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    Clinical Trial Results:
    A COMPARATIVE, RANDOMIZED, PARALLEL-GROUP, MULTI-CENTER, PHASE IIIB STUDY TO INVESTIGATE THE EFFICACY OF SUBCUTANEOUS (SC) RITUXIMAB VERSUS INTRAVENOUS (IV) RITUXIMAB BOTH IN COMBINATION WITH CHOP (R-CHOP) IN PREVIOUSLY UNTREATED PATIENTS WITH CD20-POSITIVE DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL)

    Summary
    EudraCT number
    		 2012-000669-19
    Trial protocol
    		 ES   FI   NL   GR   GB   IT   IE   FR   BE   BG   PT  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    09 Apr 2016
    First version publication date
    09 Apr 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    MO28107
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01649856
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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
    Interim
    Date of interim/final analysis
    28 Aug 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Oct 2014
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This multicenter, randomized, open-label parallel-group study evaluated the efficacy and safety of subcutaneous (SC) versus intravenous (IV) rituximab, both in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), in participants with previously untreated cluster of differentiation (CD) 20-positive diffuse large B-cell lymphoma (DLBCL). Participants were randomized 2:1 to receive either SC or IV rituximab on Day 1 of each cycle for 8 cycles, in combination with 6 to 8 cycles of CHOP chemotherapy. Cycle length (14 or 21 days) was decided by the individual study center.
    Protection of trial subjects
    The study was conducted in full conformance with the International Conference on Harmonisation (ICH)-E6 Guideline for Good Clinical Practice (GCP) and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded greater protection to the participant. The study has complied with requirements of the ICH-E2A Guideline for Clinical Safety Data Management, and for study sites in the European Union (EU)/European Economic Area (EEA), the study has also complied with the EU Clinical Trial Directive (2001/20/EC).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Aug 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 3
    Country: Number of subjects enrolled
    Belgium: 17
    Country: Number of subjects enrolled
    Brazil: 7
    Country: Number of subjects enrolled
    Bulgaria: 10
    Country: Number of subjects enrolled
    Canada: 30
    Country: Number of subjects enrolled
    Colombia: 13
    Country: Number of subjects enrolled
    Finland: 21
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Greece: 30
    Country: Number of subjects enrolled
    Ireland: 11
    Country: Number of subjects enrolled
    Israel: 30
    Country: Number of subjects enrolled
    Italy: 74
    Country: Number of subjects enrolled
    Netherlands: 43
    Country: Number of subjects enrolled
    Peru: 6
    Country: Number of subjects enrolled
    Poland: 13
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    Serbia: 7
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    Thailand: 21
    Country: Number of subjects enrolled
    Turkey: 74
    Country: Number of subjects enrolled
    Ukraine: 20
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    Venezuela, Bolivarian Republic of: 2
    Worldwide total number of subjects
    572
    EEA total number of subjects
    319
    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)
    306
    From 65 to 84 years
    266
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 662 individuals were screened for entry into the study, and 86 failed the screening procedure. Overall, 576 participants were randomized; 572 received treatment and were included in the analyses.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rituximab SC
    Arm description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For Cycle 1, rituximab was administered at a dose of 375 milligrams per meter-squared (mg/m^2) via IV infusion; subsequent doses were given as 1400 milligrams (mg) via SC injection. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved complete response (CR) or complete response unconfirmed (CRu) after 4 cycles, but all participants received a full 8 cycles of rituximab.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Concentrate and solvent for solution for infusion
    Routes of administration
    Subcutaneous use, Intravenous use
    Dosage and administration details
    Rituximab was administered as 1400 mg via SC injection or as 375 mg/m^2 via IV infusion, depending upon treatment assignment, on Day 1 of each cycle. During the first cycle, all participants received the IV formulation regardless of treatment assignment.

    Arm title
    		 Rituximab IV
    Arm description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For all cycles, rituximab was administered at a dose of 375 mg/m^2 via IV infusion. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved CR or CRu after 4 cycles, but all participants received a full 8 cycles of rituximab.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion, Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Rituximab was administered as 1400 mg via SC injection or as 375 mg/m^2 via IV infusion, depending upon treatment assignment, on Day 1 of each cycle. During the first cycle, all participants received the IV formulation regardless of treatment assignment.

    Number of subjects in period 1
    		Rituximab SC Rituximab IV
    Started
    369
    203
    Completed
    0
    0
    Not completed
    369
    203
         Consent withdrawn by subject
    6
    9
         Treatment failure
    4
    1
         Death
    37
    26
         Not specified
    1
    -
         Lack of compliance
    -
    1
         Stable or progressed disease
    5
    3
         Lost to follow-up
    9
    7
         Ongoing in follow-up
    303
    152
         Protocol deviation
    4
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rituximab SC
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For Cycle 1, rituximab was administered at a dose of 375 milligrams per meter-squared (mg/m^2) via IV infusion; subsequent doses were given as 1400 milligrams (mg) via SC injection. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved complete response (CR) or complete response unconfirmed (CRu) after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Reporting group title
    Rituximab IV
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For all cycles, rituximab was administered at a dose of 375 mg/m^2 via IV infusion. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved CR or CRu after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Reporting group values
    		 Rituximab SC Rituximab IV Total
    Number of subjects
    		 369 203 572
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.4 ( 13.78 ) 61 ( 12.63 ) -
    Gender categorical
    Units: Subjects
        Female
    		 165 100 265
        Male
    		 204 103 307

    End points

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    End points reporting groups
    Reporting group title
    Rituximab SC
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For Cycle 1, rituximab was administered at a dose of 375 milligrams per meter-squared (mg/m^2) via IV infusion; subsequent doses were given as 1400 milligrams (mg) via SC injection. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved complete response (CR) or complete response unconfirmed (CRu) after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Reporting group title
    Rituximab IV
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For all cycles, rituximab was administered at a dose of 375 mg/m^2 via IV infusion. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved CR or CRu after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Primary: Percentage of Participants With CR or CRu at the Time of Primary Analysis

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    End point title
    		 Percentage of Participants With CR or CRu at the Time of Primary Analysis
    End point description
    Tumor response was assessed per criteria published by Cheson et al (1999). According to consensus recommendations, CR was defined as complete disappearance of all clinical and radiographic evidence of disease and disease-related symptoms, regression of lymph nodes to normal size, absence of splenomegaly, and absence of bone marrow involvement. CRu was defined as disappearance of clinical and radiographic evidence of disease and absence of splenomegaly, with regression of lymph nodes by greater than (>) 75 percent (%) but still >1.5 centimeters (cm) in size, and indeterminate bone marrow assessment. The percentage of participants with either response at the end of induction (EOI) was determined with corresponding 95% Pearson-Clopper confidence interval (CI). Intent-to-Treat (ITT) Population: All participants who completed Baseline and at least one on-treatment efficacy assessment.
    End point type
    Primary
    End point timeframe
    Up to approximately 7 months (assessed at Baseline, Cycle 4, and 30 days after the start of the last rituximab cycle [maximum 8 cycles; each cycle was 14 or 21 days])
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: percentage of participants
        number (confidence interval 95%)
    52 (46.8 to 57.3)
    50.8 (43.5 to 58.2)
    Statistical analysis title
    		 Difference in response rates
    Comparison groups
    Rituximab SC v Rituximab IV
    Number of subjects included in analysis
    519
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.796
    Method
    		 Chi-squared
    Parameter type
    		 Difference in response rates
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9
         upper limit
    		 10.3

    Secondary: Cancer Treatment Satisfaction Questionnaire (CTSQ) Domain Scores

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    End point title
    		 Cancer Treatment Satisfaction Questionnaire (CTSQ) Domain Scores
    End point description
    The CTSQ is a validated 16-item questionnaire that measures three domains related to satisfaction with cancer therapy. These include expectations of therapy, feelings about side effects, and satisfaction with therapy. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all participants. ITT Population (CTSQ Subpopulation): All participants who completed the CTSQ at Cycles 3 and 7.
    End point type
    Secondary
    End point timeframe
    At Cycle 7 (each cycle was 14 or 21 days)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    280 [1]
    141 [2]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Expectations of Therapy (n=280,141)
    79.35 ( 17.422 )
    82.94 ( 16.536 )
        Feelings about Side Effects (n=276,141)
    60.69 ( 21.594 )
    57.62 ( 23.339 )
        Satisfaction with Therapy (n=278,141)
    85.92 ( 11.428 )
    83.6 ( 13.451 )
    Notes
    [1] - number (n) = number of participants in the analysis for the specified domain.
    [2] - n = number of participants in the analysis for the specified domain.
    No statistical analyses for this end point

    Secondary: Rituximab Administration Satisfaction Questionnaire (RASQ) Domain Scores

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    End point title
    		 Rituximab Administration Satisfaction Questionnaire (RASQ) Domain Scores
    End point description
    The RASQ is a 20-item questionnaire that measures five domains related to the impact of treatment administration. These include physical impact, psychological impact, impact on activities of daily living (ADLs), convenience, and satisfaction. Each domain is scored on a scale of 0 to 100, with higher scores indicative of more positive feelings toward therapy. The score for each domain was averaged among all participants. ITT Population (RASQ Subpopulation): All participants who completed the RASQ at Cycles 3 and 7.
    End point type
    Secondary
    End point timeframe
    At Cycle 7 (each cycle was 14 or 21 days)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    284 [3]
    144 [4]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Physical Impact (n=278,140)
    86.24 ( 14.012 )
    81.49 ( 16.848 )
        Psychological Impact (n=277,141)
    85.65 ( 13.92 )
    78.65 ( 18.233 )
        Impact on ADLs (n=266,140)
    83.77 ( 16.117 )
    57.38 ( 19.23 )
        Convenience (n=279,143)
    82.32 ( 13.428 )
    60.14 ( 17.473 )
        Satisfaction (n=282,141)
    89.58 ( 12.051 )
    77.39 ( 18.232 )
    Notes
    [3] - n = number of participants in the analysis for the specified domain.
    [4] - n = number of participants in the analysis for the specified domain.
    No statistical analyses for this end point

    Secondary: Median Duration of Rituximab Administration for Each Treatment Cycle

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    End point title
    		 Median Duration of Rituximab Administration for Each Treatment Cycle
    End point description
    Duration of rituximab administration was defined as the time from start to end of the SC injection or IV infusion. The median duration was reported. Safety Population: All participants who received at least one dose of study drug according to treatment received.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    369 [5]
    203 [6]
    Units: hours
    median (full range (min-max))
        Cycle 1 (n=346,190)
    4 (0.1 to 11)
    4 (1.2 to 10)
        Cycle 2 (n=361,178)
    0.1 (0.1 to 23.1)
    3 (0.5 to 10)
        Cycle 3 (n=349,177)
    0.1 (0.1 to 5.5)
    2.8 (1 to 21.4)
        Cycle 4 (n=346,173)
    0.1 (0 to 2.5)
    2.7 (0.5 to 8)
        Cycle 5 (n=332,165)
    0.1 (0 to 2.5)
    2.6 (0.1 to 8.1)
        Cycle 6 (n=319,162)
    0.1 (0 to 2.5)
    2.7 (0.1 to 20)
        Cycle 7 (n=304,156)
    0.1 (0 to 23.6)
    2.7 (0.5 to 6.7)
        Cycle 8 (n=305,152)
    0.1 (0 to 2.5)
    2.55 (0.1 to 17.9)
        Overall (n=368,201)
    4.7 (0.1 to 28.7)
    19 (1.2 to 57.4)
    Notes
    [5] - n = number of participants in the analysis for the specified timepoint.
    [6] - n = number of participants in the analysis for the specified timepoint.
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Time Spent in the Infusion Chair/Bed for Each Treatment Cycle

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    End point title
    		 Percentage of Participants by Time Spent in the Infusion Chair/Bed for Each Treatment Cycle
    End point description
    Chair time was defined as the amount of time the participant occupied an infusion chair/bed for a single treatment cycle of rituximab + CHOP chemotherapy. Where the chair time was not documented for a given cycle, it was reported as "Missing". Safety Population.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    369
    203
    Units: percentage of participants
    number (not applicable)
        Less than 30 minutes (Cycle 1)
    0
    0
        30 minutes to 1 hour (Cycle 1)
    0
    0.5
        1 to 2 hours (Cycle 1)
    1.4
    0
        2 to 4 hours (Cycle 1)
    20.3
    17.2
        4 to 12 hours (Cycle 1)
    69.4
    72.4
        More than 12 hours (Cycle 1)
    7.6
    7.9
        Missing (Cycle 1)
    1.4
    2
        Less than 30 minutes (Cycle 2)
    7.3
    0
        30 minutes to 1 hour (Cycle 2)
    2.4
    0
        1 to 2 hours (Cycle 2)
    17.1
    1.1
        2 to 4 hours (Cycle 2)
    56.1
    36.2
        4 to 12 hours (Cycle 2)
    12.2
    60.1
        More than 12 hours (Cycle 2)
    0.3
    1.1
        Missing (Cycle 2)
    4.6
    1.6
        Less than 30 minutes (Cycle 3)
    5.6
    0
        30 minutes to 1 hour (Cycle 3)
    2
    0
        1 to 2 hours (Cycle 3)
    22.1
    0.5
        2 to 4 hours (Cycle 3)
    55.9
    38.9
        4 to 12 hours (Cycle 3)
    12.6
    58.4
        More than 12 hours (Cycle 3)
    0.3
    0.5
        Missing (Cycle 3)
    1.7
    1.6
        Less than 30 minutes (Cycle 4)
    5.1
    0
        30 minutes to 1 hour (Cycle 4)
    2.8
    0
        1 to 2 hours (Cycle 4)
    21.8
    1.1
        2 to 4 hours (Cycle 4)
    55
    36.7
        4 to 12 hours (Cycle 4)
    13.9
    60.6
        More than 12 hours (Cycle 4)
    0.3
    0.6
        Missing (Cycle 4)
    1.1
    1.1
        Less than 30 minutes (Cycle 5)
    5.3
    0.6
        30 minutes to 1 hour (Cycle 5)
    2.4
    0
        1 to 2 hours (Cycle 5)
    24.9
    1.1
        2 to 4 hours (Cycle 5)
    53.4
    40.2
        4 to 12 hours (Cycle 5)
    12.8
    56.3
        More than 12 hours (Cycle 5)
    0
    0.6
        Missing (Cycle 5)
    1.2
    1.1
        Less than 30 minutes (Cycle 6)
    3.7
    0.6
        30 minutes to 1 hour (Cycle 6)
    3.1
    0
        1 to 2 hours (Cycle 6)
    22.7
    1.8
        2 to 4 hours (Cycle 6)
    56.7
    42.5
        4 to 12 hours (Cycle 6)
    12.3
    53.3
        More than 12 hours (Cycle 6)
    0
    0
        Missing (Cycle 6)
    1.5
    1.8
        Less than 30 minutes (Cycle 7)
    18.7
    0
        30 minutes to 1 hour (Cycle 7)
    7
    0
        1 to 2 hours (Cycle 7)
    26.9
    4.9
        2 to 4 hours (Cycle 7)
    40.2
    48.8
        4 to 12 hours (Cycle 7)
    6
    44.4
        More than 12 hours (Cycle 7)
    0
    0
        Missing (Cycle 7)
    1.3
    1.9
        Less than 30 minutes (Cycle 8)
    19.9
    0.6
        30 minutes to 1 hour (Cycle 8)
    6.4
    0
        1 to 2 hours (Cycle 8)
    29.6
    4.4
        2 to 4 hours (Cycle 8)
    36.7
    50.9
        4 to 12 hours (Cycle 8)
    5.8
    43.4
        More than 12 hours (Cycle 8)
    0
    0
        Missing (Cycle 8)
    1.6
    0.6
    No statistical analyses for this end point

    Secondary: Percentage of Participants by Time Spent in the Hospital for Each Treatment Cycle

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    End point title
    		 Percentage of Participants by Time Spent in the Hospital for Each Treatment Cycle
    End point description
    Hospital time was defined as the amount of time the participant was in the hospital for the course of one cycle of rituximab + CHOP chemotherapy. Where the hospital time was not documented for a given cycle, it was reported as "Missing". Safety Population.
    End point type
    Secondary
    End point timeframe
    Cycles 1, 2, 3, 4, 5, 6, 7, and 8 (each cycle was 14 or 21 days)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    369
    203
    Units: percentage of participants
    number (not applicable)
        Less than 2 hours (Cycle 1)
    0.3
    0.5
        2 to 4 hours (Cycle 1)
    3.5
    1.5
        4 to 6 hours (Cycle 1)
    19.2
    20.7
        6 to 12 hours (Cycle 1)
    38.8
    43.8
        12 to 24 hours (Cycle 1)
    8.9
    6.4
        More than 24 hours (Cycle 1)
    27.1
    24.1
        Missing (Cycle 1)
    2.2
    3
        Less than 2 hours (Cycle 2)
    3.8
    0
        2 to 4 hours (Cycle 2)
    33.1
    10.1
        4 to 6 Hours (Cycle 2)
    27.9
    33.5
        6 to 12 Hours (Cycle 2)
    16.3
    38.8
        12 to 24 Hours (Cycle 2)
    3.8
    1.1
        More than 24 Hours (Cycle 2)
    10.3
    11.7
        Missing (Cycle 2)
    4.9
    4.8
        Less Than 2 Hours (Cycle 3)
    3.6
    0.5
        2 to 4 Hours (Cycle 3)
    37.2
    11.9
        4 to 6 Hours (Cycle 3)
    30.2
    30.8
        6 to 12 Hours (Cycle 3)
    14.5
    41.6
        12 to 24 Hours (Cycle 3)
    2.8
    2.2
        More than 24 Hours (Cycle 3)
    9.8
    10.3
        Missing (Cycle 3)
    2
    2.7
        Less Than 2 Hours (Cycle 4)
    4.5
    0
        2 to 4 Hours (Cycle 4)
    36.3
    10
        4 to 6 Hours (Cycle 4)
    27.5
    31.1
        6 to 12 Hours (Cycle 4)
    17.6
    42.2
        12 to 24 Hours (Cycle 4)
    2
    2.8
        More than 24 Hours (Cycle 4)
    10.2
    10.6
        Missing (Cycle 4)
    2
    3.3
        Less Than 2 Hours (Cycle 5)
    5
    0.6
        2 to 4 Hours (Cycle 5)
    39.5
    11.5
        4 to 6 Hours (Cycle 5)
    26.7
    34.5
        6 to 12 Hours (Cycle 5)
    15.7
    37.4
        12 to 24 Hours (Cycle 5)
    2.1
    1.7
        More than 24 Hours (Cycle 5)
    8.9
    10.9
        Missing (Cycle 5)
    2.1
    3.4
        Less Than 2 Hours (Cycle 6)
    4.3
    0.6
        2 to 4 Hours (Cycle 6)
    39.9
    12.6
        4 to 6 Hours (Cycle 6)
    26.7
    34.1
        6 to 12 Hours (Cycle 6)
    15.6
    38.3
        12 to 24 Hours (Cycle 6)
    2.5
    2.4
        More than 24 Hours (Cycle 6)
    8.6
    9
        Missing (Cycle 6)
    2.5
    3
        Less Than 2 Hours (Cycle 7)
    17.7
    0
        2 to 4 Hours (Cycle 7)
    40.8
    23.5
        4 to 6 Hours (Cycle 7)
    19.9
    36.4
        6 to 12 Hours (Cycle 7)
    10.4
    30.9
        12 to 24 Hours (Cycle 7)
    2.8
    2.5
        More than 24 Hours (Cycle 7)
    5.7
    3.7
        Missing (Cycle 7)
    2.5
    3.1
        Less Than 2 Hours (Cycle 8)
    18
    0
        2 to 4 Hours (Cycle 8)
    40.5
    25.8
        4 to 6 Hours (Cycle 8)
    21.9
    34
        6 to 12 Hours (Cycle 8)
    8.7
    30.8
        12 to 24 Hours (Cycle 8)
    2.6
    1.3
        More than 24 Hours (Cycle 8)
    5.8
    5
        Missing (Cycle 8)
    2.6
    3.1
    No statistical analyses for this end point

    Secondary: Number of Participants with an Event-Free Survival (EFS) Event at the Time of Primary Analysis

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    End point title
    		 Number of Participants with an Event-Free Survival (EFS) Event at the Time of Primary Analysis
    End point description
    EFS events included disease progression, relapse, initiation of other anti-lymphoma therapy, or death. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as greater than or equal to (≥) 50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days]; every 3 months thereafter; and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: participants
    80
    40
    No statistical analyses for this end point

    Secondary: Duration of EFS at the Time of Primary Analysis

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    End point title
    		 Duration of EFS at the Time of Primary Analysis
    End point description
    EFS was defined as the time from randomization to first occurrence of disease progression, relapse, initiation of other anti-lymphoma therapy, or death, whichever occurred first. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as a ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The duration of EFS was to be determined at the time of clinical cut-off (October 2014) using Kaplan-Meier analysis. ITT Population. 99999 = estimate not available due to insufficient follow-up.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days]; every 3 months thereafter; and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Relapse or Death at the Time of Primary Analysis

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    End point title
    		 Number of Participants with Relapse or Death at the Time of Primary Analysis
    End point description
    Tumor response was assessed according to criteria published by Cheson et al (1999). Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The number of participants who had experienced relapse or death prior to the clinical cut-off date (October 2014) was determined. ITT Population (Responder Subpopulation): All participants who achieved CR or CRu after 4 cycles.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days], every 3 months thereafter, and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    178
    90
    Units: participants
    12
    5
    No statistical analyses for this end point

    Secondary: Duration of Disease-Free Survival (DFS) at the Time of Primary Analysis

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    End point title
    		 Duration of Disease-Free Survival (DFS) at the Time of Primary Analysis
    End point description
    DFS was defined as the time from date of initial CR/CRu to the date of relapse or death from any cause. Tumor response was assessed according to criteria published by Cheson et al (1999). Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The duration of DFS was to be determined at the time of clinical cut-off (October 2014) using Kaplan-Meier analysis. ITT Population (Responder Subpopulation). 99999 = estimate not available due to insufficient follow-up.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days], every 3 months thereafter, and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    178
    90
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Participants with Progression, Relapse, or Death at the Time of Primary Analysis

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    End point title
    		 Number of Participants with Progression, Relapse, or Death at the Time of Primary Analysis
    End point description
    Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The number of participants who had experienced progression, relapse, or death prior to the clinical cut-off date (October 2014) was determined. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days], every 3 months thereafter, and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: participants
    54
    28
    No statistical analyses for this end point

    Secondary: Duration of Progression-Free Survival (PFS) at the Time of Primary Analysis

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    End point title
    		 Duration of Progression-Free Survival (PFS) at the Time of Primary Analysis
    End point description
    PFS was defined as the time from randomization to first occurrence of disease progression, relapse, or death from any cause. Tumor response was assessed according to criteria published by Cheson et al (1999). Progression was defined as ≥50% increase in the sum of products of greatest diameters of any previously identified abnormal lymph node or the appearance of any new lesion. Relapse was defined as a new lesion or increase by ≥50% in size of previously involved sites, or ≥50% increase in greatest diameter of any previously identified node >1 cm, following an earlier assessment of CR or CRu. The duration of PFS was to be determined using Kaplan-Meier analysis. ITT Population. 99999 = estimate not available due to insufficient follow-up.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (assessed at Baseline, Day 1 of each cycle [maximum 8 cycles; each cycle was 14 to 21 days], every 3 months thereafter, and/or 4 weeks after early termination)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Deaths at the Time of Primary Analysis

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    End point title
    		 Number of Deaths at the Time of Primary Analysis
    End point description
    The number of participants who had experienced death prior to the clinical cut-off date (October 2014) was determined. ITT Population.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (survival followed from randomization until death)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: participants
    25
    15
    No statistical analyses for this end point

    Secondary: Duration of Overall Survival (OS) at the Time of Primary Analysis

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    End point title
    		 Duration of Overall Survival (OS) at the Time of Primary Analysis
    End point description
    OS was defined as the time from randomization to death from any cause. The duration of OS was to be determined using Kaplan-Meier analysis. ITT Population. 99999 = estimate not available due to insufficient follow-up.
    End point type
    Secondary
    End point timeframe
    Up to approximately 2 years (survival followed from randomization until death)
    End point values
    		 Rituximab SC Rituximab IV
    Number of subjects analysed
    342
    177
    Units: weeks
        median (full range (min-max))
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 2 years (from Baseline up to 4 weeks after end of study)
    Adverse event reporting additional description
    Safety Population. The adverse event terms “lumbar spondylosis” and “lung separation with small pleural effusion” were entered into an uncoded System Organ Class (SOC) at the time of reporting. The best possible option for SOC was selected for the purposes of clinical trial disclosure.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Rituximab SC
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For Cycle 1, rituximab was administered at a dose of 375 mg/m^2 via IV infusion; subsequent doses were given as 1400 mg via SC injection. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved CR or CRu after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Reporting group title
    Rituximab IV
    Reporting group description
    		 Participants with previously untreated, CD20-positive DLBCL received up to 8 cycles of rituximab in combination with CHOP. Treatment was given on Day 1 of each cycle, and the cycle length (14 or 21 days) was decided by the study center. For all cycles, rituximab was administered at a dose of 375 mg/m^2 via IV infusion. Tumor response was assessed after 4 cycles according to criteria published by Cheson et al (1999), which are presented in Endpoint 1. The duration of CHOP therapy could be reduced from 8 to 6 cycles for those who achieved CR or CRu after 4 cycles, but all participants received a full 8 cycles of rituximab.

    Serious adverse events
    		 Rituximab SC Rituximab IV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    142 / 369 (38.48%)
    71 / 203 (34.98%)
         number of deaths (all causes)
    37
    26
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Central nervous system lymphoma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flushing
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    8 / 369 (2.17%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    2 / 369 (0.54%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injection site hypertrophy
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    4 / 369 (1.08%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 369 (0.27%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Dyspnoea
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cough
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypoxia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung separation with small pleural effusion
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    7 / 369 (1.90%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    10 / 10
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    4 / 369 (1.08%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    4 / 4
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Troponin T increased
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Multiple fractures
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         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
    2 / 369 (0.54%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 369 (0.27%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Atrial flutter
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 369 (0.00%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Tachycardia
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia induced cardiomyopathy
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    2 / 369 (0.54%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Convulsion
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    48 / 369 (13.01%)
    23 / 203 (11.33%)
         occurrences causally related to treatment / all
    58 / 61
    26 / 26
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Neutropenia
         subjects affected / exposed
    17 / 369 (4.61%)
    11 / 203 (5.42%)
         occurrences causally related to treatment / all
    19 / 19
    11 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 369 (0.54%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 369 (0.27%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 369 (0.81%)
    2 / 203 (0.99%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 369 (0.81%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 369 (0.81%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fissure
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric perforation
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic colitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstruction gastric
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spondylosis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    17 / 369 (4.61%)
    6 / 203 (2.96%)
         occurrences causally related to treatment / all
    10 / 18
    3 / 6
         deaths causally related to treatment / all
    2 / 3
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 369 (0.81%)
    3 / 203 (1.48%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 3
         deaths causally related to treatment / all
    2 / 2
    0 / 3
    Lung infection
         subjects affected / exposed
    2 / 369 (0.54%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 369 (0.81%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 369 (0.81%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 369 (0.81%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes oesophagitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes simplex hepatitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral herpes
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 369 (0.27%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 369 (0.54%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 369 (0.27%)
    0 / 203 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 369 (0.00%)
    1 / 203 (0.49%)
         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: 5%
    Non-serious adverse events
    		 Rituximab SC Rituximab IV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    305 / 369 (82.66%)
    165 / 203 (81.28%)
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    24 / 369 (6.50%)
    16 / 203 (7.88%)
         occurrences all number
    56
    33
    Weight decreased
         subjects affected / exposed
    28 / 369 (7.59%)
    8 / 203 (3.94%)
         occurrences all number
    32
    8
    White blood cell count decreased
         subjects affected / exposed
    15 / 369 (4.07%)
    13 / 203 (6.40%)
         occurrences all number
    30
    44
    Nervous system disorders
    Neuropathy peripheral
         subjects affected / exposed
    42 / 369 (11.38%)
    24 / 203 (11.82%)
         occurrences all number
    54
    33
    Paraesthesia
         subjects affected / exposed
    27 / 369 (7.32%)
    12 / 203 (5.91%)
         occurrences all number
    29
    15
    Headache
         subjects affected / exposed
    20 / 369 (5.42%)
    15 / 203 (7.39%)
         occurrences all number
    28
    23
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    122 / 369 (33.06%)
    62 / 203 (30.54%)
         occurrences all number
    234
    119
    Anaemia
         subjects affected / exposed
    77 / 369 (20.87%)
    37 / 203 (18.23%)
         occurrences all number
    122
    55
    Leukopenia
         subjects affected / exposed
    35 / 369 (9.49%)
    15 / 203 (7.39%)
         occurrences all number
    69
    28
    Lymphopenia
         subjects affected / exposed
    25 / 369 (6.78%)
    14 / 203 (6.90%)
         occurrences all number
    33
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    68 / 369 (18.43%)
    29 / 203 (14.29%)
         occurrences all number
    76
    39
    Pyrexia
         subjects affected / exposed
    40 / 369 (10.84%)
    24 / 203 (11.82%)
         occurrences all number
    51
    30
    Asthenia
         subjects affected / exposed
    40 / 369 (10.84%)
    23 / 203 (11.33%)
         occurrences all number
    60
    29
    Mucosal inflammation
         subjects affected / exposed
    28 / 369 (7.59%)
    16 / 203 (7.88%)
         occurrences all number
    38
    20
    Oedema peripheral
         subjects affected / exposed
    23 / 369 (6.23%)
    8 / 203 (3.94%)
         occurrences all number
    27
    8
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    78 / 369 (21.14%)
    48 / 203 (23.65%)
         occurrences all number
    116
    70
    Constipation
         subjects affected / exposed
    53 / 369 (14.36%)
    34 / 203 (16.75%)
         occurrences all number
    63
    43
    Diarrhoea
         subjects affected / exposed
    50 / 369 (13.55%)
    20 / 203 (9.85%)
         occurrences all number
    74
    29
    Vomiting
         subjects affected / exposed
    38 / 369 (10.30%)
    17 / 203 (8.37%)
         occurrences all number
    50
    22
    Stomatitis
         subjects affected / exposed
    23 / 369 (6.23%)
    11 / 203 (5.42%)
         occurrences all number
    32
    14
    Abdominal pain
         subjects affected / exposed
    22 / 369 (5.96%)
    11 / 203 (5.42%)
         occurrences all number
    24
    11
    Dyspepsia
         subjects affected / exposed
    18 / 369 (4.88%)
    14 / 203 (6.90%)
         occurrences all number
    21
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    39 / 369 (10.57%)
    18 / 203 (8.87%)
         occurrences all number
    46
    21
    Dyspnoea
         subjects affected / exposed
    21 / 369 (5.69%)
    7 / 203 (3.45%)
         occurrences all number
    23
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    87 / 369 (23.58%)
    48 / 203 (23.65%)
         occurrences all number
    97
    57
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 369 (6.23%)
    12 / 203 (5.91%)
         occurrences all number
    23
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    26 / 369 (7.05%)
    18 / 203 (8.87%)
         occurrences all number
    27
    25

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 May 2012
    The protocol was amended to clarify reporting requirements for certain events, and also to specify the procedure for submitting protocol amendments to the Institutional Review Board (IRB)/Ethics Committee (EC) and to regulatory authorities in accordance with local requirements.
    20 Mar 2013
    The protocol was amended to clarify and correct several sections including the defined patient population (with the added exclusion of pregnant women), study treatment schedules, timing of study assessments, and description of the statistical analysis plan.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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