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    Clinical Trial Results:
    A randomized, double-blind, parallel-group, multicenter study to demonstrate similar efficacy and to compare safety and immunogenicity of GP2017 and Humira in patients with moderate to severe active rheumatoid arthritis

    Summary
    EudraCT number
    		 2015-003433-10
    Trial protocol
    		 CZ   GB   DE   HU   RO   ES   IT  
    Global end of trial date
    26 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2018
    First version publication date
    07 Oct 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    Hexal AG/Sandoz Inc
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02744755
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hexal AG/ Sandoz
    Sponsor organisation address
    Industriestr. 25, Holzkirchen, Germany, 83807
    Public contact
    Sandoz Biopharma Clinical Development - Strategic Planning, Sandoz, +49 (0)80244760, biopharma.clinicaltrials@sandoz.com
    Scientific contact
    Sandoz Biopharma Clinical Development - Strategic Planning, Sandoz, +49 (0)80244760, 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
    26 Sep 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial is to demonstrate similar efficacy of GP2017 and US-licensed Humira in patients with moderate to severe active RA with respect to DAS28-CRP score change from baseline at Week 12.
    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
    29 Mar 2016
    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
    Czech Republic: 42
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Malaysia: 4
    Country: Number of subjects enrolled
    Mexico: 38
    Country: Number of subjects enrolled
    Poland: 91
    Country: Number of subjects enrolled
    Romania: 15
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    Serbia: 11
    Country: Number of subjects enrolled
    Spain: 14
    Country: Number of subjects enrolled
    United States: 84
    Worldwide total number of subjects
    353
    EEA total number of subjects
    205
    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)
    285
    From 65 to 84 years
    67
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 353 patients were randomized (1:1)and received at least one dose of study drug; 303 patients completed the study.Eligible patients in the Humira group who completed Study Period 1 (baseline to week 24) with an at least moderate response by DAS28-CRP score were switched to GP2017 treatment during Study Period 2 (Week 24 to week 48).

    Pre-assignment
    Screening details
    		 Full analysis set: randomized patients (study drug assigned) Per protocol set study period 1 (SP1) / study period 2(SP2): patients who completed Week 12 (SP1) / Week 48 (SP2) without major protocol deviations and received at least 5 doses of study drug up to Week 10 (SP1) / 10 doses of IMP from Week 24 to Week 46 (SP2)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GP2017
    Arm description
    		 Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2017
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GP2017 in pre-filled syringes for subcutaneous injection containing 40 mg of active ingredient in 0.8 mL of solution

    Arm title
    		 Humira / switched GP2017
    Arm description
    		 Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Humira
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Humira in pre-filled syringes for subcutaneous injection containing 40 mg of active ingredient in 0.8 mL of solution

    Number of subjects in period 1
    		GP2017 Humira / switched GP2017
    Started
    177
    176
    Completed
    163
    168
    Not completed
    14
    8
         Consent withdrawn by subject
    8
    4
         not defined
    -
    1
         Adverse event, non-fatal
    1
    1
         Pregnancy
    1
    -
         Lost to follow-up
    1
    1
         Protocol deviation
    2
    1
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    Study period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GP2017
    Arm description
    		 Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2017
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GP2017 in pre-filled syringes for subcutaneous injection containing 40 mg of active ingredient in 0.8 mL of solution

    Arm title
    		 Humira / switched GP2017
    Arm description
    		 Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
    Arm type
    		 Switched to Experimental

    Investigational medicinal product name
    GP2017
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    GP2017 in pre-filled syringes for subcutaneous injection containing 40 mg of active ingredient in 0.8 mL of solution

    Number of subjects in period 2 [1]
    		GP2017 Humira / switched GP2017
    Started
    159
    166
    Completed
    145
    158
    Not completed
    14
    8
         Consent withdrawn by subject
    2
    2
         not defined
    3
    2
         Adverse event, non-fatal
    5
    -
         Lost to follow-up
    -
    2
         Protocol deviation
    1
    -
         Lack of efficacy
    3
    2
    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

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GP2017
    Reporting group description
    		 Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).

    Reporting group title
    Humira / switched GP2017
    Reporting group description
    		 Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).

    Reporting group values
    		 GP2017 Humira / switched GP2017 Total
    Number of subjects
    		 177 176 353
    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)
    		 145 140 285
        From 65-84 years
    		 32 35 67
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 12.81 ) 53.8 ( 12.22 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 153 142 295
        Male
    		 24 34 58
    Race/Ethnicity, Customized
    Units: Subjects
        White|
    		 152 152 304
        American Indian or Alaska Native|
    		 14 15 29
        Black or African American|
    		 6 3 9
        Asian|
    		 1 3 4
        Other|
    		 4 3 7

    End points

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    End points reporting groups
    Reporting group title
    GP2017
    Reporting group description
    		 Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).

    Reporting group title
    Humira / switched GP2017
    Reporting group description
    		 Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).
    Reporting group title
    GP2017
    Reporting group description
    		 Group 1 received treatment with 40 mg GP2017 in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response continued treatment with 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).

    Reporting group title
    Humira / switched GP2017
    Reporting group description
    		 Group 2 received treatment with 40 mg Humira in 0.8 mL of solution administered subcutaneously from pre-filled syringes up to 24 weeks (study Period 1) after which patients achieving at least a moderate clinical response were switched to 40mg GP2017 subcutaneous injection up to 46 weeks (study Period 2).

    Primary: Study period 1: Change in DAS28-CRP score from baseline at week 12 in patients treated with GP2017 and patients treated with Humira

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    End point title
    		 Study period 1: Change in DAS28-CRP score from baseline at week 12 in patients treated with GP2017 and patients treated with Humira
    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 (GDA) or general health (GH), 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 or GH + 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
    Study period 1: week 12
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    140
    144
    Units: scores on a scale
        least squares mean (standard error)
    -2.16 ( 0.114 )
    -2.18 ( 0.110 )
    Statistical analysis title
    		 equivalence assessment between GP2017 and Humira
    Statistical analysis description
    Therapeutic equivalence in terms of change from baseline in DAS28-CRP at week 12 will be concluded if the 95% confidence interval for the LS mean difference between GP2017 and Humira 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
    GP2017 v Humira / switched GP2017
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [1]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.24
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Notes
    [1] - A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
    Statistical analysis title
    		 equivalence assessment between GP2017 and Humira
    Statistical analysis description
    Therapeutic equivalence in terms of change from baseline in DAS28-CRP at week 12 will be concluded if the 90% confidence interval for the LS mean difference between GP2017 and Humira 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
    GP2017 v Humira / switched GP2017
    Number of subjects included in analysis
    284
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [2]
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.02
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.129
    Notes
    [2] - A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].

    Secondary: Study period 1: time-weighted averaged change from baseline in DAS28-CRP until Week 24 in patients treated with GP2017 and with Humira

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    End point title
    		 Study period 1: time-weighted averaged change from baseline in DAS28-CRP until Week 24 in patients treated with GP2017 and with Humira
    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 (GDA) or general health (GH), 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 or GH + 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
    Secondary
    End point timeframe
    Study period 1: week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: scores on a scale
        least squares mean (standard error)
    -1.85 ( 0.098 )
    -1.93 ( 0.092 )
    Statistical analysis title
    		 equivalence assessment between GP2017 and Humira
    Statistical analysis description
    ANCOVA model included treatment, body weight as per CRF, prior therapy as per CRF, region as per CRF as fixed effects and baseline DAS28-CRP values as covariate.
    Comparison groups
    GP2017 v Humira / switched GP2017
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [3]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.27
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.096
    Notes
    [3] - A 0.6 change in DAS28-CRP score is considered as no clinically meaningful difference by EULAR criteria and is therefore used as the equivalence margin limits [0.6,-0.6].
    Statistical analysis title
    		 equivalence assessment between GP2017 and Humira
    Comparison groups
    GP2017 v Humira / switched GP2017
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [4]
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.08
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 -0.08
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.096
    Notes
    [4] - ANCOVA model included treatment, body weight as per CRF, prior therapy as per CRF, region as per CRF as fixed effects and baseline DAS28-CRP values as covariate.

    Secondary: Study period 1- Proportion of patients achieving EULAR criterion for remission

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    End point title
    		 Study period 1- Proportion of patients achieving EULAR criterion for remission
    End point description
    Proportion of patients achieving European League against Rheumatism (EULAR) remission (defined as DAS28 CRP < 2.6 )
    End point type
    Secondary
    End point timeframe
    week 4, week 12 and week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: Participants
        EULAR remission week 4|
    15
    7
        EULAR remission week 12|
    32
    38
        EULAR remission week 24|
    49
    71
    No statistical analyses for this end point

    Secondary: Study period 1- Proportion of patients achieving EULAR criterion for good response

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    End point title
    		 Study period 1- Proportion of patients achieving EULAR criterion for good response
    End point description
    Proportion of patients achieving European League against Rheumatism (EULAR) good response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >1.2 in DAS28 from baseline.)
    End point type
    Secondary
    End point timeframe
    week 4, week 12 and week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: Participants
        Good response week 4|
    22
    25
        Good response week 12|
    51
    63
        Good response week 24|
    76
    93
    No statistical analyses for this end point

    Secondary: Study period 1- Proportion of patients achieving EULAR criterion for moderate response

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    End point title
    		 Study period 1- Proportion of patients achieving EULAR criterion for moderate response
    End point description
    Proportion of patients achieving European League against Rheumatism (EULAR) moderate response (defined as DAS28<=3.2 at post-baseline assessment timepoint(s) with an improvement of >0.6 to <=1.2 from baseline or DAS28 >3.2 to <=5.1 with an improvement of >0.6 to <=1.2 or of >1.2 from baseline or DAS28 >5.1 with an improvement of >1.2 from baseline) ;
    End point type
    Secondary
    End point timeframe
    week 4, week 12 and week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: Participants
        Moderate response week 4|
    63
    78
        Moderate response week 12|
    64
    62
        Moderate response week 24|
    42
    42
    No statistical analyses for this end point

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

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    End point title
    		 Study 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 joint count 28 <=1 and swollen joint count 28 <=1, CRP level (mg/dL) <=1 and patient's global assessment <=1 on a scale of 1-10 (corresponding to <=10 on a scale of 1-100).
    End point type
    Secondary
    End point timeframe
    week 4, week 12, week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: participants
        week 4|
    4
    0
        week 12|
    8
    12
        week 24|
    19
    26
    No statistical analyses for this end point

    Secondary: Study period 1: Change in DAS28-CRP and DAS28-ESR scores from baseline to week 24 in patients treated with GP2017 and patients treated with Humira

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    End point title
    		 Study period 1: Change in DAS28-CRP and DAS28-ESR scores from baseline to week 24 in patients treated with GP2017 and patients treated with Humira
    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 (GDA) or general health (GH), 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 or GH + 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. For DAS-28 ESR, DAS28-ESR = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.70 * ln(ESR) + 0.014 * GH
    End point type
    Secondary
    End point timeframe
    study period 1: week 2, 4, 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: scores on a scale
    least squares mean (standard error)
        DAS28 CRP week 2|
    -0.86 ( 0.107 )
    -0.92 ( 0.101 )
        DAS28 CRP week 4|
    -1.31 ( 0.112 )
    -1.36 ( 0.105 )
        DAS28 CRP week 24|
    -2.61 ( 0.109 )
    -2.83 ( 0.103 )
        DAS28 ESR week 2|
    -0.94 ( 0.115 )
    -0.98 ( 0.109 )
        DAS28 ESR week 4|
    -1.51 ( 0.124 )
    -1.51 ( 0.117 )
        DAS28 ESR week 24|
    -2.97 ( 0.127 )
    -3.16 ( 0.120 )
    No statistical analyses for this end point

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

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    End point title
    		 Study 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: -at least 20% improvement in tender 68 joint count -at least 20% improvement in swollen 66 joint-count; And at least 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 index(HAQ-DI© 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
    Week 4, week 12 and week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: participants
        ACR20 response Week 4|
    64
    71
        ACR20 response Week 12|
    100
    106
        ACR20 response Week 24|
    111
    130
        ACR50 response Week 4|
    25
    25
        ACR50 response Week 12|
    53
    67
        ACR50 response Week 24|
    78
    98
        ACR70 response Week 4|
    7
    9
        ACR70 response Week 12|
    24
    35
        ACR70 response Week 24|
    48
    53
    No statistical analyses for this end point

    Secondary: Study period 1 - changes from Baseline in Health assessment questionnaire-Disability index (HAQ-DI©) at Weeks 4, 12 and 24;

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    End point title
    		 Study period 1 - changes from Baseline in Health assessment questionnaire-Disability index (HAQ-DI©) at Weeks 4, 12 and 24;
    End point description
    Health assessment questionnaire (HAQ-DI©) disability index ranges from 0 (best) to 3 (worst).The HAQ© was scored in accordance with the recommendation from the developers outlined in the “HAQ PACK” from Stanford University, California. Ramey Dr, Fries JF, Singh G. in B. Spilker Quality of Life and Pharmacoleconomics in Clinical Trials, 2nd ed, The Health Assessment Questionnaire 1995 -- Status and Review. Philadelphia: Lippincott-Raven Pub., 1996, p 227 – 237. Fries JF, Spitz P, Kraines G, Holman H. Measurement of Patient Outcome in Arthritis, Arthritis and Rheumatism, 1980, 23:137-145.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24;
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 4|
    -0.32 ( 0.519 )
    -0.32 ( 0.449 )
        Week 12|
    -0.50 ( 0.576 )
    -0.47 ( 0.501 )
        Week 24|
    -0.63 ( 0.610 )
    -0.59 ( 0.543 )
    No statistical analyses for this end point

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

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    End point title
    		 Study period 1- Proportion of patients achieving HAQ-DI© in normal range (≤ 0.5) at Weeks 4, 12 and 24;
    End point description
    Health assessment questionnaire disability index (HAQ-DI©) ranges from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24;
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: participants
        Week 4|
    27
    33
        Week 12|
    38
    40
        Week 24|
    46
    50
    No statistical analyses for this end point

    Secondary: Study period 1- Proportion of patients achieving HAQ-DI© score improvement >0.3 at Weeks 4, 12 and 24

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    End point title
    		 Study period 1- Proportion of patients achieving HAQ-DI© score improvement >0.3 at Weeks 4, 12 and 24
    End point description
    Health assessment questionnaire (HAQ-DI©) disability index ranges from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24;
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: participants
        Week 4|
    106
    117
        Week 12|
    102
    109
        Week 24|
    91
    106
    No statistical analyses for this end point

    Secondary: Study period 1 - Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue scale relative to Baseline at Weeks 4, 12 and 24 (change from baseline)

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    End point title
    		 Study period 1 - Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue scale relative to Baseline at Weeks 4, 12 and 24 (change from baseline)
    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).
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12 and 24;
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: score on a scale
    arithmetic mean (standard deviation)
        Week 4|
    6.59 ( 7.949 )
    7.25 ( 8.591 )
        Week 12|
    10.49 ( 9.218 )
    10.62 ( 9.134 )
        Week 24|
    12.57 ( 10.760 )
    12.72 ( 9.451 )
    No statistical analyses for this end point

    Secondary: Study period 1 - CRP and ESR changes from baseline in GP2017 and US-licensed Humira treated patients over time

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    End point title
    		 Study period 1 - CRP and ESR changes from baseline in GP2017 and US-licensed Humira treated patients over time
    End point description
    End point type
    Secondary
    End point timeframe
    Week 4, week 12, week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    127
    138
    Units: score on a scale
    arithmetic mean (standard deviation)
        CRP change from baseline week 4|
    -4.79 ( 8.728 )
    -4.93 ( 12.128 )
        CRP change from baseline week 12|
    -5.98 ( 11.270 )
    -5.07 ( 11.791 )
        CRP change from baseline week 24|
    -2.51 ( 19.176 )
    -5.30 ( 13.726 )
        ESR change from baseline week 4|
    -16.17 ( 14.693 )
    -13.98 ( 15.823 )
        ESR change from baseline week 12|
    -17.33 ( 16.214 )
    -15.08 ( 31.150 )
        ESR change from baseline week 24|
    -19.60 ( 20.494 )
    -20.49 ( 18.255 )
    No statistical analyses for this end point

    Secondary: Study period 1: Incidence and severity of injection site reactions in GP2017 and Humira

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    End point title
    		 Study period 1: Incidence and severity of injection site reactions in GP2017 and Humira
    End point description
    Incidence of injection site reactions in GP2017 and Humira
    End point type
    Secondary
    End point timeframe
    Treatment Period 1, 24 weeks
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    177
    176
    Units: Participants
        incidence of injection site reactions|
    7
    11
        injection site reactions MILD|
    7
    7
        injection site reactions MODERATE|
    0
    4
        injection site reactions SEVERE|
    0
    0
        Injection site erythema|
    2
    6
        Injection site pruritus|
    2
    3
        Injection site pain|
    2
    1
        Injection site inflammation|
    2
    0
        Injection site rash|
    0
    2
        Injection site discolouration|
    0
    1
    No statistical analyses for this end point

    Secondary: Study period 1 - Immunogenicity by measuring the rate of anti-drug antibody (ADA) formation against adalimumab in patients treated with GP2017 or Humira (positive patients)

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    End point title
    		 Study period 1 - Immunogenicity by measuring the rate of anti-drug antibody (ADA) formation against adalimumab in patients treated with GP2017 or Humira (positive patients)
    End point description
    Frequency of patients having anti-drug antibody (ADA) during 24 weeks
    End point type
    Secondary
    End point timeframe
    baseline, week 2, week 4, week 12, week 24
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    177
    176
    Units: Participants
        Baseline|
    10
    6
        Week 2|
    12
    10
        Week 4|
    14
    22
        Week 12|
    16
    23
        Week 24|
    23
    25
    No statistical analyses for this end point

    Secondary: Study period 2 - Immunogenicity by measuring the rate of anti-drug antibody (ADA) formation against adalimumab in patients treated with GP2017 who continued GP2017 or switched to GP2017 from Humira (positive patients)

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    End point title
    		 Study period 2 - Immunogenicity by measuring the rate of anti-drug antibody (ADA) formation against adalimumab in patients treated with GP2017 who continued GP2017 or switched to GP2017 from Humira (positive patients)
    End point description
    Frequency of patients having anti-drug antibody (ADA) during 24 weeks
    End point type
    Secondary
    End point timeframe
    week 24, week 36, week 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    159
    166
    Units: Participants
        Week 24|
    22
    25
        Week 36|
    21
    22
        Week 48|
    12
    12
    No statistical analyses for this end point

    Secondary: Study period 2 : Proportion of patients achieving ACR20/50/70 response at week 48, in patients treated with GP2017 who continued GP2017 or switched to GP2017 from Humira

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    End point title
    		 Study period 2 : Proportion of patients achieving ACR20/50/70 response at week 48, in patients treated with GP2017 who continued GP2017 or switched to GP2017 from Humira
    End point description
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    108
    126
    Units: participants
        ACR20 response Week 48|
    93
    111
        ACR50 response Week 48|
    72
    81
        ACR70 response Week 48|
    49
    55
    No statistical analyses for this end point

    Secondary: Study period 2 - Health Assessment Questionnaire-Disability Index (HAQ-DI©) changes from Week 24 at Week 48 in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira

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    End point title
    		 Study period 2 - Health Assessment Questionnaire-Disability Index (HAQ-DI©) changes from Week 24 at Week 48 in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira
    End point description
    Health assessment questionnaire (HAQ-DI) disability index ranges from 0 (best) to 3 (worst)
    End point type
    Secondary
    End point timeframe
    Weeks 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    108
    126
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.01 ( 0.358 )
    -0.03 ( 0.427 )
    No statistical analyses for this end point

    Secondary: Study period 2 :Proportion of patients treated continuously with GP2017 and patients treated with GP2017 after switch from Humira achieving HAQ-DI© score in normal range ≤0.5 at Week 48

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    End point title
    		 Study period 2 :Proportion of patients treated continuously with GP2017 and patients treated with GP2017 after switch from Humira achieving HAQ-DI© score in normal range ≤0.5 at Week 48
    End point description
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    108
    126
    Units: participants
    45
    52
    No statistical analyses for this end point

    Secondary: Study period 2 : Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue scale changes from Week 24 at Week 48 in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira

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    End point title
    		 Study period 2 : Functional Assessment of Chronic Illness Therapy (FACIT©) Fatigue scale changes from Week 24 at Week 48 in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira
    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
    week 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    108
    126
    Units: score on a scale
        arithmetic mean (standard deviation)
    -0.65 ( 7.421 )
    -0.85 ( 7.476 )
    No statistical analyses for this end point

    Secondary: Study period 2: Changes from Week 24 at Week 48 in DAS28-CRP and DAS28-ESR scores in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira

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    End point title
    		 Study period 2: Changes from Week 24 at Week 48 in DAS28-CRP and DAS28-ESR scores in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira
    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 (GDA) or general health (GH), 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 or GH + 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. For DAS-28 ESR, DAS28-ESR = 0.56 * sqrt(TJC28) + 0.28 * sqrt(SJC28) + 0.70 * ln(ESR) + 0.014 * GH
    End point type
    Secondary
    End point timeframe
    week 48
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    108
    126
    Units: score on a scale
    arithmetic mean (standard deviation)
        DAS28-CRP Week 48, change from week 24|
    -0.10 ( 0.893 )
    0.00 ( 0.941 )
        DAS28-ESR Week 48, change from week 24|
    -0.04 ( 1.015 )
    0.00 ( 1.025 )
    No statistical analyses for this end point

    Secondary: Study period 2: Incidence of injection site reactions in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira

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    End point title
    		 Study period 2: Incidence of injection site reactions in patients treated continuously with GP2017 and in patients treated with GP2017 after switch from Humira
    End point description
    Incidence of injection site reactions
    End point type
    Secondary
    End point timeframe
    up to 48 weeks
    End point values
    		 GP2017 Humira / switched GP2017
    Number of subjects analysed
    159
    166
    Units: participants
        Number of patients with ISRs|
    1
    2
        Injection site erythema|
    1
    2
        Injection site pruritus|
    0
    1
        Injection site pain|
    0
    0
        Injection site inflammation|
    0
    0
        Injection site rash|
    0
    0
        Injection site discolouration|
    0
    0
        injection site reactions MILD|
    1
    1
        injection site reactions MODERATE|
    0
    1
        injection site reactions SEVERE|
    0
    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
    20.0
    Reporting groups
    Reporting group title
    Study Period 1 SP1 SAF GP2017
    Reporting group description
    		 Study Period 1 SP1 SAF GP2017

    Reporting group title
    Study Period 1 SP1 SAF Humira
    Reporting group description
    		 Study Period 1 SP1 SAF Humira

    Reporting group title
    Study Period 2 SP2 SAF Continued GP2017
    Reporting group description
    		 Study Period 2 SP2 SAF Continued GP2017

    Reporting group title
    Study Period 2 SP2 SAF Humira to GP2017
    Reporting group description
    		 Study Period 2 SP2 SAF Humira to GP2017

    Reporting group title
    Entire study SP1 SAF GP2017
    Reporting group description
    		 Entire study SP1 SAF GP2017

    Reporting group title
    Entire study SP1 SAF Humira/Switched GP2017
    Reporting group description
    		 Entire study SP1 SAF Humira/Switched GP2017

    Serious adverse events
    		 Study Period 1 SP1 SAF GP2017 Study Period 1 SP1 SAF Humira Study Period 2 SP2 SAF Continued GP2017 Study Period 2 SP2 SAF Humira to GP2017 Entire study SP1 SAF GP2017 Entire study SP1 SAF Humira/Switched GP2017
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 177 (2.82%)
    4 / 176 (2.27%)
    4 / 159 (2.52%)
    6 / 166 (3.61%)
    7 / 177 (3.95%)
    10 / 176 (5.68%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain neoplasm benign
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Uterine leiomyoma
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Injury, poisoning and procedural complications
    Humerus fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Angina pectoris
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Epilepsy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Hemianopia homonymous
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Intracranial pressure increased
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Pancreatitis acute
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Reproductive system and breast disorders
    Uterine prolapse
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Hepatitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Diverticulitis
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Pneumonia
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    2 / 166 (1.20%)
    0 / 177 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    1 / 177 (0.56%)
    0 / 176 (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
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 177 (0.00%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Study Period 1 SP1 SAF GP2017 Study Period 1 SP1 SAF Humira Study Period 2 SP2 SAF Continued GP2017 Study Period 2 SP2 SAF Humira to GP2017 Entire study SP1 SAF GP2017 Entire study SP1 SAF Humira/Switched GP2017
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 177 (46.89%)
    74 / 176 (42.05%)
    28 / 159 (17.61%)
    26 / 166 (15.66%)
    94 / 177 (53.11%)
    80 / 176 (45.45%)
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 176 (1.70%)
    1 / 159 (0.63%)
    1 / 166 (0.60%)
    1 / 177 (0.56%)
    4 / 176 (2.27%)
         occurrences all number
    0
    3
    1
    1
    1
    4
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 176 (1.70%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    2 / 177 (1.13%)
    4 / 176 (2.27%)
         occurrences all number
    2
    3
    0
    1
    2
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 177 (2.82%)
    3 / 176 (1.70%)
    2 / 159 (1.26%)
    1 / 166 (0.60%)
    6 / 177 (3.39%)
    4 / 176 (2.27%)
         occurrences all number
    5
    3
    2
    1
    7
    4
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 177 (3.95%)
    5 / 176 (2.84%)
    2 / 159 (1.26%)
    2 / 166 (1.20%)
    8 / 177 (4.52%)
    7 / 176 (3.98%)
         occurrences all number
    7
    5
    2
    2
    9
    7
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
    2 / 159 (1.26%)
    0 / 166 (0.00%)
    4 / 177 (2.26%)
    0 / 176 (0.00%)
         occurrences all number
    2
    0
    2
    0
    4
    0
    Neutropenia
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 176 (0.00%)
    2 / 159 (1.26%)
    0 / 166 (0.00%)
    5 / 177 (2.82%)
    0 / 176 (0.00%)
         occurrences all number
    3
    0
    2
    0
    5
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 177 (2.82%)
    0 / 176 (0.00%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    5 / 177 (2.82%)
    1 / 176 (0.57%)
         occurrences all number
    5
    0
    0
    1
    5
    1
    Injection site erythema
         subjects affected / exposed
    2 / 177 (1.13%)
    6 / 176 (3.41%)
    1 / 159 (0.63%)
    2 / 166 (1.20%)
    3 / 177 (1.69%)
    6 / 176 (3.41%)
         occurrences all number
    3
    17
    1
    2
    4
    19
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 177 (2.26%)
    7 / 176 (3.98%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    4 / 177 (2.26%)
    7 / 176 (3.98%)
         occurrences all number
    4
    7
    0
    0
    4
    7
    Nausea
         subjects affected / exposed
    5 / 177 (2.82%)
    1 / 176 (0.57%)
    0 / 159 (0.00%)
    0 / 166 (0.00%)
    5 / 177 (2.82%)
    1 / 176 (0.57%)
         occurrences all number
    6
    1
    0
    0
    6
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
    3 / 159 (1.89%)
    0 / 166 (0.00%)
    5 / 177 (2.82%)
    1 / 176 (0.57%)
         occurrences all number
    2
    1
    3
    0
    5
    1
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 176 (1.70%)
    0 / 159 (0.00%)
    1 / 166 (0.60%)
    0 / 177 (0.00%)
    4 / 176 (2.27%)
         occurrences all number
    0
    3
    0
    1
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    8 / 177 (4.52%)
    0 / 176 (0.00%)
    2 / 159 (1.26%)
    0 / 166 (0.00%)
    10 / 177 (5.65%)
    0 / 176 (0.00%)
         occurrences all number
    8
    0
    2
    0
    10
    0
    Rheumatoid arthritis
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 176 (0.57%)
    5 / 159 (3.14%)
    2 / 166 (1.20%)
    6 / 177 (3.39%)
    3 / 176 (1.70%)
         occurrences all number
    4
    1
    5
    2
    9
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 177 (2.26%)
    8 / 176 (4.55%)
    1 / 159 (0.63%)
    4 / 166 (2.41%)
    4 / 177 (2.26%)
    12 / 176 (6.82%)
         occurrences all number
    4
    9
    1
    4
    5
    13
    Gastroenteritis
         subjects affected / exposed
    2 / 177 (1.13%)
    4 / 176 (2.27%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    3 / 177 (1.69%)
    4 / 176 (2.27%)
         occurrences all number
    2
    4
    1
    0
    3
    4
    Influenza
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 176 (2.84%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    4 / 177 (2.26%)
    5 / 176 (2.84%)
         occurrences all number
    4
    5
    1
    0
    5
    5
    Oral herpes
         subjects affected / exposed
    4 / 177 (2.26%)
    3 / 176 (1.70%)
    1 / 159 (0.63%)
    0 / 166 (0.00%)
    5 / 177 (2.82%)
    3 / 176 (1.70%)
         occurrences all number
    6
    3
    1
    0
    7
    3
    Pharyngitis
         subjects affected / exposed
    9 / 177 (5.08%)
    10 / 176 (5.68%)
    1 / 159 (0.63%)
    3 / 166 (1.81%)
    10 / 177 (5.65%)
    10 / 176 (5.68%)
         occurrences all number
    11
    11
    1
    3
    12
    14
    Sinusitis
         subjects affected / exposed
    5 / 177 (2.82%)
    3 / 176 (1.70%)
    0 / 159 (0.00%)
    2 / 166 (1.20%)
    5 / 177 (2.82%)
    5 / 176 (2.84%)
         occurrences all number
    5
    3
    0
    2
    5
    5
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 177 (6.78%)
    7 / 176 (3.98%)
    4 / 159 (2.52%)
    3 / 166 (1.81%)
    14 / 177 (7.91%)
    9 / 176 (5.11%)
         occurrences all number
    14
    9
    4
    3
    18
    12
    Urinary tract infection
         subjects affected / exposed
    4 / 177 (2.26%)
    6 / 176 (3.41%)
    2 / 159 (1.26%)
    3 / 166 (1.81%)
    6 / 177 (3.39%)
    8 / 176 (4.55%)
         occurrences all number
    4
    6
    2
    3
    6
    9
    Viral upper respiratory tract infection
         subjects affected / exposed
    26 / 177 (14.69%)
    16 / 176 (9.09%)
    4 / 159 (2.52%)
    4 / 166 (2.41%)
    29 / 177 (16.38%)
    19 / 176 (10.80%)
         occurrences all number
    28
    18
    4
    4
    32
    22
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 177 (1.69%)
    3 / 176 (1.70%)
    2 / 159 (1.26%)
    0 / 166 (0.00%)
    5 / 177 (2.82%)
    3 / 176 (1.70%)
         occurrences all number
    3
    3
    2
    0
    5
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2015
    Amendment 1 mainly provided further clarification of some inclusion and exclusion criteria and the blood sampling schedule.
    15 Feb 2016
    Amendment 2 introduced the following changes: The patients’ HIV seronegativity was to be confirmed at the study eligibility screening. The ranges for clinically notable sodium and calcium values were amended in line with CTCAE version 4.
    01 Feb 2017
    Amendment 3 introduced the following substantial changes: The originally planned analysis and reporting of Week 12 data was removed. Instead all data were to be analyzed at the end of the study and reported in a single study report. The already collected serum samples that were left over after the assessment of adalimumab trough concentration and testing for ADAs were not to be destroyed (as originally planned) but to be stored for later additional exploratory research, if the patient agreed. The amended protocol and the additional Informed Consent to be signed by the affected patients had to be approved by or notified to the respective local authorities.

    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.
    NA
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