatment with 50mg GP2015 by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response continued treatment with 50mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator

    Reporting group title
    50mg EU-authorized Enbrel
    Reporting group description
    		 Group 2 will receive treatment with 50mg EU-authorized Enbrel by subcutaneous injection every week up to 24 weeks (Treatment Period 1) after which patients achieving at least a moderate clinical response will be switched to 50 mg GP2015 subcutaneous injection every week up to 48 weeks (Treatment Period 2). GP2015: Enbrel comparator

    Primary: Safety: Change in DAS28-CRP score from baseline to week 24 in patients treated with GP2015 and patients treated with Enbrel

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    End point title
    		 Safety: Change in DAS28-CRP score from baseline to week 24 in patients treated with GP2015 and patients treated with Enbrel
    End point description
    Disease activity score (DAS) 28-CRP is based on 28-joint count (tender and swollen joints), C-reactive protein and patient's assessment of global disease activity, values range from 0.96 to 10.0 while higher values mean a higher disease activity. • A DAS28-CRP value >5.1 corresponds to a high disease activity • A DAS28-CRP value between 3.2 and 5.1 corresponds to a moderate disease activity • A DAS28-CRP value between 2.6 and 3.2 corresponds to a low disease activity • A DAS28-CRP value < 2.6 corresponds to remission DAS28-CRP = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.36 * ln(CRP+1) + 0.014 * GDA + 0.96 where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm
    End point type
    Primary
    End point timeframe
    treatment period 1: up to 24 weeks
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: scores on a scale
        least squares mean (standard error)
    -2.80 ( 0.113 )
    -2.73 ( 0.117 )
    Statistical analysis title
    		 Therapeutic equivalence between GP2015 and Enbrel
    Statistical analysis description
    Therapeutic equivalence in terms of change from baseline in DAS28-CRP at week 24 will be concluded if the 95% confidence interval for the LS mean difference between GP2015 and Enbrel is contained within the interval [-0.6; 0.6]. A mixed-model repeated measures analysis was performed for DAS28-CRP change from baseline including treatment, stratification factors, time, the interaction between time (visits) and treatment all as categorical variables, and baseline DAS28-CRP as a continuous variable.
    Comparison groups
    50mg GP2015 v 50mg EU-authorized Enbrel
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.26
         upper limit
    		 0.12
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.097
    Notes
    [1] - A margin of 0.6 can be statistically and clinically justified based on the results Keystone et al, Arthritis and Rheumatism, p353-363, (2004) and on the EULAR response criteria. The sample size of 155 per group with 90% power is based on the common SD of 1.46 and was calculated using nQuery 7.0.

    Secondary: Treatment period 1: Frequency and severity of injection site reactions in GP2015 and Enbrel

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    End point title
    		 Treatment period 1: Frequency and severity of injection site reactions in GP2015 and Enbrel
    End point description
    Frequency of participants with injection site reactions in GP2015 and Enbrel
    End point type
    Secondary
    End point timeframe
    Treatment Period 1, up to 24 weeks
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    186
    190
    Units: Participants
        All injection site reactions|
    13
    35
        Moderate injection site reactions|
    1
    5
        Severe injection site reactions|
    0
    0
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Safety : Immunogenicity by measuring the rate of anti-drug antibody (ADA) positive patients

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    End point title
    		 Treatment period 1 - Safety : Immunogenicity by measuring the rate of anti-drug antibody (ADA) positive patients
    End point description
    Frequency of patients having anti-drug antibody (ADA) during 24 weeks (Treatment Period 1) using 1% false positive rate
    End point type
    Secondary
    End point timeframe
    Treatment Period 1, up to 24 weeks
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    186
    190
    Units: Participants
        Baseline|
    2
    0
        Week 2|
    2
    5
        Week 4|
    3
    42
        Week 12|
    0
    5
        Week 24|
    0
    0
    No statistical analyses for this end point

    Secondary: Treatment period 1- DAS28-CRP and DAS28-erythrocyte sedimentation rate (ESR) scores at Baseline and Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1- DAS28-CRP and DAS28-erythrocyte sedimentation rate (ESR) scores at Baseline and Weeks 4, 12 and 24;
    End point description
    DAS28-CRP is a disease activity score and defined in primary outcome measure. DAS28-ESR is the DAS28 erythrocyte sedimentation rate score. DAS28-CRP and DAS28-ESR: a. best is 0, b. < 2.6 – remission, c. ≥ 2.6 to ≤ 3.2 – low disease activity d. > 3.2 to ≤ 5.1 – moderate disease activity e. > 5.1 – high disease activity DAS28-ESR = 0.56 * sqrt(tender28) + 0.28* sqrt(swollen28) + 0.7 * ln(ESR) + 0.014 * GDA where • tender28 and swollen28 are the number of tender and swollen joints as assessed using 28-joint count • CRP is C-reactive protein (mg/l) • ESR is erythrocyte sedimentation rate (mm/h) • GDA is the global disease activity measured on a Visual Analogue Scale (VAS) of 100 mm
    End point type
    Secondary
    End point timeframe
    treatment period 1, week 4, 12, 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: score on a scale
    arithmetic mean (standard deviation)
        DAS28-CRP baseline|
    5.42 ( 0.921 )
    5.53 ( 0.783 )
        DAS28-CRP week 4|
    3.81 ( 1.079 )
    3.82 ( 1.077 )
        DAS28-CRP week 12|
    3.15 ( 1.045 )
    3.31 ( 1.088 )
        DAS28-CRP week 24|
    2.63 ( 0.910 )
    2.75 ( 0.928 )
        DAS28-ESR baseline|
    6.34 ( 0.882 )
    6.41 ( 0.768 )
        DAS28-ESR week 4|
    4.62 ( 1.183 )
    4.56 ( 1.204 )
        DAS28-ESR week 12|
    3.84 ( 1.216 )
    3.94 ( 1.284 )
        DAS28-ESR week 24|
    3.24 ( 1.060 )
    3.32 ( 1.099 )
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Changes from baseline in DAS28-CRP and DAS-ESR scores to weeks 4, 12 and 24

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    End point title
    		 Treatment period 1 - Changes from baseline in DAS28-CRP and DAS-ESR scores to weeks 4, 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Week 4, week 12, week 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: score on a scale
    arithmetic mean (standard deviation)
        DAS28-CRP change from baseline week 4|
    -1.59 ( 1.032 )
    -1.70 ( 1.001 )
        DAS28-CRP change from baseline week 12|
    -2.23 ( 1.030 )
    -2.20 ( 1.071 )
        DAS28-CRP change from baseline week 24|
    -2.78 ( 1.058 )
    -2.78 ( 1.028 )
        DAS28-ESR change from baseline week 4|
    -1.72 ( 1.068 )
    -1.85 ( 1.078 )
        DAS28-ESR change from baseline week 12|
    -2.50 ( 1.145 )
    -2.47 ( 1.218 )
        DAS28-ESR change from baseline week 24|
    -3.10 ( 1.157 )
    -3.09 ( 1.119 )
    No statistical analyses for this end point

    Secondary: Treatment period 1- Proportion of patients achieving EULAR response

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    End point title
    		 Treatment period 1- Proportion of patients achieving EULAR response
    End point description
    Proportion of patients achieving European League against Rheumatism (EULAR) good response (defined as DAS28 ≤ 3.2 and DAS28 improvement from Baseline > 1.2) and moderate response (defined as DAS28 ≤ 3.2 and DAS28 improvement > 0.6 and ≤ 1.2, or DAS28 > 3.2 and ≤ 5.1 and DAS28 improvement > 0.6 or DAS28 > 5.1 but DAS28 improvement > 1.2) ;
    End point type
    Secondary
    End point timeframe
    Treatment period 1, week 4, week 12 and week 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: Participants
        Good response week 4|
    26
    21
        Good response week 12|
    54
    47
        Good response week 24|
    88
    74
        Moderate response week 4|
    95
    99
        Moderate response week 12|
    103
    91
        Moderate response week 24|
    76
    77
        no response week 4|
    46
    34
        no response week 12|
    11
    16
        no response week 24|
    4
    4
    No statistical analyses for this end point

    Secondary: Treatment period 1- Proportion of patients achieving DAS28 < 2.6 at Weeks 4, 12 and 24

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    End point title
    		 Treatment period 1- Proportion of patients achieving DAS28 < 2.6 at Weeks 4, 12 and 24
    End point description
    % patients in DAS28-ESR categories up to week 24
    End point type
    Secondary
    End point timeframe
    Treatment period 1, week 4, week 12 and week 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: Participants
        Week 4 - remission (DAS28 <2.6)|
    9
    7
        Week 12 - remission (DAS28 <2.6)|
    21
    21
        Week 24 - remission (DAS28 <2.6)|
    46
    41
    No statistical analyses for this end point

    Secondary: Treatment period 1- Proportion of patients achieving EULAR/ACR Boolean remission criteria

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    End point title
    		 Treatment period 1- Proportion of patients achieving EULAR/ACR Boolean remission criteria
    End point description
    Proportion of patients achieving EULAR/American College of Rheumatology (EULAR/ACR) Boolean remission criteria (defined as number of tender joints/swollen joints ≤ 1 and CRP (mg/dL) ≤ 1 and patient global assessment (1–10) ≤ 1) at Weeks 4, 12 and 24;
    End point type
    Secondary
    End point timeframe
    Treatment period 1, week 4, week 12, week 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: participants
        week 4|
    1
    2
        week 12|
    9
    8
        week 24|
    24
    15
    No statistical analyses for this end point

    Secondary: Treatment period 1- Proportion of patients achieving ACR20/50/70 response at Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1- Proportion of patients achieving ACR20/50/70 response at Weeks 4, 12 and 24;
    End point description
    ACR20 response was defined if a patient fulfilled all 3 criteria below: -20% improvement in tender 68 joint-count -20% improvement in swollen 68 joint-count; And 20% improvement in at least 3 of the following 5 measures: - Patient’s assessment of RA pain (visual analogue scale (VAS) 100 mm), -Patient’s global assessment of disease activity (VAS 100 mm), -Physician’s global assessment of disease activity (VAS 100 mm), -Patient self-assessed disability (HAQ score), -Acute phase reactant (CRP or ESR). ACR50 and ACR70 responses were defined as ACR20 response replacing “20% improvement” by “50% improvement” and “70% improvement”, respectively.
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Week 4, week 12 and week 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: participants
        ACR20 response Week 4|
    80
    83
        ACR20 response Week 12|
    131
    116
        ACR20 response Week 24|
    147
    144
        ACR50 response Week 4|
    25
    28
        ACR50 response Week 12|
    55
    68
        ACR50 response Week 24|
    107
    110
        ACR70 response Week 4|
    8
    7
        ACR70 response Week 12|
    21
    26
        ACR70 response Week 24|
    56
    66
    No statistical analyses for this end point

    Secondary: Treatment period 1- ACR-N scores at Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1- ACR-N scores at Weeks 4, 12 and 24;
    End point description
    ACR-N (American College of Rheumatology percentage of improvement): negative is worsening, positive (up to 100) is an improvement. ACR-N is a single number that characterizes the percentage of improvement from Baseline that a patient has experienced in analogy to ACR20 described above. ACR-N of X (such as 38) means that the patient had achieved an improvement of at least X% (such as 38%) in tender and swollen joints, and an improvement of at least X% (such as 38%) in 3 of the 5 other parameters mentioned above.
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: score on a scale
    arithmetic mean (standard deviation)
        week 4|
    19.9 ( 29.89 )
    22.6 ( 34.02 )
        week 12|
    38.3 ( 27.46 )
    38.7 ( 35.32 )
        week 24|
    55.4 ( 27.61 )
    59.4 ( 25.40 )
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Proportion of patients in each disease activity category as defined by SDAI

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    End point title
    		 Treatment period 1 - Proportion of patients in each disease activity category as defined by SDAI
    End point description
    Proportion of patients in each disease activity category as defined by the Simplified Disease Activity Index (SDAI): high disease activity, SDAI > 26, moderate disease activity, SDAI > 11 to ≤ 26, low disease activity, SDAI > 3.3 to ≤ 11, and remission, SDAI ≤ 3.3 at Weeks 4, 12 and 24; SDAI and CDAI are measures of disease activity in RA. The scores were calculated by numerical summation of the number of tender and swollen joints (using the 28-joint count), and the patient’s and physician’s global assessment of disease activity.
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: Participants
        Baseline : Remission (SDAI<=3.3)|
    0
    0
        Baseline: Low (3.3 < SDAI <= 11)|
    0
    0
        Baseline : Moderate (11 < SDAI <= 26|
    26
    19
        Baseline : High (SDAI > 26)|
    142
    136
        Week 4:Remission (SDAI<=3.3)|
    5
    4
        Week 4:Low (3.3 < SDAI <= 11)|
    35
    31
        Week 4: Moderate (11 < SDAI <= 26|
    84
    82
        Week 4:High (SDAI > 26)|
    41
    36
        Week 12:Remission (SDAI<=3.3)|
    15
    13
        Week 12:Low (3.3 < SDAI <= 11)|
    61
    58
        Week 12: Moderate (11 < SDAI <= 26|
    75
    68
        Week 12:High (SDAI > 26)|
    14
    11
        Week 24: Remission (SDAI<=3.3)|
    38
    31
        Week 24: Low (3.3 < SDAI <= 11)|
    83
    81
        Week 24 : Moderate (11 < SDAI <= 26|
    45
    38
        Week 24 :High (SDAI > 26)|
    2
    5
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Proportion of patients in each disease activity category as defined by CDAI

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    End point title
    		 Treatment period 1 - Proportion of patients in each disease activity category as defined by CDAI
    End point description
    Proportion of patients in each disease activity category as defined by the Clinical Disease Activity Index (CDAI): high disease activity, CDAI > 22, moderate disease activity, CDAI > 10 to ≤ 22, low disease activity, CDAI > 2.8 to ≤ 10, and remission, CDAI ≤ 2.8 at Weeks 4, 12 and 24; SDAI and CDAI are measures of disease activity in RA. The scores were calculated by numerical summation of the number of tender and swollen joints (using the 28-joint count), and the patient’s and physician’s global assessment of disease activity.
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: Participants
        Baseline : Remission (CDAI<=2.8)|
    0
    0
        Baseline: Low (2.8 < CDAI <= 10)|
    0
    0
        Baseline : Moderate (10 < CDAI <= 22|
    17
    7
        Baseline : High (CDAI > 22)|
    151
    148
        Week 4:Remission(CDAI<=2.8)|
    4
    3
        Week 4: Low (2.8 < CDAI <= 10)|
    33
    31
        Week 4: Moderate (10 < CDAI <= 22)|
    67
    71
        Week 4:High High (CDAI > 22)|
    63
    49
        Week 12:Remission(CDAI<=2.8)|
    14
    15
        Week 12: Low (2.8 < CDAI <= 10)|
    63
    53
        Week 12: Moderate (10 < CDAI <= 22)|
    72
    63
        Week 12:High (CDAI > 22)|
    19
    23
        Week 24: Remission (CDAI<=2.8)|
    35
    31
        Week 24: Low (2.8 < CDAI <= 10)|
    81
    78
        Week 24 : (10 < CDAI <= 22)|
    46
    39
        Week 24 :High (CDAI > 22)|
    6
    7
    No statistical analyses for this end point

    Secondary: Treatment period 1- Proportion of patients achieving HAQ index in normal range (≤ 0.5) at Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1- Proportion of patients achieving HAQ index in normal range (≤ 0.5) at Weeks 4, 12 and 24;
    End point description
    Health assessment questionnaire (HAQ) disability index ranges from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: participants
        Baseline|
    11
    5
        Week 4|
    22
    30
        Week 12|
    40
    46
        Week 24|
    54
    62
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Health assessment questionnaire (HAQ) index at Baseline, Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1 - Health assessment questionnaire (HAQ) index at Baseline, Weeks 4, 12 and 24;
    End point description
    Health assessment questionnaire (HAQ) disability index ranges from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Baseline, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    1.44 ( 0.547 )
    1.47 ( 0.561 )
        Week 4|
    1.19 ( 0.558 )
    1.14 ( 0.611 )
        Week 12|
    1.02 ( 0.560 )
    0.97 ( 0.599 )
        Week 24|
    0.88 ( 0.601 )
    0.80 ( 0.589 )
    No statistical analyses for this end point

    Secondary: Treatment period 1 - Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale relative to Baseline at Weeks 4, 12 and 24;

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    End point title
    		 Treatment period 1 - Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale relative to Baseline at Weeks 4, 12 and 24;
    End point description
    FACIT fatigue scale is a 13- item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function, ranging from 0 (worst) to 52 (best). A score of less than 30 indicates severe fatigue.
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Baseline, Weeks 4, 12 and 24;
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    27.0 ( 9.67 )
    25.1 ( 10.33 )
        Week 4|
    31.6 ( 8.83 )
    30.9 ( 10.01 )
        Week 12|
    34.4 ( 8.93 )
    33.9 ( 9.6 )
        Week 24|
    36.3 ( 8.94 )
    36.7 ( 9.24 )
    No statistical analyses for this end point

    Secondary: Treatment period 1 - CRP levels at Baseline and Weeks 4, 12 and 24

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    End point title
    		 Treatment period 1 - CRP levels at Baseline and Weeks 4, 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline|
    1.19 ( 2.194 )
    1.10 ( 1.526 )
        Week 4|
    0.36 ( 0.718 )
    0.43 ( 0.693 )
        Week 12|
    0.33 ( 0.772 )
    0.48 ( 0.850 )
        Week 24|
    0.44 ( 0.949 )
    0.35 ( 0.466 )
    No statistical analyses for this end point

    Secondary: Treatment period 1 - ESR levels at Baseline and Weeks 4, 12 and 24

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    End point title
    		 Treatment period 1 - ESR levels at Baseline and Weeks 4, 12 and 24
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 1, Weeks 4, 12 and 24
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    168
    155
    Units: mm/h
    arithmetic mean (standard deviation)
        Baseline|
    41.4 ( 16.89 )
    41.8 ( 17.94 )
        Week 4|
    26.5 ( 16.51 )
    26.7 ( 17.27 )
        Week 12|
    23.2 ( 14.67 )
    23.8 ( 15.41 )
        Week 24|
    21.4 ( 15.47 )
    20.8 ( 14.05 )
    No statistical analyses for this end point

    Secondary: Treatment period 2: DAS28-CRP and DAS28-ESR scores up to Week 48;

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    End point title
    		 Treatment period 2: DAS28-CRP and DAS28-ESR scores up to Week 48;
    End point description
    DAS28-CRP and DAS28-ESR: a. best is 0, b. < 2.6 – remission, c. ≥ 2.6 to ≤ 3.2 – low disease activity d. > 3.2 to ≤ 5.1 – moderate disease activity e. > 5.1 – high disease activity
    End point type
    Secondary
    End point timeframe
    Treatment period 1 and 2, week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: score on a scale
    arithmetic mean (standard deviation)
        DAS28-CRP Baseline|
    5.45 ( 0.914 )
    5.57 ( 0.794 )
        DAS28-CRP Week 4|
    3.89 ( 1.053 )
    3.79 ( 1.101 )
        DAS28-CRP Week 12|
    3.20 ( 1.038 )
    3.27 ( 1.127 )
        DAS28-CRP Week 24|
    2.64 ( 0.863 )
    2.67 ( 0.892 )
        DAS28-CRP Week 36|
    2.65 ( 1.001 )
    2.74 ( 1.017 )
        DAS28-CRP Week 48|
    2.57 ( 1.067 )
    2.74 ( 1.062 )
        DAS28-ESR Baseline|
    6.39 ( 0.872 )
    6.43 ( 0.784 )
        DAS28-ESR Week 4|
    4.70 ( 1.175 )
    4.49 ( 1.228 )
        DAS28-ESR Week 12|
    3.90 ( 1.236 )
    3.85 ( 1.317 )
        DAS28-ESR Week 24|
    3.23 ( 1.022 )
    3.19 ( 1.048 )
        DAS28-ESR Week 36|
    3.25 ( 1.160 )
    3.28 ( 1.127 )
        DAS28-ESR Week 48|
    3.20 ( 1.201 )
    3.30 ( 1.177 )
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Changes from baseline in DAS28-CRP and DAS28-ESR scores from Week 4 up to Week 48

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    End point title
    		 Treatment period 2 : Changes from baseline in DAS28-CRP and DAS28-ESR scores from Week 4 up to Week 48
    End point description
    End point type
    Secondary
    End point timeframe
    treatment period 2, up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: score on a scale
    arithmetic mean (standard deviation)
        DAS28-CRP change from baseline, week 4|
    -1.55 ( 1.014 )
    -1.76 ( 1.014 )
        DAS28-CRP change from baseline, week 12|
    -2.22 ( 1.031 )
    -2.27 ( 1.096 )
        DAS28-CRP change from baseline, week 24|
    -2.81 ( 1.007 )
    -2.90 ( 0.988 )
        DAS28-CRP change from baseline, week 36|
    -2.80 ( 1.087 )
    -2.82 ( 1.151 )
        DAS28-CRP change from baseline, week 48|
    -2.88 ( 1.198 )
    -2.83 ( 1.176 )
        DAS28-ESR change from baseline, week 4|
    -1.69 ( 1.048 )
    -1.92 ( 1.087 )
        DAS28-ESR change from baseline, week 12|
    -2.49 ( 1.152 )
    -2.57 ( 1.235 )
        DAS28-ESR change from baseline, week 24|
    -3.16 ( 1.106 )
    -3.23 ( 1.054 )
        DAS28-ESR change from baseline, week 36|
    -3.13 ( 1.232 )
    -3.14 ( 1.154 )
        DAS28-ESR change from baseline, week 48|
    -3.20 ( 1.297 )
    -3.14 ( 1.190 )
    No statistical analyses for this end point

    Secondary: Treatment period 2: proportion of patients achieving EULAR reponse

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    End point title
    		 Treatment period 2: proportion of patients achieving EULAR reponse
    End point description
    Proportion of patients achieving EULAR good response (defined as DAS28 ≤ 3.2 and DAS28 improvement from Baseline > 1.2) and moderate response (defined as DAS28 ≤ 3.2 and DAS28 improvement > 0.6 and ≤ 1.2, or DAS28 > 3.2 and ≤ 5.1 and DAS28 improvement > 0.6 or DAS28 > 5.1 but DAS28 improvement > 1.2) at Weeks 36 and 48;
    End point type
    Secondary
    End point timeframe
    Treatment period 2: Week 36, week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: Participants
        Good response week 4|
    20
    20
        Good response week 12|
    43
    43
        Good response week 24|
    77
    68
        Good response week 36|
    82
    65
        Good response week 48|
    80
    67
        Moderate response week 4|
    85
    82
        Moderate response week 12|
    95
    75
        Moderate response week 24|
    71
    63
        Moderate response week 36|
    62
    64
        Moderate response week 48|
    61
    57
        no response week 4|
    42
    28
        no response week 12|
    10
    12
        no response week 24|
    0
    0
        no response week 36|
    3
    2
        no response week 48|
    6
    5
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Proportion of patients achieving DAS28 < 2.6 at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 : Proportion of patients achieving DAS28 < 2.6 at Weeks 36 and 48;
    End point description
    percentage of participants in DAS28-ESR categories up to week 48
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: Participants
        Week 36 Remission (DAS28 < 2.6)|
    45
    38
        Week 48 Remission (DAS28 < 2.6)|
    44
    35
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Proportion of patients achieving EULAR/ACR Boolean remission criteria

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    End point title
    		 Treatment period 2 : Proportion of patients achieving EULAR/ACR Boolean remission criteria
    End point description
    Proportion of patients achieving EULAR/ACR Boolean remission criteria (defined as number of tender joints/swollen joints ≤ 1 and CRP (mg/dL) ≤ 1 and patient global assessment (1–10) ≤ 1) at Weeks 36 and 48;
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: participants
        Week 4|
    0
    2
        Week 12|
    9
    8
        Week 24|
    22
    13
        Week 36|
    25
    15
        Week 48|
    28
    20
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Proportion of patients achieving ACR20/50/70 response at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 : Proportion of patients achieving ACR20/50/70 response at Weeks 36 and 48;
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: participants
        ACR20 response Week 36|
    128
    114
        ACR20 response Week 48|
    131
    108
        ACR50 response Week 36|
    90
    83
        ACR50 response Week 48|
    93
    86
        ACR70 response Week 36|
    47
    50
        ACR70 response Week 48|
    54
    55
    No statistical analyses for this end point

    Secondary: Treatment period 2 : ACR-N scores at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 : ACR-N scores at Weeks 36 and 48;
    End point description
    ACR-N: negative is worsening, positive (up to 100) is an improvement
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 4|
    19.7 ( 27.72 )
    24.9 ( 29.40 )
        Week 12|
    38.3 ( 27.84 )
    40.7 ( 34.80 )
        Week 24|
    56.3 ( 26.58 )
    60.9 ( 24.79 )
        Week 36|
    53.8 ( 28.21 )
    55.7 ( 28.37 )
        Week 48|
    56.9 ( 29.18 )
    56.4 ( 30.58 )
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Proportion of patients in each disease activity category as defined by SDAI

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    End point title
    		 Treatment period 2 : Proportion of patients in each disease activity category as defined by SDAI
    End point description
    Proportion of patients in each disease activity category as defined by the Simplified Disease Activity Index (SDAI): high disease activity, SDAI > 26, moderate disease activity, SDAI > 11 to ≤ 26, low disease activity, SDAI > 3.3 to ≤ 11, and remission, SDAI ≤ 3.3 at Weeks 36 and 48.
    End point type
    Secondary
    End point timeframe
    treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: Participants
        Baseline : Remission (SDAI <= 3.3)|
    0
    0
        Baseline : Low (3.3 < SDAI <= 11)|
    0
    0
        Baseline : Moderate (11 < SDAI <= 26)|
    20
    16
        Baseline : High (SDAI > 26 )|
    128
    115
        Week 4 : Remission (SDAI <= 3.3)|
    2
    4
        Week 4 : Low (3.3 < SDAI <= 11)|
    29
    27
        Week 4 : Moderate (11 < SDAI <= 26|
    75
    69
        Week 4 : High (SDAI > 26 )|
    39
    29
        Week 12: Remission (SDAI <= 3.3)|
    14
    12
        Week 12 : Low (3.3 < SDAI <= 11)|
    50
    51
        Week 12 : Moderate (11 < SDAI <= 26|
    69
    53
        Week 12 : High (SDAI > 26 )|
    13
    11
        Week 24: Remission (SDAI <= 3.3)|
    31
    29
        Week 24 : Low (3.3 < SDAI <= 11)|
    74
    71
        Week 24 : Moderate (11 < SDAI <= 26|
    43
    29
        Week 24 : High (SDAI > 26 )|
    0
    2
        Week 36: Remission (SDAI <= 3.3)|
    34
    29
        Week 36 : Low (3.3 < SDAI <= 11|
    69
    66
        Week 36 : Moderate (11 < SDAI <= 26|
    43
    30
        Week 36 : High (SDAI > 26 )|
    1
    5
        Week 48: Remission (SDAI <= 3.3)|
    39
    32
        Week 48 : Low (3.3 < SDAI <= 11|
    72
    62
        Week 48 : Moderate (11 < SDAI <= 26|
    30
    29
        Week 48 : High (SDAI > 26 )|
    6
    8
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Proportion of patients in each disease activity category as defined by CDAI

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    End point title
    		 Treatment period 2 : Proportion of patients in each disease activity category as defined by CDAI
    End point description
    Proportion of patients in each disease activity category as defined by the Clinical Disease Activity Index (CDAI): high disease activity, CDAI > 22, moderate disease activity, CDAI > 10 to ≤ 22, low disease activity, CDAI > 2.8 to ≤ 10, and remission, CDAI ≤ 2.8 at Weeks 36 and 48;
    End point type
    Secondary
    End point timeframe
    treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: Participants
        Baseline : Remission (CDAI <=2.8)|
    0
    0
        Baseline : Low (2.8 < CDAI <= 10)|
    0
    0
        Baseline : Moderate (10 < CDAI <= 22)|
    14
    6
        Baseline : High (CDAI > 22 )|
    134
    125
        Week 4 : Remission (CDAI <=2.8)|
    2
    3
        Week 4 : Low (2.8 < CDAI <= 10)|
    27
    28
        Week 4 : Moderate (11 < SDAI <= 26|
    60
    60
        Week 4 : High (CDAI > 22 )|
    58
    39
        Week 12: Remission (CDAI <=2.8)|
    12
    14
        Week 12 : Low (2.8 < CDAI <= 10)|
    52
    47
        Week 12 : Moderate (10 < CDAI <= 22)|
    67
    50
        Week 12 : High (CDAI > 22 )|
    17
    19
        Week 24: Remission (CDAI <=2.8)|
    29
    29
        Week 24 : Low (2.8 < CDAI <= 10)|
    71
    68
        Week 24 : Moderate (10 < CDAI <= 22)|
    45
    30
        Week 24 : High (CDAI > 22 )|
    3
    4
        Week 36: Remission (CDAI <=2.8)|
    32
    29
        Week 36 : Low (2.8 < CDAI <= 10)|
    67
    63
        Week 36 : Moderate (10 < CDAI <= 22)|
    41
    32
        Week 36 : High (CDAI > 22 )|
    7
    7
        Week 48: Remission (CDAI <=2.8)|
    37
    29
        Week 48 : Low (2.8 < CDAI <= 10)|
    71
    63
        Week 48 : Moderate (10 < CDAI <= 22)|
    32
    31
        Week 48 : High (CDAI > 22 )|
    7
    8
    No statistical analyses for this end point

    Secondary: Treatment period 2 :Proportion of patients achieving HAQ index in normal range (≤ 0.5) at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 :Proportion of patients achieving HAQ index in normal range (≤ 0.5) at Weeks 36 and 48;
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: participants
        Baseline|
    8
    4
        Week 4|
    17
    25
        Week 12|
    33
    39
        Week 24|
    47
    51
        Week 36|
    46
    48
        Week 48|
    51
    51
    No statistical analyses for this end point

    Secondary: Treatment period 2 :HAQ index at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 :HAQ index at Weeks 36 and 48;
    End point description
    HAQ: from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    1.47 ( 0.547 )
    1.50 ( 0.554 )
        Week 4|
    1.22 ( 0.554 )
    1.14 ( 0.620 )
        Week 12|
    1.04 ( 0.560 )
    0.97 ( 0.614 )
        Week 24|
    0.88 ( 0.594 )
    0.83 ( 0.603 )
        Week 36|
    0.89 ( 0.584 )
    0.85 ( 0.651 )
        Week 48|
    0.85 ( 0.609 )
    0.84 ( 0.652 )
    No statistical analyses for this end point

    Secondary: Treatment period 2 : Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale relative to Baseline at Weeks 36 and 48;

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    End point title
    		 Treatment period 2 : Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale relative to Baseline at Weeks 36 and 48;
    End point description
    FACIT: from 0 (worst) to 52 (best), a score of less than 30 indicates severe fatigue
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline|
    26.6 ( 9.71 )
    25.5 ( 10.78 )
        Week 4|
    31.5 ( 8.72 )
    31.3 ( 10.07 )
        Week 12|
    34.4 ( 8.89 )
    34.1 ( 9.69 )
        Week 24|
    36.6 ( 8.75 )
    36.7 ( 9.05 )
        Week 36|
    36.9 ( 8.79 )
    36.4 ( 9.50 )
        Week 48|
    38.0 ( 8.74 )
    35.8 ( 9.97 )
    No statistical analyses for this end point

    Secondary: Treatment period 2 : CRP levels at week 36 and 48

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    End point title
    		 Treatment period 2 : CRP levels at week 36 and 48
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: mg/dL
    arithmetic mean (standard deviation)
        Baseline|
    1.21 ( 2.244 )
    1.17 ( 1.589 )
        Week 4|
    0.36 ( 0.733 )
    0.42 ( 0.625 )
        Week 12|
    0.36 ( 0.817 )
    0.50 ( 0.910 )
        Week 24|
    0.44 ( 0.964 )
    0.36 ( 0.487 )
        Week 36|
    0.39 ( 0.758 )
    0.39 ( 0.655 )
        Week 48|
    0.35 ( 0.623 )
    0.40 ( 0.878 )
    No statistical analyses for this end point

    Secondary: Treatment period 2 : ESR levels at week 36 and 48

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    End point title
    		 Treatment period 2 : ESR levels at week 36 and 48
    End point description
    End point type
    Secondary
    End point timeframe
    Treatment period 2 : up to week 48
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    148
    131
    Units: mm/h
    arithmetic mean (standard deviation)
        Baseline|
    42.2 ( 16.99 )
    41.7 ( 17.99 )
        Week 4|
    26.8 ( 16.33 )
    25.3 ( 16.11 )
        Week 12|
    23.8 ( 15.07 )
    23.0 ( 15.38 )
        Week 24|
    21.3 ( 15.66 )
    19.3 ( 12.66 )
        Week 36|
    22.1 ( 16.41 )
    20.3 ( 14.28 )
        Week 48|
    22.8 ( 16.66 )
    20.8 ( 14.62 )
    No statistical analyses for this end point

    Secondary: Safety - Overall study : Frequency and severity of injection site reactions in GP2015 and Enbrel

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    End point title
    		 Safety - Overall study : Frequency and severity of injection site reactions in GP2015 and Enbrel
    End point description
    Frequency of participants with injection site reactions in GP2015 and Enbrel
    End point type
    Secondary
    End point timeframe
    up to 48 weeks
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    186
    190
    Units: participants
        participants with at least one ISR|
    13
    37
        participants with at least one moderate ISR|
    1
    7
        participants with at least one severe ISR|
    0
    0
    No statistical analyses for this end point

    Secondary: Safety : Overall study: Immunogenicity by measuring the rate of anti-drug antibody (ADA) positive patients

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    End point title
    		 Safety : Overall study: Immunogenicity by measuring the rate of anti-drug antibody (ADA) positive patients
    End point description
    To assess the immunogenicity of continuous GP2015 treatment versus a treatment transition from Enbrel to GP2015 after 24 weeks of treatment by measuring the rate of ADA positive participants at Weeks 24, 30, 36 and 48. summary of ADA positive data up to week 48 using a 1% false positive cut point
    End point type
    Secondary
    End point timeframe
    up to 48 weeks
    End point values
    		 50mg GP2015 50mg EU-authorized Enbrel
    Number of subjects analysed
    186
    190
    Units: participants
        Baseline|
    2
    0
        Week 2|
    2
    5
        Week 4|
    3
    42
        Week 12|
    0
    5
        Week 24|
    0
    0
        Week 30|
    2
    0
        Week 36|
    0
    0
        Week 48|
    2
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Treatment Period 1 TP1 SAF GP2015
    Reporting group description
    		 Treatment Period 1 TP1 SAF GP2015

    Reporting group title
    Treatment Period 1 TP1 SAF Enbrel
    Reporting group description
    		 Treatment Period 1 TP1 SAF Enbrel

    Reporting group title
    Treatment Period 2 TP2 SAF Continued GP2015
    Reporting group description
    		 Treatment Period 2 TP2 SAF Continued GP2015

    Reporting group title
    Treatment Period 2 TP2 SAF Enbrel switched to GP2015
    Reporting group description
    		 Treatment Period 2 TP2 SAF Enbrel switched to GP2015

    Reporting group title
    Entire study SAF GP2015
    Reporting group description
    		 Entire study SAF GP2015

    Reporting group title
    Entire study SAF Enbrel/GP2015
    Reporting group description
    		 Entire study SAF Enbrel/GP2015

    Serious adverse events
    		 Treatment Period 1 TP1 SAF GP2015 Treatment Period 1 TP1 SAF Enbrel Treatment Period 2 TP2 SAF Continued GP2015 Treatment Period 2 TP2 SAF Enbrel switched to GP2015 Entire study SAF GP2015 Entire study SAF Enbrel/GP2015
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 186 (0.54%)
    5 / 190 (2.63%)
    4 / 175 (2.29%)
    4 / 166 (2.41%)
    5 / 186 (2.69%)
    9 / 190 (4.74%)
         number of deaths (all causes)
    0
    1
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    1 / 166 (0.60%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon adenoma
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    1 / 166 (0.60%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Injury, poisoning and procedural complications
    Spinal fracture
         subjects affected / exposed
    1 / 186 (0.54%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    1 / 175 (0.57%)
    0 / 166 (0.00%)
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    1 / 166 (0.60%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Salivary gland cyst
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    1 / 175 (0.57%)
    0 / 166 (0.00%)
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    1 / 166 (0.60%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis haemorrhagic
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    1 / 175 (0.57%)
    0 / 166 (0.00%)
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 186 (0.00%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    0 / 166 (0.00%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    0 / 175 (0.00%)
    1 / 166 (0.60%)
    0 / 186 (0.00%)
    1 / 190 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 186 (0.00%)
    0 / 190 (0.00%)
    1 / 175 (0.57%)
    0 / 166 (0.00%)
    1 / 186 (0.54%)
    0 / 190 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Treatment Period 1 TP1 SAF GP2015 Treatment Period 1 TP1 SAF Enbrel Treatment Period 2 TP2 SAF Continued GP2015 Treatment Period 2 TP2 SAF Enbrel switched to GP2015 Entire study SAF GP2015 Entire study SAF Enbrel/GP2015
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 186 (27.96%)
    64 / 190 (33.68%)
    42 / 175 (24.00%)
    37 / 166 (22.29%)
    79 / 186 (42.47%)
    81 / 190 (42.63%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 186 (4.30%)
    4 / 190 (2.11%)
    4 / 175 (2.29%)
    6 / 166 (3.61%)
    12 / 186 (6.45%)
    8 / 190 (4.21%)
         occurrences all number
    8
    4
    4
    6
    12
    10
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 186 (1.08%)
    2 / 190 (1.05%)
    2 / 175 (1.14%)
    0 / 166 (0.00%)
    4 / 186 (2.15%)
    2 / 190 (1.05%)
         occurrences all number
    2
    2
    2
    0
    4
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 186 (0.54%)
    1 / 190 (0.53%)
    0 / 175 (0.00%)
    4 / 166 (2.41%)
    1 / 186 (0.54%)
    5 / 190 (2.63%)
         occurrences all number
    1
    1
    0
    4
    1
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 186 (1.08%)
    1 / 190 (0.53%)
    2 / 175 (1.14%)
    1 / 166 (0.60%)
    4 / 186 (2.15%)
    2 / 190 (1.05%)
         occurrences all number
    3
    1
    2
    1
    5
    2
    General disorders and administration site conditions
    Injection site reaction
         subjects affected / exposed
    13 / 186 (6.99%)
    35 / 190 (18.42%)
    0 / 175 (0.00%)
    6 / 166 (3.61%)
    13 / 186 (6.99%)
    37 / 190 (19.47%)
         occurrences all number
    37
    155
    0
    33
    37
    188
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 186 (1.61%)
    4 / 190 (2.11%)
    1 / 175 (0.57%)
    2 / 166 (1.20%)
    4 / 186 (2.15%)
    6 / 190 (3.16%)
         occurrences all number
    3
    4
    1
    2
    4
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 186 (2.69%)
    1 / 190 (0.53%)
    3 / 175 (1.71%)
    0 / 166 (0.00%)
    8 / 186 (4.30%)
    1 / 190 (0.53%)
         occurrences all number
    5
    1
    3
    0
    8
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 190 (2.11%)
    2 / 175 (1.14%)
    2 / 166 (1.20%)
    4 / 186 (2.15%)
    6 / 190 (3.16%)
         occurrences all number
    2
    4
    2
    2
    4
    6
    Cystitis
         subjects affected / exposed
    2 / 186 (1.08%)
    4 / 190 (2.11%)
    2 / 175 (1.14%)
    1 / 166 (0.60%)
    4 / 186 (2.15%)
    5 / 190 (2.63%)
         occurrences all number
    2
    4
    2
    1
    4
    5
    Nasopharyngitis
         subjects affected / exposed
    9 / 186 (4.84%)
    4 / 190 (2.11%)
    13 / 175 (7.43%)
    9 / 166 (5.42%)
    18 / 186 (9.68%)
    12 / 190 (6.32%)
         occurrences all number
    9
    4
    13
    10
    22
    14
    Pharyngitis
         subjects affected / exposed
    1 / 186 (0.54%)
    3 / 190 (1.58%)
    2 / 175 (1.14%)
    1 / 166 (0.60%)
    3 / 186 (1.61%)
    4 / 190 (2.11%)
         occurrences all number
    1
    3
    2
    1
    3
    4
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 186 (3.23%)
    7 / 190 (3.68%)
    9 / 175 (5.14%)
    9 / 166 (5.42%)
    13 / 186 (6.99%)
    15 / 190 (7.89%)
         occurrences all number
    6
    7
    11
    10
    17
    17
    Urinary tract infection
         subjects affected / exposed
    8 / 186 (4.30%)
    8 / 190 (4.21%)
    7 / 175 (4.00%)
    2 / 166 (1.20%)
    13 / 186 (6.99%)
    8 / 190 (4.21%)
         occurrences all number
    8
    8
    7
    3
    15
    11
    Viral upper respiratory tract infection
         subjects affected / exposed
    2 / 186 (1.08%)
    0 / 190 (0.00%)
    2 / 175 (1.14%)
    2 / 166 (1.20%)
    4 / 186 (2.15%)
    2 / 190 (1.05%)
         occurrences all number
    2
    0
    2
    2
    4
    2
    Metabolism and nutrition disorders
    Hyperuricaemia
         subjects affected / exposed
    3 / 186 (1.61%)
    1 / 190 (0.53%)
    2 / 175 (1.14%)
    0 / 166 (0.00%)
    4 / 186 (2.15%)
    1 / 190 (0.53%)
         occurrences all number
    4
    1
    2
    0
    6
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Sep 2015
    This amendment contains changes requested by Competent Authorities/Ethics Committees as part of the Voluntary Harmonisation Procedure (VHP) approval process. In addition, minor discrepancies and misspellings were corrected (changes in excl. criteria )
    15 Feb 2016
    This amendment contains changes recommended by the health authorities and in reply to the questions related to IND/CTA submission, such as clarification related to the use of DAS28 (based on ESR) for the decision about transition, and change in incl. excl. criteria. In addition, minor discrepancies,misspellings, and organizational details were corrected and clarifications added.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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