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    Clinical Trial Results:
    Efficacy, pharmacokinetics, and safety of BI 695500 versus rituximab in patients with moderately to severely active rheumatoid arthritis: a randomized, double-blind, parallel arm, multiple dose, active comparator trial

    Summary
    EudraCT number
    2011-002894-48
    Trial protocol
    GB   EE   PT   NL   BE   DE   HU   NO   GR   ES   BG  
    Global end of trial date
    28 Oct 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    1301.1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01682512
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination, Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.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
    13 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Oct 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of this trial are: To show pharmacokinetic (PK) similarity of BI 695500 to MabThera® and Rituxan® and of Rituxan® to MabThera® (three-way PK similarity). To establish statistical equivalence of efficacy of BI 695500 and Rituxan® in patients with moderately to severely active rheumatoid arthritis (RA), based on the change in Disease Activity Score 28 (DAS28) measured at 24 weeks compared to Baseline.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Other medication considered necessary for the patient’s safety, including rescue medication for the treatment of infusion-related reactions, was permitted at the Investigator’s discretion.
    Background therapy
    Patients continued to receive an appropriate standard of care by continuing to take their regular methotrexate (MTX) therapy (15-25 milligram (mg)/week) and a stable weekly dose of adequate folic acid (at least 5 mg per week or as per local practice), from their usual source. Patients may also continue to receive treatment with oral corticosteroids at a dose of ≤ 10 mg/day prednisolone or equivalent
    Evidence for comparator
    Rituxan® and MabThera®
    Actual start date of recruitment
    27 Sep 2012
    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
    Spain: 9
    Country: Number of subjects enrolled
    Ukraine: 19
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 331
    Country: Number of subjects enrolled
    Argentina: 65
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 18
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Chile: 6
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Mexico: 14
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 20
    Country: Number of subjects enrolled
    Portugal: 7
    Worldwide total number of subjects
    509
    EEA total number of subjects
    73
    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)
    395
    From 65 to 84 years
    114
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Subjects were enrolled into this multi-center, randomized, double-blind, parallel arm, multiple dose, active comparator 2 part trial from 27 September 2017. Trial was terminated on 3 September 2015 and last subject completed 28 October 2016.

    Pre-assignment
    Screening details
    509 subjects were screened for eligibility to participate in the trial. 293 subjects met all inclusion and exclusion criteria and were randomised to receive treatment. 6 subjects were included in an open-label safety run-in prior to randomisation in Part I.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Carer, Subject, Investigator
    Blinding implementation details
    Subjects, investigators and trial personnel remained blinded with regard to the randomized treatment assignments until after database lock.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    BI 695500
    Arm description
    Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.
    Arm type
    Experimental

    Investigational medicinal product name
    BI 695500
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Arm title
    Rituxan®
    Arm description
    Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-II but not treated. Consequently, number of subjects that randomized were 111 but only 110 reported to ensure consistent reporting with baseline characteristics that include only treated patients.
    Arm type
    Active comparator

    Investigational medicinal product name
    Rituxan®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Arm title
    MabThera®
    Arm description
    Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-I but not treated. Consequently, number of subjects that randomized were 66 but only 65 reported to ensure consistent reporting with baseline characteristics that include only treated patients.
    Arm type
    Active comparator

    Investigational medicinal product name
    MabThera®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Number of subjects in period 1 [1]
    BI 695500 Rituxan® MabThera®
    Started
    116
    110
    65
    Completed
    44
    40
    48
    Not completed
    72
    70
    17
         Protocol deviation
    2
    3
    2
         Physician decision
    -
    2
    -
         Secondary lack of efficacy
    1
    1
    -
         Study terminated by sponsor
    46
    42
    -
         Adverse event, non-fatal
    6
    5
    2
         Primary lack of efficacy
    10
    7
    7
         Consent withdrawn by subject
    2
    6
    2
         Other than stated above
    2
    4
    2
         Lost to follow-up
    3
    -
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomized after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Reporting group title
    Rituxan®
    Reporting group description
    Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-II but not treated. Consequently, number of subjects that randomized were 111 but only 110 reported to ensure consistent reporting with baseline characteristics that include only treated patients.

    Reporting group title
    MabThera®
    Reporting group description
    Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-I but not treated. Consequently, number of subjects that randomized were 66 but only 65 reported to ensure consistent reporting with baseline characteristics that include only treated patients.

    Reporting group values
    BI 695500 Rituxan® MabThera® Total
    Number of subjects
    116 110 65 291
    Age categorical
    The safety randomized analysis set (SAFR) contained all randomized subjects who received at least one dose of trial medication and subjects were classified according to treatment received.
    Units: Subjects
    Age Continuous
    The safety randomized analysis set (SAFR) contained all randomized subjects who received at least one dose of trial medication and subjects were classified according to treatment received.
    Units: years
        arithmetic mean (standard deviation)
    54.7 ± 10.46 54.0 ± 11.10 54.8 ± 12.22 -
    Gender, Male/Female
    The safety randomized analysis set (SAFR) contained all randomized subjects who received at least one dose of trial medication and subjects were classified according to treatment received.
    Units: Subjects
        Female
    94 96 52 242
        Male
    22 14 13 49

    End points

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    End points reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Reporting group title
    Rituxan®
    Reporting group description
    Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-II but not treated. Consequently, number of subjects that randomized were 111 but only 110 reported to ensure consistent reporting with baseline characteristics that include only treated patients.

    Reporting group title
    MabThera®
    Reporting group description
    Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26. One subject was randomized in part-I but not treated. Consequently, number of subjects that randomized were 66 but only 65 reported to ensure consistent reporting with baseline characteristics that include only treated patients.

    Primary: Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) from Baseline to Week 24 - Part I

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    End point title
    Change of Disease Activity Score 28 Erythrocyte Sedimentation Rate (DAS28 [ESR]) from Baseline to Week 24 - Part I [1]
    End point description
    The DAS28 score was derived using the formula: DAS28 (ESR) = 0.56*√(TJC28) + 0.28*√(SJC28) + 0.70*ln(ESR) + 0.014*(GH), where, TJC28 = 28 joint count for tenderness, SJC28 = 28 joint count for swelling, Ln(ESR) = natural logarithm of ESR, GH = the General Health component of the DAS [Patients mark on a visual analogue scale (VAS) their overall assessment of how their rheumatoid arthritis (RA) affects them, rating how they are managing from 0 (very well) to 100 (very poor). This is equivalent to the General Health component of the DAS (GH)]. DAS28 values range from 2.0 to 10.0 while higher values mean a higher disease activity. A clinically important change in DAS28 score is defined as an improvement in DAS28 score of at least 1.2. The full analysis set (FAS) contained all randomized subjects who received at least one dose of trial medication, had at least one assessment of primary efficacy endpoint at Baseline and at post-baseline visit prior or at Week 24 visit.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    BI 695500 Rituxan®
    Number of subjects analysed
    58 [2]
    61 [3]
    Units: Unit on scale
        least squares mean (confidence interval 90%)
    -1.8 (-2.08 to -1.50)
    -1.4 (-1.64 to -1.09)
    Notes
    [2] - FAS
    [3] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Adjusted mean difference was calculated as: BI 695500 – Rituxan®. A restricted maximum likelihood (REML)-based Mixed-Effect Model Repeated Measure (MMRM) approach was used.
    Comparison groups
    Rituxan® v BI 695500
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    equivalence [4]
    Method
    Mixed models analysis
    Parameter type
    Adjusted mean difference
    Point estimate
    -0.4
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.83
         upper limit
    -0.03
    Notes
    [4] - Equivalence for the change in DAS28 (ESR) was evaluated based on the two-sided 90% Confidence Interval (CI) for the treatment difference with respect to the mean change in the DAS28(ESR) score compared to baseline. Null hypothesis of non-equivalence was to be rejected if the 90% CI is fully contained within the interval of [-0.5, 0.5].

    Primary: PK (Part I only): AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined over both dosages)

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    End point title
    PK (Part I only): AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined over both dosages)
    End point description
    Pharmacokinetic (PK) (Part I only): AUC0-tz (area under the plasma concentration versus time curve from time zero to the last measurable concentration, determined over both dosages). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included. As per protocol all the following criteria had to be fulfilled for a patient to be defined as PK evaluable for the Pharmacokinetic analysis set (PKS): Full first and second dose given. Pre-dose concentration available prior to the second dose. Ability to estimate AUC during the infusion phases. Ability to estimate the AUC for the distribution phase after the second dose. Ability to estimate the terminal half-life (t1/2) after the second dose. Pharmacokinetic analysis set (PKS) consisted of all randomized subjects who were PK evaluable based on protocol defined criteria.
    End point type
    Primary
    End point timeframe
    Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    56 [5]
    56 [6]
    55 [7]
    Units: Hour(h)*Microgram(ug)/Milliliter (mL)
        geometric mean (geometric coefficient of variation)
    171000 ± 41.1
    167000 ± 40.5
    193000 ± 37.9
    Notes
    [5] - PKS
    [6] - PKS
    [7] - PKS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-tz)=overall mean+treatment effect+random error. Adjusted ratio of Geometric Means (gMeans): BI 695500 versus Rituxan®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v Rituxan®
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    102.35
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    90.5
         upper limit
    115.76
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.7
    Notes
    [8] - The similarity of AUC(o- tz) was compared between treatment groups BI 695500 and Rituxan.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-tz)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    88.21
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    78.24
         upper limit
    99.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.5
    Notes
    [9] - The similarity of AUC(o- tz) was compared between treatment groups BI 695500 and MabThera.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-tz)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error.
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    86.18
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    76.5
         upper limit
    97.09
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.449
    Notes
    [10] - The similarity of AUC(o- tz) was compared between treatment groups Rituxan and MabThera.

    Primary: PK (Part I only): AUC0-inf pred (area under the plasma concentration versus time curve from time zero to infinity, determined over both dosages)

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    End point title
    PK (Part I only): AUC0-inf pred (area under the plasma concentration versus time curve from time zero to infinity, determined over both dosages)
    End point description
    PK (Part I only): AUC0-inf pred (area under the plasma concentration versus time curve from time zero to infinity, determined over both dosages, and extrapolated to infinity using predicted last observed quantifiable concentration). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included. PKS
    End point type
    Primary
    End point timeframe
    Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    56 [11]
    56 [12]
    54 [13]
    Units: h*ug/mL
        geometric mean (geometric coefficient of variation)
    174000 ± 42.2
    169000 ± 42.0
    202000 ± 35.3
    Notes
    [11] - PKS
    [12] - PKS
    [13] - PKS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf pred)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v Rituxan®
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other [14]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    102.46
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    90.26
         upper limit
    116.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.939
    Notes
    [14] - The similarity of AUC(o-inf pred) was compared between treatment groups BI 695500 and Rituxan.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf pred)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v MabThera®
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other [15]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    86
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    76.38
         upper limit
    96.82
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.404
    Notes
    [15] - The similarity of AUC(o-inf pred) was compared between treatment groups BI 695500 and MabThera.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf pred)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error.
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    other [16]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    83.93
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    74.57
         upper limit
    94.47
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.386
    Notes
    [16] - The similarity of AUC(o-inf pred) was compared between treatment groups Rituxan and MabThera.

    Primary: PK (Part I only): AUC0-336 (area under the plasma concentration versus time curve from time zero to 336 hours)

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    End point title
    PK (Part I only): AUC0-336 (area under the plasma concentration versus time curve from time zero to 336 hours)
    End point description
    PK (Part I only): AUC0-336 (area under the plasma concentration versus time curve from time zero to 336 hours after the first dose). Time zero was the time the first dose started. Only subjects randomized in part I of this study are included. AUC0-336 was calculated as a partial area i.e., as the AUC from time zero to time point 336 hours, following the algorithm defined for AUCs (linear up-log down trapezoidal rule). If the end time did not coincide exactly with 336 hours, then a linear or logarithmic interpolation was done to estimate the concentration at 336 hours, according to the AUC calculation method. PKS
    End point type
    Primary
    End point timeframe
    Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    56 [17]
    56 [18]
    55 [19]
    Units: h*ug/mL
        geometric mean (geometric coefficient of variation)
    49800 ± 40.1
    51900 ± 28.9
    55600 ± 30.7
    Notes
    [17] - PKS
    [18] - PKS
    [19] - PKS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-336)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v Rituxan®
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other [20]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    95.87
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    86.21
         upper limit
    106.62
    Variability estimate
    Standard error of the mean
    Dispersion value
    106.608
    Notes
    [20] - The similarity of AUC(0-336) was compared between treatment groups BI 695500 and Rituxan.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-336)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [21]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    89.46
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    80.23
         upper limit
    99.74
    Variability estimate
    Standard error of the mean
    Dispersion value
    106.775
    Notes
    [21] - The similarity of AUC(0-336) was compared between treatment groups BI 695500 and MabThera.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-336)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error.
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [22]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    93.31
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    85.11
         upper limit
    102.29
    Variability estimate
    Standard error of the mean
    Dispersion value
    105.7
    Notes
    [22] - The similarity of AUC(0-336) was compared between treatment groups Rituxan and MabThera.

    Primary: PK (Part I only): observed Cmax (maximum plasma concentration, determined after the second dose)

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    End point title
    PK (Part I only): observed Cmax (maximum plasma concentration, determined after the second dose)
    End point description
    PK (Part I only): observed Cmax (observed maximum plasma concentration, determined after the second dose). Only subjects randomized in part I of this study are included. PKS.
    End point type
    Primary
    End point timeframe
    Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    56 [23]
    56 [24]
    55 [25]
    Units: microgram per milliliter (ug/mL)
        geometric mean (geometric coefficient of variation)
    434 ± 31.1
    462 ± 32.0
    486 ± 28.1
    Notes
    [23] - PKS
    [24] - PKS
    [25] - PKS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(Cmax)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v Rituxan®
    Number of subjects included in analysis
    112
    Analysis specification
    Pre-specified
    Analysis type
    other [26]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    93.97
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    85.32
         upper limit
    103.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    105.995
    Notes
    [26] - The similarity of observed Cmax was compared between treatment groups BI 695500 and Rituxan.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(Cmax)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [27]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    89.3
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    81.51
         upper limit
    97.83
    Variability estimate
    Standard error of the mean
    Dispersion value
    105.657
    Notes
    [27] - The similarity of observed Cmax was compared between treatment groups BI 695500 and MabThera.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(Cmax)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error.
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    other [28]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    95.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    86.62
         upper limit
    104.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    105.744
    Notes
    [28] - The similarity of observed Cmax was compared between treatment groups Rituxan and MabThera.

    Secondary: Percentage of patients meeting the ACR20 (American College of Rheumatology 20% response criteria) at week 24

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    End point title
    Percentage of patients meeting the ACR20 (American College of Rheumatology 20% response criteria) at week 24
    End point description
    A subject has an ACR20 response if all of the following occur: - a > 20% improvement in the swollen joint count (66 joints) - a > 20% improvement in the tender joint count (68 joints) - a > 20% improvement in at least 3 of the following assessments: patient's assessment of pain, patient's global assessment of disease activity, physician's global assessment of disease activity, patient's assessment of physical function, as measured by the Health Assessment Questionnaire - Disability Index, or Acute phase reactant (C-reactive protein). The percentage of subjects meeting the ACR20 response criteria at Week 24 is presented for subjects randomised to receive BI 695500, Rituxan and MabThera. FAS. Missing data have been imputed according to LOCF (last observation carried forward) and/or NRI (Non Responder Imputation).
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    94 [29]
    90 [30]
    64 [31]
    Units: Percentage of participants
        number (not applicable)
    26.6
    23.3
    56.3
    Notes
    [29] - FAS
    [30] - FAS
    [31] - FAS
    No statistical analyses for this end point

    Secondary: PK (Part I only): AUC0-inf, ppk (area under the plasma concentration versus time curve from time zero to infinity, based on individual predicted concentrations for missing data derived from a population PK model, determined over both dosages)

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    End point title
    PK (Part I only): AUC0-inf, ppk (area under the plasma concentration versus time curve from time zero to infinity, based on individual predicted concentrations for missing data derived from a population PK model, determined over both dosages)
    End point description
    Time zero was the time the first dose started. Only subjects randomized in part I are included. Modeling approach was used to impute missing values as well as impute missing concentrations after the first dose with a sampling schedule identical to the first 2 weeks after the second dose. A unit dose 1000 mg was used in calculating the imputed values. The resulting dataset thus consisted of PK evaluable and PK non-evaluable patients with both measured as well as imputed concentration values. The prediction of these concentrations was based on a mixed effect modeling approach and included significant covariates identified during the PK model development (including age, body surface area, body mass index, weight, gender, race, and formulation). Pharmacokinetic full analysis set (PKFS) included all randomized subjects with at least one valid PK concentration measurement. A valid PK concentration measurement is a value greater than lower limit of quantification provided by Charles River
    End point type
    Secondary
    End point timeframe
    Blood PK samples were collected at -00:05 (hours: min) prior to first infusion and 03:55, 24:00, 335:55, 338:00, 339:55, 342:00, 344:00, 360:00, 432:00, 504:00, 672:00, 1176:00, 1512:00, 2352:00 and 2688:00 after first infusion.
    End point values
    BI 695500 Rituxan® MabThera®
    Number of subjects analysed
    66 [32]
    65 [33]
    65 [34]
    Units: h*ug/mL
        geometric mean (geometric coefficient of variation)
    165000 ± 42.9
    158000 ± 50.0
    180000 ± 40.6
    Notes
    [32] - PKFS
    [33] - PKFS
    [34] - PKFS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf, ppk)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus Rituxan®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v Rituxan®
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other [35]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    104.49
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    91.92
         upper limit
    118.78
    Variability estimate
    Standard error of the mean
    Dispersion value
    108.044
    Notes
    [35] - The similarity of AUC(0-inf, ppk) was compared between treatment groups BI 695500 and Rituxan.
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf, ppk)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: BI 695500 versus MabThera®; standard error is geometric standard error.
    Comparison groups
    BI 695500 v MabThera®
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    other [36]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    91.39
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    81.38
         upper limit
    102.64
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.253
    Notes
    [36] - The similarity of AUC(0-inf, ppk) was compared between treatment groups BI 695500 and MabThera.
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Analysis of variance (ANOVA) model on logarithmic scale: Ln(AUC0-inf, ppk)=overall mean+treatment effect+random error. Adjusted ratio of gMeans: Rituxan® versus MabThera®; standard error is geometric standard error.
    Comparison groups
    Rituxan® v MabThera®
    Number of subjects included in analysis
    130
    Analysis specification
    Pre-specified
    Analysis type
    other [37]
    Method
    ANOVA
    Parameter type
    Adjusted ratio of gMeans (%)
    Point estimate
    87.47
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    77.12
         upper limit
    99.21
    Variability estimate
    Standard error of the mean
    Dispersion value
    107.896
    Notes
    [37] - The similarity of AUC(0-inf, ppk) was compared between treatment groups Rituxan and MabThera.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study medication and prior to the last date of study medication plus 6 months (180 days); up to 48 weeks
    Adverse event reporting additional description
    The safety randomized analysis set (SAFR) contained all randomized subjects who received at least one dose of trial medication and subjects were classified according to treatment received.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    BI 695500
    Reporting group description
    Patients administered 1000 milligram per 100 milliliter (1000 mg per 100 mL) of BI 695500 concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Reporting group title
    Rituxan®
    Reporting group description
    Patients administered 1000 mg per 100 mL of Rituxan® injection for intravenous (IV) use each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Reporting group title
    MabThera®
    Reporting group description
    Patients administered 1000 mg per 100 mL of MabThera® concentrate for solution for intravenous (IV) infusion each at Day 1 and 15. Patients with response to treatment were administered additional infusions at Week 24 and 26.

    Serious adverse events
    BI 695500 Rituxan® MabThera®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 116 (7.76%)
    9 / 110 (8.18%)
    5 / 65 (7.69%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 116 (0.00%)
    2 / 110 (1.82%)
    0 / 65 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Femoral neck fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Hip fracture
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Joint injury
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Multiple fractures
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Road traffic accident
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 116 (0.86%)
    2 / 110 (1.82%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaphylactoid reaction
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Intervertebral disc degeneration
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    0 / 65 (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
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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 pain
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         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 neck
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Diverticulitis
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Gastroenteritis viral
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 116 (0.00%)
    0 / 110 (0.00%)
    1 / 65 (1.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 110 (0.91%)
    0 / 65 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 116 (0.86%)
    0 / 110 (0.00%)
    0 / 65 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    BI 695500 Rituxan® MabThera®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 116 (14.66%)
    14 / 110 (12.73%)
    24 / 65 (36.92%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 110 (0.91%)
    4 / 65 (6.15%)
         occurrences all number
    1
    1
    4
    Headache
         subjects affected / exposed
    5 / 116 (4.31%)
    7 / 110 (6.36%)
    4 / 65 (6.15%)
         occurrences all number
    5
    7
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 116 (0.00%)
    1 / 110 (0.91%)
    5 / 65 (7.69%)
         occurrences all number
    0
    1
    5
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 116 (2.59%)
    3 / 110 (2.73%)
    4 / 65 (6.15%)
         occurrences all number
    4
    3
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 116 (0.86%)
    1 / 110 (0.91%)
    4 / 65 (6.15%)
         occurrences all number
    1
    1
    4
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    8 / 116 (6.90%)
    2 / 110 (1.82%)
    6 / 65 (9.23%)
         occurrences all number
    8
    2
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Apr 2012
    Logistical & administrative changes including clarifying schedule of assessments for open-label run-in, adding cut-off for platelet count to exclusion criteria, clarifying endpoints, adding AUC(0-336).
    22 May 2012
    Logistical & administrative changes including change to product descriptions for MabThera and Rituxan, allowing unblinded treatment, removing reference to human anti-chimeric antibodies sampling
    20 Dec 2012
    Logistical & administrative changes including addition of ESR measurements, updating primary PK endpoint in synopsis, change minimum improvement in DAS28-CRP, addition of blood sampling to Week 32.
    04 Feb 2013
    Administrative changes to reflect removal of text relating to unblinding subjects discontinuing trial and additional blood sampling at Week 32 in Part I.
    05 Apr 2013
    Logistical & administrative changes including additional blood sampling for first 8 subjects of each dose group for stability testing, moving text for listedness evaluation.
    02 Jul 2014
    Logistical & administrative changes including change of Trial Clinical Monitor, interim analysis to include PK similarity primary analysis, all subjects to enter safety follow up, expand PK endpoints.
    09 Sep 2014
    Logistical & administrative changes including all PK data to be reviewed by independent data monitoring committee, clarifications regarding re-randomisation, clarify serious AE reporting for cancers.
    23 Dec 2014
    Logistical & administrative changes including change in Part II comparison product, revise subject numbers based on change in margin, change ACR20 response rate at Week 24 to secondary endpoint.

    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.
    The study program was terminated and this study was discontinued on 3 September 2015. As a result no patients receiving study treatment in Part II of the study reached Week 24, and no conclusions regarding the efficacy of BI 695500 can be made.
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