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    Clinical Trial Results:
    A randomized, double-blind, controlled study to evaluate pharmacokinetics, pharmacodynamics, safety and efficacy of GP2013 and rituximab in patients with rheumatoid arthritis refractory or intolerant to standard DMARDs and one or two anti- TNF therapies

    Summary
    EudraCT number
    		 2010-021184-32
    Trial protocol
    		 DE   FR   ES   AT   IT   BE   EE   HU   PL   BG   GB  
    Global end of trial date
    10 Nov 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Nov 2017
    First version publication date
    26 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GP13-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01274182
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hexal AG
    Sponsor organisation address
    Industriestrasse 25, Holzkirchen, Germany, 83607
    Public contact
    Strategic Planning Biopharma Clinical Development , Sandoz , 0049 80244760, biopharma.clinicaltrials@sandoz.com
    Scientific contact
    Strategic Planning Biopharma Clinical Development , Sandoz , 0049 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
    11 Sep 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate bioequivalence between GP2013 and rituximab in combination with MTX in patients with active RA who have not responded adequately, or have shown intolerance, to DMARDs, including MTX, and one or two anti-TNF therapies. Bioequivalence is defined as AUC(0-inf) and Cmax of blood concentrations of the drugs being comparable, i.e. the 90% confidence interval for the ratio of the geometric means (GP2013/rituximab) estimated based on non-compartmental analysis based on assessments up to week 24 must be within the standard bioequivalence limits 0.8 to 1.25.
    Protection of trial subjects
    This clinical study was designed and was implemented and reported in accordance with the International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good Clinical Practice (GCP), with applicable local regulations (including European Directive 2001/20/EC), and with the ethical principles laid down in the Declaration of Helsinki. Safety assessment included adverse events (AEs), vital signs, 12-lead ECG parameters, clinical laboratory, immunogenicity, physical examination and other parameters considered relevant for the safety assessments.
    Background therapy
    		 Methotrexate and folic acid
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Dec 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 23
    Country: Number of subjects enrolled
    Turkey: 7
    Country: Number of subjects enrolled
    India: 24
    Country: Number of subjects enrolled
    Argentina: 20
    Country: Number of subjects enrolled
    Brazil: 50
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    United States: 29
    Country: Number of subjects enrolled
    Spain: 33
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    Estonia: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 62
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 11
    Worldwide total number of subjects
    312
    EEA total number of subjects
    165
    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)
    246
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in two parts with similar study designs. In Study Part I patients were randomized to either GP2013 or MabThera. In Study Part II patients were randomized to either GP2013 or Rituxan.

    Pre-assignment
    Screening details
    		 An optional anti-TNF or DMARD (except MTX, sulfasalazine, chloroquine, and hydrochloroquine) washout period could be performed between Visit 1- Screening and Visit 2 -Baseline. At Visit 2 the RA status and associated laboratory testing was reassessed in order to confirm eligibility of the patient. Visit 3- Randomization was within 7 days ± 2 days.

    Period 1
    Period 1 title
    Entire study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Data analyst, Carer, Subject, Assessor
    Blinding implementation details
    Patients, investigators, assessors, and blinded staff of the CRO remained blinded to the identity of the treatment from the time of randomization until database lock. Investigational product was packed in an open label design. Receipt, storage and preparation of the medication were performed by unblinded site staff only. They ensured that no other persons than unblinded staff embers (site and CRO) had access to the medication and the documentation of study medication.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 GP2013 (pooled)
    Arm description
    		 This treatment arm includes all patients, randomized to GP2013 in both Study Part I and Study Part II.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2013
    Investigational medicinal product code
    rituximab
    Other name
    Sandoz biosimilar rituximab
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 15)

    Arm title
    		 Rituxan®
    Arm description
    		 This treatment arm includes patients, randomized to Rituxan® in the Study Part II
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituxan®
    Investigational medicinal product code
    rituximab
    Other name
    rituximab-US
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 15)

    Arm title
    		 MabThera®
    Arm description
    		 This treatment arm includes patients, randomized to MabThera® in the Study Part I
    Arm type
    		 Active comparator

    Investigational medicinal product name
    MabThera®
    Investigational medicinal product code
    rituximab
    Other name
    rituximab-EU
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 15)

    Arm title
    		 GP2013 (Part I)
    Arm description
    		 This treatment arm includes patents randomized to GP2013 in Study Part I only. Patients from this treatment arm are also included in the treatment arm GP2013 (pooled). This treatment arm is used for some of efficacy comparisons (secondary endpoints), which were done on the resulst of the Study Part I only.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GP2013
    Investigational medicinal product code
    rituximab
    Other name
    Sandoz biosimilar rituximab
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    10 mg/mL in 500 mg (50 mL) single-use vials. For i.v. administration, two 500 mg vials (1000 mg of active molecule) of concentrate are diluted in 0.9% NaCl solution and infused i.v. The treatment course consists of 2 i.v. infusions 2 weeks apart (at Day 1 and Day 15)

    Number of subjects in period 1
    		GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Started
    133
    92
    87
    86
    24 weeks
    123
    84
    83
    79
    Completed
    112
    80
    69
    73
    Not completed
    21
    12
    18
    13
         Adverse event, serious fatal
    1
    1
    -
    1
         Consent withdrawn by subject
    5
    3
    5
    1
         Adverse event, non-fatal
    4
    3
    5
    3
         Lost to follow-up
    2
    1
    3
    1
         Lack of efficacy
    6
    4
    3
    5
         Protocol deviation
    3
    -
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GP2013 (pooled)
    Reporting group description
    		 This treatment arm includes all patients, randomized to GP2013 in both Study Part I and Study Part II.

    Reporting group title
    Rituxan®
    Reporting group description
    		 This treatment arm includes patients, randomized to Rituxan® in the Study Part II

    Reporting group title
    MabThera®
    Reporting group description
    		 This treatment arm includes patients, randomized to MabThera® in the Study Part I

    Reporting group title
    GP2013 (Part I)
    Reporting group description
    		 This treatment arm includes patents randomized to GP2013 in Study Part I only. Patients from this treatment arm are also included in the treatment arm GP2013 (pooled). This treatment arm is used for some of efficacy comparisons (secondary endpoints), which were done on the resulst of the Study Part I only.

    Reporting group values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I) Total
    Number of subjects
    		 133 92 87 86
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 54.42 ( 11.779 ) 54.95 ( 10.750 ) 52.17 ( 12.531 ) 54.72 ( 12.135 ) -
    Gender categorical
    Units: Subjects
        Female
    		 111 78 73 76 262
        Male
    		 22 14 14 10 50
    Number of prior anti-TNFs
    Units: Subjects
        One
    		 109 73 70 72 252
        Two
    		 18 13 16 10 47
        More than two
    		 6 6 1 4 13
    Anti-drug antibodies (ADA)
    Units: Subjects
        Negative
    		 132 87 85 85 304
        Positive
    		 0 3 2 0 5
        Missing
    		 1 2 0 1 3
    BMI
    Analysis was performed on data of BMI available at the baseline visit: GP2013 (pooled) - 133 patients; Rituxan - 92 patients; MabThera - 85 patients; GP2013 part I - 86 patients.
    Units: kg/m2
        arithmetic mean (standard deviation)
    		 27.37 ( 6.230 ) 29.66 ( 6.606 ) 27.25 ( 6.000 ) 27.20 ( 6.121 ) -
    Duration of RA
    Analysis was done on data of Duration of RA available at the baseline visit: GP2013 (pooled) - 133 patients; Rituxan - 92 patients; MabThera - 86 Patients; GP2013 Part I - 86 patients.
    Units: years
        arithmetic mean (standard deviation)
    		 10.53 ( 8.074 ) 11.10 ( 8.299 ) 10.81 ( 7.137 ) 9.34 ( 6.818 ) -
    DAS28-CRP
    Analysis was done on data of DAS28-CRP, available at the baseline visit: GP2013 (pooled) - 132 patients; Rituxan - 91 patients; MabThera - 87 patients; GP2013 Part I - 85 patients.
    Units: units
        arithmetic mean (standard deviation)
    		 5.83 ( 0.922 ) 5.91 ( 1.009 ) 5.85 ( 0.880 ) 5.81 ( 0.916 ) -
    Dose of methotrexate at baseline
    Analysis was done on data of Dose of methotrexate, available at the baseline visit: GP2013 (pooled) - 131 patients; Rituxan - 91 patients; MabThera - 84 patients; GP2013 Part I - 84 patients.
    Units: mg/week
        arithmetic mean (standard deviation)
    		 15.09 ( 4.856 ) 15.29 ( 4.888 ) 14.65 ( 5.154 ) 14.59 ( 4.618 ) -

    End points

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    End points reporting groups
    Reporting group title
    GP2013 (pooled)
    Reporting group description
    		 This treatment arm includes all patients, randomized to GP2013 in both Study Part I and Study Part II.

    Reporting group title
    Rituxan®
    Reporting group description
    		 This treatment arm includes patients, randomized to Rituxan® in the Study Part II

    Reporting group title
    MabThera®
    Reporting group description
    		 This treatment arm includes patients, randomized to MabThera® in the Study Part I

    Reporting group title
    GP2013 (Part I)
    Reporting group description
    		 This treatment arm includes patents randomized to GP2013 in Study Part I only. Patients from this treatment arm are also included in the treatment arm GP2013 (pooled). This treatment arm is used for some of efficacy comparisons (secondary endpoints), which were done on the resulst of the Study Part I only.

    Primary: Pharmacokinetics (PK): AUC(0-inf) in serum samples, collected over 24 weeks

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    End point title
    		 Pharmacokinetics (PK): AUC(0-inf) in serum samples, collected over 24 weeks [1]
    End point description
    PK bioequivalence is defined as AUC(0-inf) of the drugs being comparable, i.e. the two-sided 90% CI for the ratio of the geometric means (GP2013/MabThera) is within the predefined bioequivalence limits of 0.8 to 1.25. The PK parameters were transformed prior to analysis using a logarithmic transformation. An analysis of variance (ANOVA) was used to analyze the transformed data including treatment group only as a factor in the model. The confidence interval for the difference between the two products on the transformed scale was obtained from the ANOVA model, which was then be back-transformed (exp base e) to obtain the confidence interval for the ratio on the original scale.
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 3-way equivalence testing, comparing entire GP2013 cohort (GP2013 pooled treatment arm); MabThera treatment arm and Rituxan treatment arm was performed. Results of comparison of GP2013 Part I, being a subpopulation of the GP2013 cohort, are not provided.
    End point values
    		 GP2013 (pooled) Rituxan® MabThera®
    Number of subjects analysed
    124 [2]
    80 [3]
    79 [4]
    Units: units on a scale
        geometric mean (geometric coefficient of variation)
    7627.44 ( 38.60 )
    7536.89 ( 40.28 )
    6896.97 ( 40.56 )
    Notes
    [2] - PK analysis set
    [3] - PK analysis set
    [4] - PK analysis set
    Statistical analysis title
    		 Bioequivalence GP2013 vs MabThera
    Comparison groups
    GP2013 (pooled) v MabThera®
    Number of subjects included in analysis
    203
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [5]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.106
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.01
         upper limit
    		 1.21
    Notes
    [5] - GP2013 arm is the numerator and MabThera arm is the denominator for the geometric mean ratio
    Statistical analysis title
    		 Bioequivalence GP2013 vs Rituxan
    Comparison groups
    GP2013 (pooled) v Rituxan®
    Number of subjects included in analysis
    204
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [6]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.012
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.925
         upper limit
    		 1.108
    Notes
    [6] - GP2013 arm is the numerator and Rituxan arm is the denominator for the geometric mean ratio.
    Statistical analysis title
    		 Bioequivalence of Rituxan vs MabThera
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [7]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.093
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.989
         upper limit
    		 1.208
    Notes
    [7] - Rituxan arm is the numerator and MabThera arm is the denominator for the geometric mean ratio.

    Secondary: Pharmacokinetics (PK): Cmax after first infusion (Cmax1)

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    End point title
    		 Pharmacokinetics (PK): Cmax after first infusion (Cmax1) [8]
    End point description
    A key secondary PK endpoint was the maximum serum concentration after the first infusion (Cmax1). In order to claim bioequivalence, the 90% CI must be entirely within the standard equivalence limits of 0.8-1.25. The PK parameters were transformed prior to analysis using a logarithmic transformation. An analysis of variance (ANOVA) was used to analyze the transformed data including treatment group only as a factor in the model. The confidence interval for the difference between the two products on the transformed scale was obtained from the ANOVA model, which was then be back-transformed (exp base e) to obtain the confidence interval for the ratio on the original scale.
    End point type
    Secondary
    End point timeframe
    not applicable
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 3-way equivalence testing, comparing entire GP2013 cohort (GP2013 pooled treatment arm); MabThera treatment arm and Rituxan treatment arm was performed. Results of comparison of GP2013 Part I, being a subpopulation of the GP2013 cohort, are not provided.
    End point values
    		 GP2013 (pooled) Rituxan® MabThera®
    Number of subjects analysed
    120 [9]
    82 [10]
    78 [11]
    Units: unit(s)
        geometric mean (geometric coefficient of variation)
    361.53 ( 40.82 )
    335.88 ( 42.65 )
    319.80 ( 42.75 )
    Notes
    [9] - PK-Analysis set, patients with available data
    [10] - PK-analysis set, patients with available data
    [11] - PK-analysis set, patients with available data
    Statistical analysis title
    		 Bioequivalence GP2013 vs MabThera
    Comparison groups
    GP2013 (pooled) v MabThera®
    Number of subjects included in analysis
    198
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [12]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.131
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.027
         upper limit
    		 1.244
    Notes
    [12] - GP2013 arm is the numerator and MabThera arm is the denominator for the geometric mean ratio.
    Statistical analysis title
    		 Bioequivalence of GP2013 vs Rituxan
    Comparison groups
    GP2013 (pooled) v Rituxan®
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [13]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.076
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.979
         upper limit
    		 1.184
    Notes
    [13] - GP2013 arm is the numerator and Rituxan arm is the denominator for the geometric mean ratio.
    Statistical analysis title
    		 Bioequivalence of Rituxan vs MabThera
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [14]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.05
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.946
         upper limit
    		 1.167
    Notes
    [14] - Rituxan arm is the numerator and MabThera arm is the denominator for the geometric mean ratio.

    Secondary: Pharmacodynamics (PD): AUEC(0-14d) of percent B-cells relative to baseline

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    End point title
    		 Pharmacodynamics (PD): AUEC(0-14d) of percent B-cells relative to baseline [15]
    End point description
    The key secondary PD endpoint was depletion of peripheral B-cells, defined as the area under the effect time curves (AUEC) of the percent change of blood CD20+ B-cell count relative to baseline, up to Day 15 (i.e., up to the second infusion). To conclude equivalence the 95% CI must be entirely within the standard equivalencelimits of 0.8-1.25 Ratio of geometric means and 95% confidence interval were estimated by an analysis of variance (ANOVA) on log-transformed PD parameter with treatment as the factor. Results were then back-transformed to the original scale.
    End point type
    Secondary
    End point timeframe
    14 days
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: 3-way equivalence testing, comparing entire GP2013 cohort (GP2013 pooled treatment arm); MabThera treatment arm and Rituxan treatment arm was performed. Results of comparison of GP2013 Part I, being a subpopulation of the GP2013 cohort, are not provided.
    End point values
    		 GP2013 (pooled) Rituxan® MabThera®
    Number of subjects analysed
    110 [16]
    80 [17]
    76 [18]
    Units: unit(s)
        geometric mean (geometric coefficient of variation)
    1226.53 ( 2.83 )
    1240.57 ( 1.95 )
    1201.15 ( 8.91 )
    Notes
    [16] - PK analysis set, patients with available data
    [17] - PK analysis set, patients with available data
    [18] - PK analysis set, patients with available data
    Statistical analysis title
    		 PD equivalence GP2013 vs Rituxan
    Comparison groups
    GP2013 (pooled) v Rituxan®
    Number of subjects included in analysis
    190
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [19]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    0.989
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.974
         upper limit
    		 1.004
    Notes
    [19] - GP2013 arm is the numerator and Rituxan arm is the denominator for the geometric mean ratio.
    Statistical analysis title
    		 PD equivalence GP2013 vs. MabThera
    Comparison groups
    GP2013 (pooled) v MabThera®
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [20]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.021
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.003
         upper limit
    		 1.04
    Notes
    [20] - GP2013 arm is the numerator and MabThera arm is the denominator for the geometric mean ratio.
    Statistical analysis title
    		 PD equivalence Rituxan vs MabThera
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence [21]
    Method
    Parameter type
    		 Geometric mean ratio
    Point estimate
    1.033
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.016
         upper limit
    		 1.05
    Notes
    [21] - Rituxan arm is the numerator and MabThera arm is the denominator for the geometric mean ratio.

    Secondary: Efficacy: Change from baseline in DAS28 (CRP) at Week 24

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    End point title
    		 Efficacy: Change from baseline in DAS28 (CRP) at Week 24
    End point description
    The key secondary efficacy endpoint was change from baseline in DAS28 (CRP) at Week 24. This efficacy endpoint was analyzed using the PP analysis set as it constitutes the most conservative approach for non-inferiority evaluation. Non-inferiority was to be concluded if the upper limit of the 95% CI for the mean difference between GP2013 and MabThera® or GP2013 and Rituxan® was less than or equal to the non-inferiority margin of 0.6. This margin was statistically justified by the results of the REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) trial (Cohen et al 2006) providing a 95% CI for the mean difference between rituximab/MTX and MTX alone of (-1.74;-1.25). The margin of 0.6 was determined by retaining more than 50% of the reference treatment effect which was considered clinically acceptable. The non-inferiority margin is further justified by the EULAR criteria which define "no response" as change from baseline being < 0.6.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Number of subjects analysed
    128 [22]
    85 [23]
    82 [24]
    85 [25]
    Units: unit(s)
        least squares mean (standard error)
    -2.07 ( 0.103 )
    -1.99 ( 0.126 )
    -2.23 ( 0.143 )
    -2.16 ( 0.142 )
    Notes
    [22] - PP analysis set, patients with available data
    [23] - PP analysis set, patients with available data
    [24] - PP analysis set, patients with available data
    [25] - PP analysis set, patients with available data
    Statistical analysis title
    		 Non-Inferiority of GP2013 vs Rituxan
    Statistical analysis description
    LS means, standard errors and 95% CI were estimated by a repeated measures mixed model with treatment, time and treatment*time interaction term as categorical variables and baseline DAS28 as a continuous variable. A negative change from baseline represents an improvement in assessment of rheumatoid arthritis.
    Comparison groups
    GP2013 (pooled) v Rituxan®
    Number of subjects included in analysis
    213
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [26]
    Method
    Parameter type
    		 LS Mean difference
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.397
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.162
    Notes
    [26] - The direction of comparison is LS mean of GP2013 - LS mean of Rituxan
    Statistical analysis title
    		 Non-Inferiority of GP2013 vs. MabThera
    Statistical analysis description
    LS means, standard errors and 95% CI were estimated by a repeated measures mixed model with treatment, time and treatment*time interaction term as categorical variables and baseline DAS28 as a continuous variable. A negative change from baseline represents an improvement in assessment of rheumatoid arthritis.
    Comparison groups
    MabThera® v GP2013 (Part I)
    Number of subjects included in analysis
    167
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [27]
    Method
    Parameter type
    		 LS Mean difference
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.328
         upper limit
    		 0.462
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.201
    Notes
    [27] - The direction of comparison is LS mean of GP2013 Part I - LS mean of MabThera

    Secondary: Efficacy: ACR20 (CRP) response at Week 24

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    End point title
    		 Efficacy: ACR20 (CRP) response at Week 24
    End point description
    A two-sided 95% CI for the difference in the ACR20 (CRP) response rates at Week 24 was estimated. The lower bound of the CI was compared to a margin of -15.0% and had to be greater than -15.0% to conclude non-inferiority.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Number of subjects analysed
    119 [28]
    80 [29]
    76 [30]
    78 [31]
    Units: Number of patients with ACR20 response
    86
    50
    55
    56
    Notes
    [28] - PP analysis set, patients with available data
    [29] - PP analysis set, patients with available data
    [30] - PP analysis set, patients with available data
    [31] - PP analysis set, patients with available data
    Statistical analysis title
    		 Non-Inferiority of GP2013 vs. Rituxan
    Statistical analysis description
    To conclude non-inferiority the lower 95% CI should be greater than -15.0%. The predefined noninferiority margin of 0.15 for ACR20 is based on the historical placebo-controlled phase III study to evaluate the response rate benefit of adding rituximab to the conventional small molecule-based treatment of patients with RA (Cohen et al. 2006).
    Comparison groups
    GP2013 (pooled) v Rituxan®
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [32]
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    9.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.54
         upper limit
    		 23.08
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.79
    Notes
    [32] - The direction of comparison is response rate of GP2013 - response rate of Rituxan
    Statistical analysis title
    		 Non-Inferiority of GP2013 vs. MabThera
    Statistical analysis description
    To conclude non-inferiority the lower 95% CI should be greater than -15.0%. The predefined noninferiority margin of 0.15 for ACR20 is based on the historical placebo-controlled phase III study to evaluate the response rate benefit of adding rituximab to the conventional small molecule-based treatment of patients with RA (Cohen et al. 2006).
    Comparison groups
    MabThera® v GP2013 (Part I)
    Number of subjects included in analysis
    154
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [33]
    Method
    Parameter type
    		 Response rate difference
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.74
         upper limit
    		 13.6
    Variability estimate
    Standard error of the mean
    Dispersion value
    7.23
    Notes
    [33] - The direction of comparison is response rate of GP2013 Part I - response rate of MabThera

    Secondary: Efficacy: Summary of disease activity according to CDAI

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    End point title
    		 Efficacy: Summary of disease activity according to CDAI
    End point description
    A proportion of patients with different levels of RA disease activity according to CDAI at study week 24 is presented
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Number of subjects analysed
    119 [34]
    80 [35]
    75 [36]
    78 [37]
    Units: Patients
        High disease activity
    26
    20
    18
    18
        Moderate disease activity
    45
    32
    26
    24
        Low disease activity
    41
    25
    19
    30
        Remission
    7
    3
    12
    6
    Notes
    [34] - PP analysis set, patients with available data
    [35] - PP analysis set, patients with available data
    [36] - PP analysis set, patients with available data
    [37] - PP analysis set, patients with available data
    No statistical analyses for this end point

    Secondary: Efficacy: Summary of disease activity according to SDAI

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    End point title
    		 Efficacy: Summary of disease activity according to SDAI
    End point description
    A proportion of patients with different levels of RA disease activity according to SDAI at study week 24 is presented
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Number of subjects analysed
    117 [38]
    77 [39]
    74 [40]
    77 [41]
    Units: Patients
        High disease activity
    20
    15
    15
    13
        Moderate disease activity
    48
    34
    29
    27
        Low disease activity
    41
    26
    18
    31
        Remission
    8
    2
    12
    6
    Notes
    [38] - PP analysis set - patients with available values
    [39] - PP analysis set - patients with available values
    [40] - PP analysis set - patients with available values
    [41] - PP analysis set - patients with available values
    No statistical analyses for this end point

    Secondary: Efficacy: EULAR response at week 24

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    End point title
    		 Efficacy: EULAR response at week 24
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 GP2013 (pooled) Rituxan® MabThera® GP2013 (Part I)
    Number of subjects analysed
    116 [42]
    77 [43]
    75 [44]
    76 [45]
    Units: Patients
        Good response
    0
    0
    0
    0
        Moderate response
    101
    61
    63
    67
        No response
    15
    16
    12
    9
    Notes
    [42] - PP analysis set, patients with available data
    [43] - PP analysis set, patients with available data
    [44] - PP analysis set, patients with available data
    [45] - PP analysis set, patients with available data
    No statistical analyses for this end point

    Other pre-specified: Immunogenicity (ADA Formation)

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    End point title
    		 Immunogenicity (ADA Formation) [46]
    End point description
    For patients, who received a second optional treatment course, which could be given at any time between week 24 and week 52 an additional follow-up period of 26 weeks after the first infusion of the second treatment course was required. Immunogenicity was also assessed in that 26 weeks follow up study visit.
    End point type
    Other pre-specified
    End point timeframe
    Entire study duration, which means at least 52 weeks for patients who completed the study.
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data of immunogenicity is provided for GP2013 pooled treatment arm, it includes immunogenicity data of the GP2013 Part I patients. For this no data are separately provided for GP2013 Part I.
    End point values
    		 GP2013 (pooled) Rituxan® MabThera®
    Number of subjects analysed
    127 [47]
    82 [48]
    84 [49]
    Units: Patients with at least 1 ADA+ sample
    21
    11
    18
    Notes
    [47] - Safety analysis set, patients with negative ADA results at randomization and available data
    [48] - Safety analysis set, patients with negative ADA results at randomization and available data
    [49] - Safety analysis set, patients with negative ADA results at randomization and available data
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study duration, which means at least 52 weeks for patients who completed the study.
    Adverse event reporting additional description
    For patients, who received a second optional treatment course, which could be given at any time between week 24 and week 52 an additional follow-up period of 26 weeks after the first infusion of the second treatment course was required. These patients had respectively longer study duration of maximally 1.5 years.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    GP2013 (pooled)
    Reporting group description
    		 This treatment arm includes all patients, randomized to GP2013 in both Study Part I and Study Part II.

    Reporting group title
    Rituxan®
    Reporting group description
    		 This treatment arm includes patients, randomized to Rituxan® in the Study Part II

    Reporting group title
    MabThera®
    Reporting group description
    		 This treatment arm includes patients, randomized to MabThera® in the Study Part I

    Serious adverse events
    		 GP2013 (pooled) Rituxan® MabThera®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    16 / 133 (12.03%)
    9 / 92 (9.78%)
    14 / 87 (16.09%)
         number of deaths (all causes)
    1
    1
    0
         number of deaths resulting from adverse events
    1
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Vasculitis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipogranuloma
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Urogenital prolapse
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural effusion
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 133 (1.50%)
    2 / 92 (2.17%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    2 / 92 (2.17%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone fissure
    Additional description: SAEs: bone fissure, Vitamid D defficiency and fractured sacrum occurred in same patient as a sequence of events
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured sacrum
    Additional description: SAEs: bone fissure, Vitamid D defficiency and fractured sacrum occurred in same patient as a sequence of events
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial rupture
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
    Additional description: SAEs chest pain and sinus tachycardia were diagnosed in same patient at the same time.
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 133 (0.75%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningoradiculitis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone marrow failure
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Microcytic anaemia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    2 / 133 (1.50%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
    Additional description: SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lyme disease
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pilonidal cyst
    Additional description: SAEs Fistula, Groin Abscess and Pilonidal cyst occurred in same patient as a sequence of events
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Purulent pericarditis
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 133 (0.00%)
    0 / 92 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
    Additional description: SAEs: Bone marrow failure, Pancytopenia, Sepsis, Septic shock, Multiple organ dysfunction syndrome and Overdose occurred in same patient as a sequence of events due to Methotrexate overdose.
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 133 (0.75%)
    0 / 92 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Vitamin D deficiency
    Additional description: SAEs: bone fissure, Vitamid D defficiency and fractured sacrum occurred in same patient as a sequence of events
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 GP2013 (pooled) Rituxan® MabThera®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 133 (65.41%)
    60 / 92 (65.22%)
    56 / 87 (64.37%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 133 (3.76%)
    3 / 92 (3.26%)
    5 / 87 (5.75%)
         occurrences all number
    5
    3
    8
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 133 (4.51%)
    1 / 92 (1.09%)
    0 / 87 (0.00%)
         occurrences all number
    6
    1
    0
    Pyrexia
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 92 (1.09%)
    3 / 87 (3.45%)
         occurrences all number
    3
    1
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 133 (3.76%)
    7 / 92 (7.61%)
    4 / 87 (4.60%)
         occurrences all number
    5
    7
    4
    Throat irritation
         subjects affected / exposed
    0 / 133 (0.00%)
    3 / 92 (3.26%)
    2 / 87 (2.30%)
         occurrences all number
    0
    4
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 133 (0.00%)
    3 / 92 (3.26%)
    0 / 87 (0.00%)
         occurrences all number
    0
    3
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 133 (2.26%)
    3 / 92 (3.26%)
    1 / 87 (1.15%)
         occurrences all number
    4
    4
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    4 / 133 (3.01%)
    2 / 92 (2.17%)
    3 / 87 (3.45%)
         occurrences all number
    4
    2
    6
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 133 (4.51%)
    6 / 92 (6.52%)
    5 / 87 (5.75%)
         occurrences all number
    6
    10
    7
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 133 (0.75%)
    3 / 92 (3.26%)
    1 / 87 (1.15%)
         occurrences all number
    1
    3
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 133 (6.77%)
    5 / 92 (5.43%)
    3 / 87 (3.45%)
         occurrences all number
    9
    10
    3
    Diarrhoea
         subjects affected / exposed
    4 / 133 (3.01%)
    1 / 92 (1.09%)
    3 / 87 (3.45%)
         occurrences all number
    4
    1
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    5 / 133 (3.76%)
    1 / 92 (1.09%)
    4 / 87 (4.60%)
         occurrences all number
    5
    1
    5
    Rash
         subjects affected / exposed
    2 / 133 (1.50%)
    1 / 92 (1.09%)
    6 / 87 (6.90%)
         occurrences all number
    3
    2
    6
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    6 / 133 (4.51%)
    8 / 92 (8.70%)
    5 / 87 (5.75%)
         occurrences all number
    6
    14
    5
    Back pain
         subjects affected / exposed
    4 / 133 (3.01%)
    3 / 92 (3.26%)
    4 / 87 (4.60%)
         occurrences all number
    4
    3
    5
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 133 (6.77%)
    9 / 92 (9.78%)
    5 / 87 (5.75%)
         occurrences all number
    12
    11
    6
    Urinary tract infection
         subjects affected / exposed
    11 / 133 (8.27%)
    2 / 92 (2.17%)
    5 / 87 (5.75%)
         occurrences all number
    12
    2
    7
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 133 (4.51%)
    6 / 92 (6.52%)
    5 / 87 (5.75%)
         occurrences all number
    7
    6
    5
    Bronchitis
         subjects affected / exposed
    5 / 133 (3.76%)
    1 / 92 (1.09%)
    5 / 87 (5.75%)
         occurrences all number
    6
    1
    6
    Oral herpes
         subjects affected / exposed
    5 / 133 (3.76%)
    1 / 92 (1.09%)
    2 / 87 (2.30%)
         occurrences all number
    6
    1
    2
    Sinusitis
         subjects affected / exposed
    0 / 133 (0.00%)
    5 / 92 (5.43%)
    1 / 87 (1.15%)
         occurrences all number
    0
    5
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 133 (0.00%)
    1 / 92 (1.09%)
    3 / 87 (3.45%)
         occurrences all number
    0
    1
    4
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    2 / 133 (1.50%)
    5 / 92 (5.43%)
    2 / 87 (2.30%)
         occurrences all number
    3
    5
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Mar 2011
    The co-primary endpoints (AUC0-inf and Cmax) were changed to one single primary endpoint (AUC0-inf) and a key secondary endpoint (Cmax). Changing infusion rates due to long time of rituximab infusions in accordance with SmPC were expected to cause larger variability for Cmax than for AUC0-inf and therefore AUC0-inf was considered a more reliable parameter for the PK comparability. The CI was changed from 90% to 95% CI for the PD endpoints according to the “Guideline on the Choice of the Non-Inferiority margin” (EMEA/CPMP/EWP/2158/99). In the original protocol, patients were requested to take a short course of oral corticosteroids (60 mg/day on Days 2-7 and 30 mg/day on Days 8-14). Amendment 1 eliminated this to reflect the recommendations of the current MabThera SmPC.
    04 Apr 2011
    A mandatory HIV test was added at Screening as per request of the Argentinean Health Authority. This change was applicable in Argentina only.
    21 Nov 2011
    The inclusion/exclusion criteria were amended to reflect more current practice since the time the REFLEX trial was conducted
    06 Mar 2013
    Introduced a third treatment arm Rituxan (reference rituximab licensed in the USA) to be compared to both GP2013 and MabThera (EU) aiming the clinical bridge between MabThera and Rituxan. The mean change from Baseline in DAS28 at Week 24 was made a key secondary endpoint. A supportive analysis of ACR20, similar to that of DAS28, was added.
    30 Oct 2013
    was implemented following a Drug Safety Communication from the US Health Authority (Food and Drug Administration; FDA) on 25-Sep-2013 announcing the addition of a Boxed Warning to Rituxan prescribing information concerning the potential for hepatitis B virus (HBV) reactivation.
    23 Jun 2014
    Gender was removed as a covariate from all PK analyses performed in Study Part II following discussions with the US FDA. Specifically mentioned “MabThera” or “Rituxan” instead of the general term “reference product” in order to clearly distinguish between EU-approved rituximab (MabThera), used as comparator in part I of the study, and US-licensed rituximab (Rituxan), used as comparator in Study Part II.
    04 Aug 2014
    The wording and use of terms were adapted to implement FDA´s advice for clear distinction between the terms and underlying concepts of “comparability” and “similarity”.
    09 Jun 2015
    Safety precautions, in accordance with the MTX label, in relation to contraception requirements to prevent fathering a child or becoming pregnant were included. As per request of the Polish Health Authority, the time frame in which a highly effective method of birth control, required for women of child bearing potential treated with rituximab, is specified to be consistent with the requirements currently in the Informed Consent Form.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28637670
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