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    Clinical Trial Results:
    A Randomized, Controlled, Double-Blind, Parallel-Group, Phase 3 Study to Compare the Pharmacokinetics, Efficacy and Safety between CT-P10, Rituxan and MabThera in Patients with Rheumatoid Arthritis

    Summary
    EudraCT number
    2013-004555-21
    Trial protocol
    AT   LV   PT   DE   SK   HU   GR  
    Global end of trial date
    25 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Jan 2018
    First version publication date
    04 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CT-P10 3.2
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02149121
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Celltrion, Inc.
    Sponsor organisation address
    23 Academy-ro (13-6, Songdo-dong), Yeonsu-gu, Incheon, Korea, Republic of, 22014
    Public contact
    Clinical Operations Management Department, CELLTRION, Inc., +82 32 850 6724, SuEun.Song@celltrion.com
    Scientific contact
    Clinical Planning Department, CELLTRION, Inc., +82 32 850 6532, SungYoung.Lee@celltrion.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
    25 Jan 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Part 1 of the study is: • To evaluate and compare pharmacokinetics in terms of area under the serum concentration-time curve from zero to time of last quantifiable concentration (AUC0-last), AUC from zero to infinity (AUC0-∞) and maximum serum concentration (Cmax) (after the second infusion) of CT-P10 to Rituxan, CT-P10 to MabThera and Rituxan to MabThera during the first course of treatment (over the first 24 weeks). The primary objective of Part 2 of the study is: • To demonstrate that CT-P10 is similar to Rituxan and MabThera in terms of efficacy as determined by clinical response according to change from baseline in disease activity measured by Disease Activity Score using 28 joint counts (DAS28) (C-reactive protein [CRP]) at Week 24.
    Protection of trial subjects
    Hypersensitivity had been assessed by vital sign monitoring on each dosing day and recorded on each dosing day at the following time points: • Before administration (within 15 minutes prior to the beginning of the study drug infusion) • Within 15 minutes after the end of the study drug infusion • 1 hour (±15 minutes) after the end of the study drug infusion In addition, hypersensitivity should be monitored by routine continuous clinical monitoring including 12-lead ECG monitoring 1 hour (±15 minutes) after the end of the study drug infusion. Emergency equipment, such as adrenaline, antihistamines, corticosteroids, and respiratory support including inhalational therapy, oxygen, and artificial ventilator must be available. For patients who experience or develop life threatening infusion related anaphylactic reactions, study treatment must be stopped immediately and the patient withdrawn from the study.
    Background therapy
    Methotrexate will be administered at a dosage of between 7.5 and 25 mg orally or parenterally every week (dose and route must be maintained from beginning to study end). Folic acid will be administered at a dosage of at least 5 mg/week for as long as MTX treatment is continued.
    Evidence for comparator
    CT P10 is being developed as a biosimilar candidate of Rituxan and MabThera, a compound with established efficacy in its registered indications and CT-P10 is intended to offer a more affordable treatment than Rituxan and MabThera, if similar efficacy and safety can be demonstrated during the conduct of these key clinical studies.
    Actual start date of recruitment
    06 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Ukraine: 38
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Bosnia and Herzegovina: 34
    Country: Number of subjects enrolled
    Chile: 13
    Country: Number of subjects enrolled
    Colombia: 18
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Israel: 17
    Country: Number of subjects enrolled
    Korea, Republic of: 24
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Mexico: 41
    Country: Number of subjects enrolled
    Peru: 63
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Portugal: 5
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 21
    Worldwide total number of subjects
    372
    EEA total number of subjects
    103
    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)
    326
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First patient randomly assigned to treatment: 06 August 2014 A toal of 98 study centers were initiated in Europe, Asia Pacific, and Latin America.

    Pre-assignment
    Screening details
    Key Inclusion Criteria 1.Patient is male or female between 18 and 75 years old, inclusive 2.Patient has a diagnosis of RA according to the revised 1987 ACR classification criteria for at least 6 months prior to randomization 3.Patient has experienced an inadequate or intolerance response to previous treatment with the antitumor necrosis factor

    Pre-assignment period milestones
    Number of subjects started
    495 [1]
    Intermediate milestone: Number of subjects
    Subject screened: 495
    Intermediate milestone: Number of subjects
    Enrolled: 372
    Number of subjects completed
    372

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Screening Failure: 111
    Reason: Number of subjects
    GCP non-compliant site: 12
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The 'Number of subjects reported to have started the pre-assignment period' means subjects who consented to participate in this trial through the Screening procedure. If these subjects meet Inclusion and Exclusion criteria defined by the protocol, they can be randomized which will have study drug administration. Subject who received at least 1 dose of study drug (CT-P10, Rituxan or MabThera) is considered as 'Enrolled' in the trial.
    Period 1
    Period 1 title
    Main Study Period-1st treatment course
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CT-P10
    Arm description
    CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    Rituxan
    Arm description
    US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    MabThera
    Arm description
    EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Active comparator

    Investigational medicinal product name
    MabThera
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MabThera (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Number of subjects in period 1
    CT-P10 Rituxan MabThera
    Started
    161
    151
    60
    Completed
    145
    142
    58
    Not completed
    16
    9
    2
         Patient died
    1
    -
    -
         Protocol deviation
    2
    -
    -
         Physician decision
    1
    -
    -
         Lack of efficacy
    2
    1
    -
         Adverse event, non-fatal
    2
    4
    1
         Consent withdrawn by subject
    7
    4
    1
         Lost to follow-up
    1
    -
    -
    Period 2
    Period 2 title
    Main Study Period-2nd treatment course
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CT-P10
    Arm description
    CT-P10 (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    Rituxan
    Arm description
    US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    MabThera
    Arm description
    EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Arm type
    Active comparator

    Investigational medicinal product name
    MabThera
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    MabThera (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Number of subjects in period 2 [2]
    CT-P10 Rituxan MabThera
    Started
    142
    138
    58
    Completed
    140
    134
    56
    Not completed
    2
    4
    2
         Lack of efficacy
    -
    -
    1
         Developed any malignancy
    -
    1
    1
         Adverse event, non-fatal
    -
    1
    -
         Consent withdrawn by subject
    1
    1
    -
         Lost to follow-up
    1
    1
    -
    Notes
    [2] - 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: Seven subjects did not initiated the 2nd course after completion of the 1st course. Among them, 4 subjects did not meet safety criteria for the 2nd course initiation (each 2 subjects from the CT-P10 and Rituxan groups), and were monitored up to Week 48. The other 3 subjects were discontinued after Week 24 and entered as "discontinued after course 2, not treated" in Period 2 Section (1 subject in CT-P10: withdrew consent; 2 subjects in Rituxan: 1 lack of efficacy and 1 disease progression).
    Period 3
    Period 3 title
    Extension Study Period
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    CT-P10 maintenance
    Arm description
    Patients who were assigned to receive CT-P10 for their first infusion in the study were considered to be CT-P10 maintenance and continued to receive CT-P10 for the treatment course in the Extension Study Period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)
    Arm type
    Experimental

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    Rituxan maintenance
    Arm description
    Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again at Extension Week 0 to Rituxan maintenance group, who continued to receive Rituxan for the treatment course of the Extension Study PEriod. Rituxan (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituxan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rituxan (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    Switched from Rituxan
    Arm description
    Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again to Switched from Rituxan group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week).
    Arm type
    Active comparator

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Arm title
    Switched from MabThera
    Arm description
    Patients who were assigned to receive MabThera for their first infusion in the study were considered to be Switched from MabThera group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)
    Arm type
    Active comparator

    Investigational medicinal product name
    CT-P10
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    CT-P10 (1000mg), MTX (between 7.5 to 25 mg/week, oral or parenteral dose), folic acid (≥ 5mg/week)

    Number of subjects in period 3 [3]
    CT-P10 maintenance Rituxan maintenance Switched from Rituxan Switched from MabThera
    Started
    122
    64
    62
    47
    Completed
    121
    64
    60
    47
    Not completed
    1
    0
    2
    0
         Consent withdrawn by subject
    1
    -
    2
    -
    Notes
    [3] - 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: According to the protocol, only the eligible subjects can be participated in the Extension Study Period. When the subjects had completed the Main Study Period, and met the predefined safety criteria based on the results assess within 8 weeks from Week 0 of the Extension Study period, subjects could continue on to the Extension Study Period with an additional treatment course. Due to the ineligibility of evaluation result, some of subjects were not enrolled in the Extension study period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    Rituxan
    Reporting group description
    US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    MabThera
    Reporting group description
    EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group values
    CT-P10 Rituxan MabThera Total
    Number of subjects
    161 151 60 372
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0
        Adults (18-64 years)
    143 127 56 326
        From 65-84 years
    18 24 4 46
        85 years and over
    0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    53.0 (18 to 74) 53.0 (21 to 74) 51.5 (20 to 74) -
    Gender categorical
    Units: Subjects
        Female
    138 130 50 318
        Male
    23 21 10 54

    End points

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    End points reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    CT-P10 (1000mg) coadministered with MTX between 7.5 and 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    Rituxan
    Reporting group description
    US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    MabThera
    Reporting group description
    EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Reporting group title
    CT-P10
    Reporting group description
    CT-P10 (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    Rituxan
    Reporting group description
    US-licensed reference product. Rituxan (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)

    Reporting group title
    MabThera
    Reporting group description
    EU-approved reference product. MabThera (1000mg) coadministered with MTX between 7.5 to 25 mg/week (oral or parenteral dose) and folic acid (≥ 5mg/week)
    Reporting group title
    CT-P10 maintenance
    Reporting group description
    Patients who were assigned to receive CT-P10 for their first infusion in the study were considered to be CT-P10 maintenance and continued to receive CT-P10 for the treatment course in the Extension Study Period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)

    Reporting group title
    Rituxan maintenance
    Reporting group description
    Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again at Extension Week 0 to Rituxan maintenance group, who continued to receive Rituxan for the treatment course of the Extension Study PEriod. Rituxan (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)

    Reporting group title
    Switched from Rituxan
    Reporting group description
    Patients who were assigned to receive Rituxan for their first infusion in the study were assigned again to Switched from Rituxan group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week).

    Reporting group title
    Switched from MabThera
    Reporting group description
    Patients who were assigned to receive MabThera for their first infusion in the study were considered to be Switched from MabThera group and received CT-P10 for the treatment course of the Extension study period. CT-P10 (1000mg) coadministered with MTX between 7.5 to 25mg/week (oral or parenteral dose) and folic acid (≥ 5mg.week)

    Subject analysis set title
    All-randomized population
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The all-randomized population consisted of all patients enrolled and randomly assigned to receive a dose of study drug, regardless of whether or not any study drug dosing was completed.

    Subject analysis set title
    Pharmacokinetic Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PK population of the Main Study Period consisted of all patients who received 2 full doses (Week 0 and Week 2) of the study drug and provided at least 1 post-treatment PK concentration result during the first course of treatment in the Main Study Period. Note. The PK population was the primary population for the summary of PK data.

    Subject analysis set title
    Efficacy Population
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The efficacy population for the Main Study Period consisted of all patients who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the first course of treatment in the Main Study Period

    Subject analysis set title
    Pharmacodynamic Population
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The PD population for the Main Study Period consisted of all patients who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment PD result during the first course of treatment in the Main Study Period.

    Subject analysis set title
    Safety Population
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population consisted of all patients who received at least 1 (full or partial) dose of study drug during any dosing period.

    Subject analysis set title
    All-randomized - Extension Study Period subset
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The “all-randomized population – Extension Study Period subset” consisted of all patients in the all-randomized population who received at least 1 (full or partial) dose of study drug in the Extension Study Period.

    Subject analysis set title
    Efficacy - Extension Study Period subset
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The “efficacy – Extension Study Period subset” consisted of all patients in the efficacy population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment efficacy result during the Extension Study Period.

    Subject analysis set title
    Pharmacodynamic - Extension Study Period subset
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The “pharmacodynamic – Extension Study Period subset” consisted of all patients in the PD population who received at least 1 full dose (1000 mg) of study drug and provided at least 1 post-treatment PD result during the Extension Study Period.

    Subject analysis set title
    Safety - Extension Study Period subset
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    The “safety – Extension Study Period subset” consisted of all patients in the safety population who received at least 1 (full or partial) dose of study drug during the Extension Study Period.

    Subject analysis set title
    CT-P10: 1st treatment course in the Main Study Period
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This subject analysis set received an infusion of study drug (CT-P10) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.

    Subject analysis set title
    Reference products: 1st treatment course in Main Study Period
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This subject analysis set received an infusion of reference products (Rituxan and MabThera) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.

    Subject analysis set title
    Rituxan: 1st treatment course in Main Study Period
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This subject analysis set received an infusion of reference product (Rituxan) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.

    Subject analysis set title
    MabThera: 1st treatment course in Main Study Period
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    This subject analysis set received an infusion of reference product (MabThera) at Week 0 and Week 2 of the 1st treatment course in the Main Study Period.

    Primary: AUC0-last

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    End point title
    AUC0-last
    End point description
    AUC0-last: Area under the concentration-time curve from time 0 to the last measurable concentration. Note: Measure Type is geometric least squares mean.
    End point type
    Primary
    End point timeframe
    over the first 24 weeks
    End point values
    CT-P10: 1st treatment course in the Main Study Period Rituxan: 1st treatment course in Main Study Period MabThera: 1st treatment course in Main Study Period
    Number of subjects analysed
    62 [1]
    60 [2]
    59 [3]
    Units: h*μg/mL
        geometric mean (standard error)
    162414.81 ± 1.073
    167309.07 ± 1.073
    172450.97 ± 1.075
    Notes
    [1] - Pharmacokinetics population
    [2] - Pharmacokinetics population
    [3] - Pharmacokinetics population
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-last
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [4]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    97.07
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    88.08
         upper limit
    106.99
    Notes
    [4] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-last
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [5]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    94.18
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    85.4
         upper limit
    103.86
    Notes
    [5] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-last
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-last, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [6]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    103.07
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    93.32
         upper limit
    113.85
    Notes
    [6] - Equivalence margin: 80%-125%

    Primary: AUC0-inf

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    End point title
    AUC0-inf
    End point description
    AUC0-inf: Area under the concentration-time curve from time 0 extrapolated to infinity Note: Measure Type is geometric least squares mean.
    End point type
    Primary
    End point timeframe
    over the first 24 weeks
    End point values
    CT-P10: 1st treatment course in the Main Study Period Rituxan: 1st treatment course in Main Study Period MabThera: 1st treatment course in Main Study Period
    Number of subjects analysed
    59 [7]
    60 [8]
    56 [9]
    Units: h*ug/mL
        geometric mean (standard error)
    162377.28 ± 1.068
    169480.80 ± 1.069
    180637.81 ± 1.072
    Notes
    [7] - Pharmacokinetics population
    [8] - Pharmacokinetics population
    [9] - Pharmacokinetics population
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-inf
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [10]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    95.81
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    87.39
         upper limit
    105.04
    Notes
    [10] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-inf
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    115
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [11]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    89.89
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    81.85
         upper limit
    98.72
    Notes
    [11] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - AUC0-inf
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of AUC0-inf, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [12]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    106.58
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    97.03
         upper limit
    117.08
    Notes
    [12] - Equivalence margin: 80%-125%

    Primary: Cmax

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    End point title
    Cmax
    End point description
    Cmax: Observed maximum concentration after the second infusion Note: Measure Type is geometric least squares mean.
    End point type
    Primary
    End point timeframe
    over the first 24 weeks
    End point values
    CT-P10: 1st treatment course in the Main Study Period Rituxan: 1st treatment course in Main Study Period MabThera: 1st treatment course in Main Study Period
    Number of subjects analysed
    62 [13]
    59 [14]
    59 [15]
    Units: ug/mL
        geometric mean (standard error)
    367.03 ± 1.042
    386.65 ± 1.042
    412.40 ± 1.043
    Notes
    [13] - Pharmacokinetics population
    [14] - Pharmacokinetics population
    [15] - Pharmacokinetics population
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - Cmax
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v Rituxan: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [16]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    94.92
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    89.61
         upper limit
    100.55
    Notes
    [16] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - Cmax
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    121
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [17]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    89
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    84.01
         upper limit
    94.28
    Notes
    [17] - Equivalence margin: 80%-125%
    Statistical analysis title
    Co-primary Pharmacokinetics Endpoints - Cmax
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of Cmax, Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Point estimates (geometric means and ratio of geometric means) and 90% confidence intervals for differences on the log scale were exponentiated to obtain estimates for ratios of geometric least square means on the original scale.
    Comparison groups
    Rituxan: 1st treatment course in Main Study Period v MabThera: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [18]
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    106.66
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    100.56
         upper limit
    113.13
    Notes
    [18] - Equivalence margin: 80%-125%

    Primary: Change from baseline of DAS28 (CRP)

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    End point title
    Change from baseline of DAS28 (CRP)
    End point description
    Note: Measure Type is adjusted least squares mean.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    CT-P10: 1st treatment course in the Main Study Period Reference products: 1st treatment course in Main Study Period
    Number of subjects analysed
    138 [19]
    196 [20]
    Units: Score
        least squares mean (standard error)
    -2.13 ± 0.175
    -2.09 ± 0.176
    Notes
    [19] - Efficacy population
    [20] - The combined Rituxan and MabThera treatment groups. Efficacy population
    Statistical analysis title
    Co-primary Efficacy Endpoint - CFB of DAS28 (CRP)
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value: change from baseline of DAS28 (CRP), Fixed effect: treatment group, Covariates: gender, region, race, prior anti-TNF-α blocker status, and RF or anti-CCP status. Adjusted least squares means and standard error, estimate of treatment difference [CT-P10 - (Reference products)] and 2-sided 95% confidence interval calculated from the ANCOVA model.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v Reference products: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [21]
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.29
         upper limit
    0.21
    Notes
    [21] - Equivalence margin: +/- 0.60

    Secondary: B-cell counts

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    End point title
    B-cell counts
    End point description
    Note: Measure Type is geometric least squares mean.
    End point type
    Secondary
    End point timeframe
    up to 24 weeks
    End point values
    CT-P10: 1st treatment course in the Main Study Period Reference products: 1st treatment course in Main Study Period
    Number of subjects analysed
    123 [22]
    173 [23]
    Units: cells/mcL
        geometric mean (standard error)
    25.30 ± 1.073
    24.66 ± 1.072
    Notes
    [22] - Pharmacodynamic population
    [23] - The combined Rituxan and MabThera treatment groups. Pharmacodynamic Population
    Statistical analysis title
    Secondary Pharmacodynamics endpoint-B-cell kinetic
    Statistical analysis description
    Analysis Method: Analysis of covariance (ANCOVA). Response value:log transformed values of B-cell kinetics, Fixed effect: treatment group, Covariates:baseline result, gender, region, race, prior anti-TNF-α blocker status and RF or anti-CCP status. Estimate of Geometric Least Square Mean and ratio of Geometric Least Square Means (CT-P10 / reference products) were obtained from back transforming the least square means from the ANCOVA model.
    Comparison groups
    CT-P10: 1st treatment course in the Main Study Period v Reference products: 1st treatment course in Main Study Period
    Number of subjects included in analysis
    296
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Ratio of geometric least square means
    Point estimate
    102.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    92.86
         upper limit
    113.39

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 48 weeks (Main Study Period)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    CT-P10
    Reporting group description
    The safety population consisted of all patients who received at least 1 (full or partial) dose of study drug during any dosing period.

    Reporting group title
    Rituxan
    Reporting group description
    -

    Reporting group title
    MabThera
    Reporting group description
    -

    Serious adverse events
    CT-P10 Rituxan MabThera
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 161 (8.07%)
    14 / 151 (9.27%)
    4 / 60 (6.67%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    4 / 161 (2.48%)
    2 / 151 (1.32%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 161 (0.00%)
    2 / 151 (1.32%)
    0 / 60 (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
    Joint dislocation
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphangioma
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 151 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 151 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea exertional
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 151 (0.66%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    0 / 161 (0.00%)
    0 / 151 (0.00%)
    1 / 60 (1.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Tremor
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Gastrointestinal disorders
    Intestinal obstruction
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Colitis ischaemic
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Cholecystitis
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Arthralgia
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Hand deformity
         subjects affected / exposed
    1 / 161 (0.62%)
    0 / 151 (0.00%)
    0 / 60 (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
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 151 (0.66%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Localised infection
         subjects affected / exposed
    0 / 161 (0.00%)
    1 / 151 (0.66%)
    0 / 60 (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
    Cellulitis
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 151 (0.66%)
    0 / 60 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    CT-P10 Rituxan MabThera
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    112 / 161 (69.57%)
    83 / 151 (54.97%)
    35 / 60 (58.33%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    6 / 161 (3.73%)
    4 / 151 (2.65%)
    0 / 60 (0.00%)
         occurrences all number
    6
    5
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    33 / 161 (20.50%)
    12 / 151 (7.95%)
    13 / 60 (21.67%)
         occurrences all number
    39
    15
    15
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 161 (3.11%)
    7 / 151 (4.64%)
    0 / 60 (0.00%)
         occurrences all number
    5
    10
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 161 (3.73%)
    5 / 151 (3.31%)
    2 / 60 (3.33%)
         occurrences all number
    7
    5
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 161 (4.97%)
    8 / 151 (5.30%)
    2 / 60 (3.33%)
         occurrences all number
    9
    9
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 161 (0.62%)
    1 / 151 (0.66%)
    2 / 60 (3.33%)
         occurrences all number
    1
    1
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 161 (2.48%)
    5 / 151 (3.31%)
    1 / 60 (1.67%)
         occurrences all number
    4
    6
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 161 (1.86%)
    1 / 151 (0.66%)
    3 / 60 (5.00%)
         occurrences all number
    3
    1
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    5 / 161 (3.11%)
    4 / 151 (2.65%)
    1 / 60 (1.67%)
         occurrences all number
    5
    5
    1
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    7 / 161 (4.35%)
    4 / 151 (2.65%)
    1 / 60 (1.67%)
         occurrences all number
    7
    5
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    24 / 161 (14.91%)
    30 / 151 (19.87%)
    9 / 60 (15.00%)
         occurrences all number
    32
    31
    12
    Urinary tract infection
         subjects affected / exposed
    15 / 161 (9.32%)
    8 / 151 (5.30%)
    2 / 60 (3.33%)
         occurrences all number
    23
    14
    2
    Lower respiratory tract infection
         subjects affected / exposed
    10 / 161 (6.21%)
    7 / 151 (4.64%)
    3 / 60 (5.00%)
         occurrences all number
    11
    9
    3
    Rhinitis
         subjects affected / exposed
    3 / 161 (1.86%)
    6 / 151 (3.97%)
    1 / 60 (1.67%)
         occurrences all number
    4
    6
    1
    Influenza
         subjects affected / exposed
    2 / 161 (1.24%)
    0 / 151 (0.00%)
    2 / 60 (3.33%)
         occurrences all number
    2
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2013
    Summary of significant changes included the following: • Downgraded ACR20 as a secondary endpoint. • Clarified follow-up of B-cell, IgM and IgG monitoring. • Clarified the schedule of infusions in the second treatment course. • Other administrative changes.
    02 Jun 2014
    Summary of significant change included the following: • Changed equivalence margin of DAS28 from 0.75 to 0.6 to reflect recommendation from the Committee for Medicinal Products for Human Use and other regulatory agencies. • Updated sections regarding statistical analysis according to the update of DAS28 margin. • Added AUC0-day14 as one of secondary PK endpoints to reflect recommendation from the Food and Drug Administration. • Added mean change in DAS28 at Week 12 as one of secondary efficacy endpoints to reflect recommendation from the European Medicines Agency. • Combined Rituxan and MabThera groups for the Part 2 analyses. • Added a section for diagnosis of anaphylactic reactions based on the Sampson criteria (Sampson et al., 2006). • Clarified EOS visit. • Other administrative changes.
    05 Aug 2015
    Summary of significant changes included the following: • Revised to have additional course of treatment with single transition to evaluate additional safety and efficacy. • Other administrative changes.
    11 Mar 2016
    Summary of significant changes includes the followings: • Updated covariates of ANCOVA for PK and efficacy primary endpoints and the comparison of the concentration of B-cell counts to include clinically relevant variables at baseline. • Updated Section to prepare additional clinical study report(s) by regulatory or academic purpose and to remove a report to be developed for data from each patient up to Week 48. • Other administrative changes.
    29 Mar 2016
    Summary of significant changes included the following: • Updated covariates of ANCOVA for PK and efficacy primary endpoints and the comparison of the concentration of B-cell counts to include clinically relevant variables at baseline. • Updated Section to prepare additional clinical study report(s) by regulatory or academic purpose and to remove a report to be developed for data from each patient up to Week 48. • Added immunogenicity sampling time points at Extension Weeks 8 and 16 for further evaluation of immunogenicity in the Extension Study Period. • Other administrative changes.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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