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    Clinical Trial Results:
    A randomized, double- blind, controlled, parallel-group, multicenter study to assess the safety and immunogenicity of transitioning to GP2013 or re-treatment with Rituxan® or MabThera® in patients with active rheumatoid arthritis, previously treated with Rituxan® or MabThera®

    Summary
    EudraCT number
    2012-003876-38
    Trial protocol
    DE   HU   PL  
    Global end of trial date
    12 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Oct 2017
    First version publication date
    27 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GP13-302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02514772
    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, +49 80244760, biopharma.clinicaltrials@sandoz.com
    Scientific contact
    Strategic Planning Biopharma Clinical Development, Sandoz, +49 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
    12 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study objective is to identify potential safety risk of the transition from the originator product (US-licensed Rituxan® or EU-approved MabThera®) to GP2013 (proposed biosimilar product) as compared to continuous treatment with the originator product in terms of general safety and immunogenicity.
    Protection of trial subjects
    This trial was designed, conducted and reported in accordance with the international Conference on Harmonization (ICH) Guidelines for Good Clinical Practice (GCP), applicable local regulations (including European Directive 2001/20/EC), and following the ethical principles laid down in the Declaration of Helsinki. Specific ICH adopted and other relevant international guidelines and recommendations were taken into account as far as meaningfully possible. Safety assessments included adverse events (AEs), vital signs, 12-lead ECG parameters, clinical laboratory, immunogenicity, physical examination and other parameters considered relevant for the safety assessment, of Rituximab.
    Background therapy
    Metothrexate and Folic Acid
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Jun 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Germany: 50
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    107
    EEA total number of subjects
    72
    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)
    83
    From 65 to 84 years
    23
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 194 patients were screened at 54 centers in 4 countries, i.e. USA, Germany, Hungary, and Poland. Of these, 107 patients were randomized to either GP2013 (53 patients) or Rituxan/MabThera (54 patients).

    Pre-assignment
    Screening details
    In the screening period of 4 weeks patients' eligibility and status regarding positivity of anti-drug-antibodies (ADA; since study patients had already been treated previously with either commercial Rituxan® or MabThera® were tested.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    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 members (site and CRO) had access to the medication and the documentation of study medication.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GP2013
    Arm description
    Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab
    Arm type
    Experimental

    Investigational medicinal product name
    GP2013
    Investigational medicinal product code
    rituximab
    Other name
    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 14)

    Arm title
    Rituxan®/MabThera®
    Arm description
    Patients in this group received same originator rituximab version as they had received before study participation.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituxan®/MabThera®
    Investigational medicinal product code
    rituximab
    Other name
    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 14)

    Number of subjects in period 1
    GP2013 Rituxan®/MabThera®
    Started
    53
    54
    Completed
    50
    52
    Not completed
    3
    2
         Adverse event, serious fatal
    -
    1
         Adverse event, non-fatal
    1
    -
         Consent withdrawn by subject
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GP2013
    Reporting group description
    Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab

    Reporting group title
    Rituxan®/MabThera®
    Reporting group description
    Patients in this group received same originator rituximab version as they had received before study participation.

    Reporting group values
    GP2013 Rituxan®/MabThera® Total
    Number of subjects
    53 54 107
    Age categorical
    Units: Subjects
        18-44
    6 9 15
        45-64
    38 30 68
        65 and over
    9 15 24
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    56.8 ± 9.91 57.1 ± 12.14 -
    Gender categorical
    Units: Subjects
        Female
    46 39 85
        Male
    7 15 22
    Race
    Units: Subjects
        White
    51 52 103
        Black
    0 2 2
        Asian
    1 0 1
        American Native or Alaska Native
    1 0 1
    Experienced infusion-related reactions during rituximab treatments prior to randomization
    Units: Subjects
        No
    51 51 102
        Yes
    2 3 5
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    80.12 ± 20.22 81.62 ± 20.46 -
    Number of previous treatment courses with rituximab
    Units: treatment courses
        arithmetic mean (standard deviation)
    4.1 ± 3.32 5 ± 3.75 -
    Duration since initial diagnosis of rheumatoid arthritis
    Units: years
        arithmetic mean (standard deviation)
    13.46 ± 9.39 14.01 ± 8.51 -
    Dose of MTX at baseline
    Units: mg/week
        arithmetic mean (standard deviation)
    14.53 ± 6.20 15.46 ± 5.14 -
    C-reactive protein (CRP) at baseline
    Units: mg/L
        arithmetic mean (standard deviation)
    9.67 ± 24.25 11.64 ± 23.63 -

    End points

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    End points reporting groups
    Reporting group title
    GP2013
    Reporting group description
    Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab

    Reporting group title
    Rituxan®/MabThera®
    Reporting group description
    Patients in this group received same originator rituximab version as they had received before study participation.

    Primary: Hypersensitivity reactions

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    End point title
    Hypersensitivity reactions
    End point description
    The standardized MedDRA query (SMQ) - Hypersensitivity reactions (SMQ 20000214) was used for the identification of hypersensitivity reactions in the adverse event database.
    End point type
    Primary
    End point timeframe
    24 weeks study duration
    End point values
    GP2013 Rituxan®/MabThera®
    Number of subjects analysed
    53
    54
    Units: Patients
        After first infusion
    3
    4
        After second infusion
    2
    3
        Overall from first infusion
    5
    6
    Statistical analysis title
    Analysis of hypersensitivity reactions
    Comparison groups
    Rituxan®/MabThera® v GP2013
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.6
         upper limit
    16.9

    Primary: Incidence of anaphylactic reactions

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    End point title
    Incidence of anaphylactic reactions
    End point description
    2006 NIAID/FAAN criteria were used for identification of anaphylactic reactions
    End point type
    Primary
    End point timeframe
    Within 24 hours of each study drug infusion
    End point values
    GP2013 Rituxan®/MabThera®
    Number of subjects analysed
    53
    54
    Units: Patients
        Within 24 hours of first infusion
    0
    1
        Within 24 hours of second infusion
    0
    0
        Within 24 hours of either infusion
    0
    1
    Statistical analysis title
    Analysis of anaphylactic reactions
    Comparison groups
    Rituxan®/MabThera® v GP2013
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -20.6
         upper limit
    16.9

    Primary: Incidence of potential infusion-related reactions

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    End point title
    Incidence of potential infusion-related reactions
    End point description
    End point type
    Primary
    End point timeframe
    On days of and on days after study drug infusions
    End point values
    GP2013 Rituxan®/MabThera®
    Number of subjects analysed
    53
    54
    Units: Patients
        On day of or on day after first infusion
    4
    7
        On day of or on day after second infusion
    2
    5
        Overall on day(s) of or after either infusion
    6
    10
    Statistical analysis title
    Analysis of potential infusion-related reactions
    Comparison groups
    GP2013 v Rituxan®/MabThera®
    Number of subjects included in analysis
    107
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -7.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -26
         upper limit
    11.4

    Primary: Immunogenicity

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    End point title
    Immunogenicity
    End point description
    Incidence of anti-drug-antibodies (ADA). Patients with negative ADA results at screening and at least one evaluable post-randomization ADA assessment are included in the analysis
    End point type
    Primary
    End point timeframe
    24 weeks study duration
    End point values
    GP2013 Rituxan®/MabThera®
    Number of subjects analysed
    51 [1]
    53 [2]
    Units: Patients with ADA post treatment
    0
    1
    Notes
    [1] - Patients with a negative ADA result at screening and an evaluable post-randomization ADA assessment
    [2] - Patients with a negative ADA result at screening and an evaluable post-randomization ADA assessment
    Statistical analysis title
    Analysis of anti-drug antibodies
    Comparison groups
    GP2013 v Rituxan®/MabThera®
    Number of subjects included in analysis
    104
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -21.2
         upper limit
    17.6

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs are reported from date patient has provided informed consent and until 30 days after the patient has stopped study participation. AEs are analyzed from start date of study treatment to date of study completion/early discontinuation.
    Adverse event reporting additional description
    The investigator was additionally requested to consult with the patient via phone on the next day after the infusion to document AEs, occurred within 24h of the infusion.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    GP2013
    Reporting group description
    Patients in this group were switched from originator rituximab (which they received before study participation) to GP2013 - biosimilar rituximab

    Reporting group title
    Rituxan®/MabThera®
    Reporting group description
    Patients in this group received same originator rituximab version as they had received before study participation.

    Serious adverse events
    GP2013 Rituxan®/MabThera®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 54 (5.56%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Fibrin D dimer increased
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Hiatus hernia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    GP2013 Rituxan®/MabThera®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 53 (69.81%)
    28 / 54 (51.85%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 54 (3.70%)
         occurrences all number
    3
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 53 (1.89%)
    2 / 54 (3.70%)
         occurrences all number
    1
    2
    Vomiting
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 53 (0.00%)
    2 / 54 (3.70%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 54 (3.70%)
         occurrences all number
    2
    2
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Osteoarthritis
         subjects affected / exposed
    2 / 53 (3.77%)
    0 / 54 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 54 (5.56%)
         occurrences all number
    1
    3
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 54 (5.56%)
         occurrences all number
    1
    4
    Nasopharyngitis
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Sinusitis
         subjects affected / exposed
    2 / 53 (3.77%)
    1 / 54 (1.85%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Aug 2015
    After finalization of the study protocol FDA recommended to include unscheduled Anti-Drug-Antibody (ADA) blood sampling triggered by suspected immunologically related adverse events, to assess the clinical relevance of ADAs. In order to fulfill the recommendation of the methotrexate label for males on methotrexate to prevent fathering a child, respective recommendations were included in the protocol and ICF. Additionally, the informed consent procedure for following up of partner pregnancies of male study participants was introduced.

    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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