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    Clinical Trial Results:
    A Randomized, Open Label Study of Ofatumumab and Bendamustine Combination Therapy Compared with Bendamustine Monotherapy in Indolent B-cell Non- Hodgkin’s Lymphoma Unresponsive to Rituximab or a Rituximab-Containing Regimen During or Within Six Months of Treatment Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2008-004177-17
    Trial protocol
    		 BE   FR   DE   PL   IT   GR   GB   AT   SK  
    Global end of trial date
    26 Dec 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jan 2020
    First version publication date
    12 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    COMB157E2301/OMB110918
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01077518
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.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
    26 Dec 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To establish the effectiveness of ofatumumab in combination with bendamustine (Ofa+Benda) in subjects with indolent B-cell Non-Hodgkin's Lymphoma disease refractory to rituximab-containing therapy
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 5
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    Belgium: 39
    Country: Number of subjects enrolled
    Canada: 54
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    United Kingdom: 7
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Italy: 31
    Country: Number of subjects enrolled
    Japan: 26
    Country: Number of subjects enrolled
    Poland: 29
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Slovakia: 3
    Country: Number of subjects enrolled
    Ukraine: 9
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    346
    EEA total number of subjects
    182
    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)
    195
    From 65 to 84 years
    149
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 346 (173 randomized to Ofa+benda arm and 173 randomized to benda arm)

    Pre-assignment
    Screening details
    		 346 (173 randomized to Ofa+benda arm and 173 randomized to benda arm)

    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
    		 Ofa + benda (Arm A)
    Arm description
    		 ofatumumab and bendamustine arm. Participants received up to 8 cycles of bendamustine (90 mg/m2) on Days 1,2 every 21 days with 12 doses of ofatumumab (1000 mg, Day 1 q21 days when with bendamustine and every 28 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ofatumumab
    Investigational medicinal product code
    OMB157
    Other name
    Ofa
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Ofatumumab was a liquid concentrate solution for infusion presented in glass vials containing 50 mL of solution at a concentration of 20 mg/mL to provide 1000 mg per vial. The ofatumumab infusions were prepared in 1000 mL sterile, pyrogen-free 0.9% NaCl to yield a 1 mg/mL ofatumumab concentration infusion.

    Investigational medicinal product name
    bendamustine
    Investigational medicinal product code
    Other name
    benda
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Bendamustine 100 mg/vial, injection 120 mg/m2 Days 1 and 2, every 21 days

    Arm title
    		 Benda (Arm B)
    Arm description
    		 Bendamustine monotherapy. Participants received up to 8 cycles of bendamustine (120 mg/m2 on Days 1, 2 every 21 days
    Arm type
    		 Active comparator

    Investigational medicinal product name
    bendamustine
    Investigational medicinal product code
    Other name
    benda
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intracavernous use
    Dosage and administration details
    Bendamustine 100 mg/vial, injection 120 mg/m2 Days 1 and 2, every 21 days

    Number of subjects in period 1
    		Ofa + benda (Arm A) Benda (Arm B)
    Started
    173
    173
    Completed 5-year follow-up
    64 [1]
    64 [2]
    Completed
    95
    108
    Not completed
    78
    65
         Physician decision
    10
    11
         Consent withdrawn by subject
    32
    28
         Study Terminated by Sponsor
    28
    22
         Lost to follow-up
    8
    4
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This is correct as these subjects completed the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: This is correct as these subjects completed the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ofa + benda (Arm A)
    Reporting group description
    		 ofatumumab and bendamustine arm. Participants received up to 8 cycles of bendamustine (90 mg/m2) on Days 1,2 every 21 days with 12 doses of ofatumumab (1000 mg, Day 1 q21 days when with bendamustine and every 28 days

    Reporting group title
    Benda (Arm B)
    Reporting group description
    		 Bendamustine monotherapy. Participants received up to 8 cycles of bendamustine (120 mg/m2 on Days 1, 2 every 21 days

    Reporting group values
    		 Ofa + benda (Arm A) Benda (Arm B) Total
    Number of subjects
    		 173 173 346
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 100 95 195
        From 65-84 years
    		 72 77 149
        85 years and over
    		 1 1 2
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.8 ± 61.0 62.6 ± 63.0 -
    Sex: Female, Male
    Units: participants
        Female
    		 72 71 143
        Male
    		 101 102 203
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 10 6 16
        Not Hispanic or Latino
    		 163 167 330
        Unknown or Not Reported
    		 0 0 0
    FLIPI-1 Score at Screening
    Units: Subjects
        0 - 2
    		 100 93 193
        3 - 5
    		 66 75 141
        Missing
    		 7 5 12
    Baseline Absolute Lymphocyte Count
    Units: Subjects
        < LLN
    		 41 41 82
        >= LLN
    		 131 131 262
        Missing
    		 1 1 2
    FcR Gamma 3A Variation
    Units: Subjects
        The GG
    		 21 18 39
        The TG
    		 77 59 136
        The TT
    		 61 62 123
        Missing
    		 14 34 48
    Human Anti-Chimeric Antibodies (HACA)
    Units: Subjects
        Negative
    		 141 116 257
        Positive
    		 21 23 44
        Missing
    		 11 34 45
    Subject analysis sets

    Subject analysis set title
    Optional Ofa
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eligible benda arm participants who were offered optional ofatumumab following disease progression

    Subject analysis sets values
    		 Optional Ofa
    Number of subjects
    30
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    21
        From 65-84 years
    11
        85 years and over
    0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    17 ±
    Sex: Female, Male
    Units: participants
        Female
        Male
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Unknown or Not Reported
    FLIPI-1 Score at Screening
    Units: Subjects
        0 - 2
        3 - 5
        Missing
    Baseline Absolute Lymphocyte Count
    Units: Subjects
        < LLN
        >= LLN
        Missing
    FcR Gamma 3A Variation
    Units: Subjects
        The GG
        The TG
        The TT
        Missing
    Human Anti-Chimeric Antibodies (HACA)
    Units: Subjects
        Negative
        Positive
        Missing

    End points

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    End points reporting groups
    Reporting group title
    Ofa + benda (Arm A)
    Reporting group description
    		 ofatumumab and bendamustine arm. Participants received up to 8 cycles of bendamustine (90 mg/m2) on Days 1,2 every 21 days with 12 doses of ofatumumab (1000 mg, Day 1 q21 days when with bendamustine and every 28 days

    Reporting group title
    Benda (Arm B)
    Reporting group description
    		 Bendamustine monotherapy. Participants received up to 8 cycles of bendamustine (120 mg/m2 on Days 1, 2 every 21 days

    Subject analysis set title
    Optional Ofa
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Eligible benda arm participants who were offered optional ofatumumab following disease progression

    Primary: Progression-free survival (PFS) as assessed by the Independent Review Committee (IRC)

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    End point title
    		 Progression-free survival (PFS) as assessed by the Independent Review Committee (IRC)
    End point description
    PFS is defined as the time interval between randomization until disease progression or death (due to any cause).
    End point type
    Primary
    End point timeframe
    From randomization to the date of first documented disease progression or death due to any cause (67.5 months)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    16.66 (12.81 to 19.68)
    13.83 (11.30 to 16.89)
    Statistical analysis title
    		 PFS per IRC
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.139
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Stratified Cox propor.hazards regression
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.07

    Secondary: Progression-free survival (PFS) in participants with Follicular Lymphoma (FL) per IRC

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    End point title
    		 Progression-free survival (PFS) in participants with Follicular Lymphoma (FL) per IRC
    End point description
    PFS is defined as the time interval between randomization until disease progression or death (due to any cause).
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented disease progression or death due to any cause (67.5 months)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    16.62 (11.17 to 20.47)
    12.12 (10.94 to 16.62)
    Statistical analysis title
    		 PFS for FL per IRC
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.1076
    Method
    		 Stratified Log-Rank
    Parameter type
    		 Stratified Cox propor.hazards regression
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.06

    Secondary: Overall response rate (ORR) in All participants per IRC

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    End point title
    		 Overall response rate (ORR) in All participants per IRC
    End point description
    ORR: Percentage of subjects achieving a complete response (CR) or partial response (PR) from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B. based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymophoma (RRCML) with response criteria defined as CR, PR, standard disease (SD), progressine disease (PD) or NE
    End point type
    Secondary
    End point timeframe
    From randomization until the 217th PFS event occurred, up to about 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Percentage of participants
        number (confidence interval 95%)
    73 (66 to 80)
    75 (67 to 81)
    Statistical analysis title
    		 for All participants
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.8003
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Overall response rate (ORR) in participants with FL per IRC

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    End point title
    		 Overall response rate (ORR) in participants with FL per IRC
    End point description
    ORR: Percentage of subjects achieving a complete response (CR) or partial response (PR) from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B. based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymophoma (RRCML) with response criteria defined as CR, PR, standard disease (SD), progressine disease (PD) or NE
    End point type
    Secondary
    End point timeframe
    From randomization until the 217th PFS event occurred, up to about 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Percentage of participants
        number (confidence interval 95%)
    77 (68 to 84)
    76 (67 to 83)
    Statistical analysis title
    		 ORR with FL
    Statistical analysis description
    for Follicular Lymphoma (FL) participants
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.613
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Secondary: Overall Survival (OS) in All participants

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    End point title
    		 Overall Survival (OS) in All participants
    End point description
    The interval of time between the date of randomization and the date of death due to any cause. For subjects who are alive, time of death will be censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    From randomization up to about 89 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    59.76 (46.63 to 999)
    58.22 (36.44 to 999)
    Statistical analysis title
    		 OS for all patients
    Statistical analysis description
    for All patients
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.4046
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.21

    Secondary: Overall Survival (OS) in participants with FL

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    End point title
    		 Overall Survival (OS) in participants with FL
    End point description
    The interval of time between the date of randomization and the date of death due to any cause. For subjects who are alive, time of death will be censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    From randomization up to about 89 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    99 (45.60 to 999)
    53.59 (36.44 to 999)
    Statistical analysis title
    		 OS for FL patients
    Statistical analysis description
    for FL participants
    Comparison groups
    Ofa + benda (Arm A) v Benda (Arm B)
    Number of subjects included in analysis
    346
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.3768
    Method
    		 Stratified Log Rank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.25

    Secondary: Time to response in All participants per IRC

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    End point title
    		 Time to response in All participants per IRC
    End point description
    Time to response = time from randomization to the first response (CR/ PR). If no CR/PR value was present data was to be censored at last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    2.86 (2.83 to 2.92)
    2.89 (2.83 to 2.92)
    No statistical analyses for this end point

    Secondary: Time to response in participants with FL per IRC

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    End point title
    		 Time to response in participants with FL per IRC
    End point description
    Time to response = time from randomization to the first response (CR/ PR). If no CR/PR value was present data was to be censored at last adequate assessment.
    End point type
    Secondary
    End point timeframe
    From randomization to up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    2.86 (2.83 to 2.92)
    2.86 (2.83 to 2.89)
    No statistical analyses for this end point

    Secondary: Duration of response in All participants per IRC

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    End point title
    		 Duration of response in All participants per IRC
    End point description
    Time (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    time from the initial response (CR/PR) (Day 84) to first documented sign of disease progression or death due to any cause up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    17.71 (13.04 to 22.57)
    14.49 (10.84 to 16.76)
    No statistical analyses for this end point

    Secondary: Duration of response in participants with FL per IRC

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    End point title
    		 Duration of response in participants with FL per IRC
    End point description
    Time (in months) from the initial response (CR/PR) to first documented sign of disease progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    time from the initial response (CR/PR) (Day 84) to first documented sign of disease progression or death due to any cause up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: months
        median (confidence interval 95%)
    16.39 (11.53 to 20.53)
    11.20 (8.61 to 16.43)
    No statistical analyses for this end point

    Secondary: Time to progression in All participants per IRC

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    End point title
    		 Time to progression in All participants per IRC
    End point description
    Time from randomization until disease progression
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented disease progression, whichever occurred first, reported betwen day of first participant randomized up to about 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    19.35 (14.32 to 23.10)
    16.56 (13.63 to 19.75)
    No statistical analyses for this end point

    Secondary: Time to progression in participants with FL per IRC

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    End point title
    		 Time to progression in participants with FL per IRC
    End point description
    Time from randomization until disease progression
    End point type
    Secondary
    End point timeframe
    From randomization to the date of first documented disease progression, whichever occurred first, reported betwen day of first participant randomized up to about 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    19.35 (14.16 to 24.87)
    13.80 (11.14 to 16.85)
    No statistical analyses for this end point

    Secondary: Time to next therapy in All participants per IRC

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    End point title
    		 Time to next therapy in All participants per IRC
    End point description
    Time to next therapy was defined as the time (in months) from randomization date to the date of receiving the next line treatment, including all therapy types.
    End point type
    Secondary
    End point timeframe
    from randomization date to the date of receiving the next line treatment or death, up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    39.82 (28.81 to 999)
    26.94 (21.72 to 39.75)
    No statistical analyses for this end point

    Secondary: Time to next therapy in participants with FL per IRC

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    End point title
    		 Time to next therapy in participants with FL per IRC
    End point description
    Time to next therapy was defined as the time (in months) from randomization date to the date of receiving the next line treatment, including all therapy types
    End point type
    Secondary
    End point timeframe
    from randomization date to the date of receiving the next line treatment or death, up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: Months
        median (confidence interval 95%)
    36.96 (23.79 to 999)
    25.43 (18.37 to 47.70)
    No statistical analyses for this end point

    Secondary: PRO - Change from baseline in Health Related Quality of Life (HRQL) measures in All participants: The FACT-Lym

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    End point title
    		 PRO - Change from baseline in Health Related Quality of Life (HRQL) measures in All participants: The FACT-Lym
    End point description
    The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is intended as a lymphoma specific additional concerns subscale that is designed to supplement the FACT-G. The subscale consists of 15 items. Subjects respond to the items on a five point Likert scale ranging from 0 ‘Not at all’ to 4 ‘Very much’ and are asked to think back over the past 7 days when responding to each of the items. C =cycle; D = day
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Physical well-being score: C5D1(n=126,118)
    0.2 ± 4.36
    -2.8 ± 5.54
        Physical well-being score C11D1(n=104,78)
    1.1 ± 4.58
    1.0 ± 4.25
        Physical well-being score D252 (n=3, 6)
    -5.0 ± 9.64
    1.7 ± 9.18
        Physical well-being score 12M post-D252 (n=67,53)
    0.9 ± 5.59
    1.3 ± 4.52
        Physical well-being score Withdrawal(n=12, 15)
    -4.1 ± 6.78
    -1.5 ± 6.61
        Social/Family well-being score C5D1(n=126,118)
    0.2 ± 4.94
    -0.5 ± 5.24
        Social/Family well-being score C11D1(n=104,78)
    -1.2 ± 6.09
    -1.1 ± 6.45
        Social/Family well-being score D252 (n=3,6)
    -1.6 ± 3.24
    -5.4 ± 9.08
        Soc./Fam. well-being score 12M post-D252(n=67,53)
    0.3 ± 5.21
    -1.3 ± 4.81
        Social/Family well-being score Withdrawal(n=12,15)
    0.9 ± 7.69
    0.3 ± 3.53
        Emotional well-being score C5D1(n=126,118)
    1.7 ± 3.97
    0.1 ± 4.10
        Emotional well-being score C11D1(n=103,78)
    1.4 ± 4.12
    0.7 ± 3.90
        Emotional well-being score D252(n=3,6)
    -5.3 ± 2.08
    -2.5 ± 5.89
        Emotional well-being score 12M post-D252(n=67,53)
    1.5 ± 4.45
    0.7 ± 4.15
        Emotional well-being score Withdrawal(n=12,15)
    -2.2 ± 4.80
    -2.3 ± 4.12
        Functional well-being score C5D1(n=126,118)
    0.7 ± 5.08
    -1.5 ± 5.79
        Functional well-being score C11D1(n=103,78)
    1.1 ± 5.62
    -0.6 ± 5.52
        Functional well-being score D252(n=3, 6)
    -4.3 ± 5.69
    -2.2 ± 13.76
        Functional well-being score 12M post-D252(n=67,53)
    1.1 ± 4.82
    0.8 ± 5.55
        Functional well-being score Withdrawal(n=12,15)
    -2.3 ± 4.27
    -1.6 ± 6.47
        Lymphoma subscale score C5D1(n=126,118)
    3.6 ± 7.88
    -1.0 ± 9.65
        Lymphoma subscale score C11D1(n=104,78)
    4.4 ± 8.88
    2.3 ± 6.53
        Lymphoma subscale score D252(n=3, 6)
    -2.3 ± 14.98
    0.7 ± 18.22
        Lymphoma subscale score 12M post-D252(n=67,53)
    3.2 ± 7.77
    2.0 ± 7.71
        Lymphoma subscale score Withdrawal(n=12,15)
    -1.4 ± 6.16
    -1.6 ± 7.65
        FACT-Lymphoma TOI C1D1(n=126, 118)
    4.5 ± 14.64
    -5.3 ± 18.67
        FACT-Lymphoma TOI C11D1(n=103,78)
    6.7 ± 15.84
    2.7 ± 13.24
        FACT-Lymphoma TOI D252 (n=3, 6)
    -11.7 ± 28.75
    0.2 ± 36.56
        FACT-Lymphoma TOI 12M post-D252 (n=67,53)
    5.1 ± 15.94
    4.1 ± 14.62
        FACT-Lymphoma TOI Withdrawal(n=12,14)
    -7.8 ± 14.55
    -4.3 ± 16.77
        FACT-G Total Score C5D1 (n=126,118)
    2.7 ± 12.82
    -4.7 ± 15.26
        FACT-G Total Score C11D1 (n=103,78)
    2.3 ± 13.00
    0.1 ± 14.11
        FACT-G Total score D252 (n=3, 6)
    -16.2 ± 15.71
    -8.4 ± 31.22
        FACT-G Total Score 12M post-D252(n=67, 53)
    3.7 ± 13.75
    1.5 ± 13.44
        FACT-G Total Score Withdrawal (n=12, 15)
    -7.7 ± 11.91
    -5.3 ± 13.10
        FACT-Lymph. Tot. score C5D1 (n=126,118)
    6.3 ± 18.78
    -5.8 ± 23.05
        FACT-Lymph. Tot. score C11D1 (n=103,78)
    6.7 ± 18.95
    2.4 ± 18.73
        FACT-Lymph. Tot. score D252(n=3, 6)
    -18.6 ± 30.50
    -7.7 ± 44.64
        FACT-Lymph. Tot. score 12M post-D252 (n=67, 53)
    6.9 ± 19.78
    3.5 ± 18.77
        FACT-Lymph. Tot. score Withdrawal (n=12, 14)
    -9.1 ± 15.96
    -6.5 ± 18.53
    No statistical analyses for this end point

    Secondary: PRO - Change from baseline in Health Related Quality of Life (HRQL) measures in participants with FL: The FACT-Lym

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    End point title
    		 PRO - Change from baseline in Health Related Quality of Life (HRQL) measures in participants with FL: The FACT-Lym
    End point description
    The Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) is intended as a lymphoma specific additional concerns subscale that is designed to supplement the FACT-G. The subscale consists of 15 items. Subjects respond to the items on a five point Likert scale ranging from 0 ‘Not at all’ to 4 ‘Very much’ and are asked to think back over the past 7 days when responding to each of the items.
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Physical well-being score C5D1(n=87,78)
    0.0 ± 4.66
    -3.4 ± 5.87
        Physical well-being score C11D1(n=72,47)
    0.9 ± 4.16
    1.2 ± 4.74
        Physical well-being score D252 (n=1, 2)
    2.0 ± 999
    7.5 ± 17.68
        Physical well-being score 12M post-D252 (n=48, 30)
    0.5 ± 6.15
    1.8 ± 4.37
        Physical well-being score Withdrawal(n=6,11 )
    -5.0 ± 7.64
    -0.6 ± 6.31
        Social/Family well-being score C5D1(n=87,78)
    -0.1 ± 4.38
    -0.7 ± 5.48
        Social/Family well-being score C11D1(n=72,47)
    -1.6 ± 5.38
    -1.4 ± 5.61
        Social/Family well-being score D252 (n=1, 2)
    2.0 ± 999
    2.5 ± 3.54
        Soc./Fam. well-being score 12M post-D252(n=48,30)
    0.3 ± 5.35
    -1.9 ± 5.14
        Social/Family well-being score Withdrawal(n=6,11)
    1.1 ± 5.79
    0.6 ± 2.57
        Emotional well-being score C5D1(n=87,78)
    1.8 ± 3.65
    -0.0 ± 4.41
        Emotional well-being score C11D1(n=72, 47)
    1.2 ± 4.30
    0.5 ± 4.10
        Emotional well-being score D252(n=1,2)
    -6.0 ± 999
    -1.0 ± 9.90
        Emotional well-being score 12M post-D252(n=48,30)
    1.5 ± 4.85
    0.6 ± 2.68
        Emotional well-being score Withdrawal(n=6,11)
    -2.3 ± 5.28
    -1.9 ± 4.59
        Functional well-being score C5D1(n=87, 78)
    0.1 ± 4.58
    -1.7 ± 5.74
        Functional well-being score C11D1(n=72, 47)
    0.5 ± 4.99
    -0.0 ± 4.84
        Functional well-being score D252(n=1, 2)
    -6.0 ± 999
    7.0 ± 15.56
        Functional well-being score 12M post-D252(n=48,30)
    0.7 ± 4.99
    1.0 ± 5.75
        Functional well-being score Withdrawal(6,11)
    -1.6 ± 4.06
    -1.5 ± 7.15
        Lymphoma subscale score C5D1(n=87,78)
    3.7 ± 7.33
    -2.2 ± 9.71
        Lymphoma subscale score C11D1(n=72,47)
    3.7 ± 8.70
    2.4 ± 6.79
        Lymphoma subscale score D252(n=1, 2)
    -18.7 ± 999
    7.0 ± 38.18
        Lymphoma subscale score 12M post-D252(n=48,30)
    2.6 ± 8.00
    2.2 ± 6.63
        Lymphoma subscale score Withdrawal(n=6,11)
    -2.5 ± 6.76
    -0.4 ± 7.17
        FACT-Lymphoma TOI C5D1(n=87,78)
    3.7 ± 13.51
    -7.3 ± 18.77
        FACT-Lymphoma TOI C11D1(n=72,47)
    5.0 ± 14.74
    3.6 ± 14.01
        FACT-Lymphoma TOI D252(n=1, 2)
    -2.0 ± 999
    21.5 ± 71.42
        FACT-Lymphoma TOI 12M post-D252(n=48,30)
    3.7 ± 16.94
    4.9 ± 12.32
        FACT-Lymphoma TOI Withdrawal(n=6, 10)
    -9.2 ± 15.40
    -1.7 ± 15.26
        FACT-G Total score C5D1(n=87,78)
    1.7 ± 11.40
    -5.8 ± 16.32
        FACT-G Total score C11D1(n=72,47)
    1.0 ± 12.17
    0.2 ± 13.96
        FACT-G Total score D252(n=1, 2)
    -8.0 ± 999
    16.0 ± 39.60
        FACT-G Total score 12M post-D252(n=48,30)
    2.9 ± 14.62
    1.4 ± 11.25
        FACT-Lymphoma Tot. score C5D1(n=87,78)
    5.4 ± 16.55
    -8.0 ± 24.11
        FACT-Lymphoma Tot. score C11D1(n=72,47)
    4.7 ± 17.52
    2.7 ± 19.60
        FACT-Lymphoma Tot. score D252(n=1, 2)
    -6.0 ± 999
    23.0 ± 77.78
        FACT-Lymphoma Tot. score 12M post-D252(n=48,30)
    5.5 ± 20.73
    3.6 ± 14.44
        FACT-Lymphoma Tot. score Withdrawal(n=6, 10)
    -10.4 ± 15.02
    -3.1 ± 18.48
    No statistical analyses for this end point

    Secondary: PRO - Change from baseline in HRQL measures in all participants: The EQ-5D

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    End point title
    		 PRO - Change from baseline in HRQL measures in all participants: The EQ-5D
    End point description
    The EuroQoL Five-Dimension (EQ-5D) is a self-administered, generic, indirect utility measure used for health economic analysis. It consists of a 0-100 Visual Analogue Scale (VAS) on which subjects are asked to rate their current overall health status & 5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 single items can be summed and expressed as a single global index of health-related quality of life. For each of the 5 items subjects must choose between 3 levels of difficulty in accomplishing tasks in that dimension. The VAS is then used in combination with the dimension scores to generate a subject profile. 1 response exists per dimension: Level 1 (no problem) is coded as “1”; Level 2 (some or moderate problems) is coded as “2”; Level 3 (unable, or extreme problems) is coded as “3”.
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: scores on a scale
    arithmetic mean (standard deviation)
        EQ5D01-EQ VAS Score C5D1(n=124,115)
    5.8 ± 18.10
    -3.8 ± 19.25
        EQ5D01-EQ VAS Score C11D1(n=101,78)
    12.9 ± 19.38
    2.7 ± 18.96
        EQ5D01-EQ VAS Score D252 (n=3,6)
    -11.7 ± 16.07
    -0.8 ± 19.66
        EQ5D01-EQ VAS Score 12M post-D252(n=65,52)
    14.7 ± 19.71
    7.1 ± 19.14
        EQ5D01-EQ VAS Score Withdrawal (n=12, 15)
    -14.7 ± 17.03
    0.7 ± 34.41
        EuroQoL Tariffs C5D1(n=122,116)
    0.21 ± 0.24
    0.0 ± 0.22
        EuroQoL Tariffs C11D1(n=102,78)
    0.1 ± 0.22
    0.0 ± 0.19
        EuroQoL Tariffs D252 (n=3, 6)
    -0.4 ± 0.79
    0.1 ± 0.36
        EuroQoL Tariffs 12M post-D252(n=65,51)
    0.0 ± 0.22
    0.0 ± 0.20
        EuroQoL Tariffs Withdrawal (n=12,15)
    -0.2 ± 0.22
    0.1 ± 0.32
    No statistical analyses for this end point

    Secondary: PRO - Change from baseline in HRQL measures in participants with FL: The EQ-5D

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    End point title
    		 PRO - Change from baseline in HRQL measures in participants with FL: The EQ-5D
    End point description
    The EuroQoL Five-Dimension (EQ-5D) is a self-administered, generic, indirect utility measure used for health economic analysis. It consists of a 0-100 Visual Analogue Scale (VAS) on which subjects are asked to rate their current overall health status & 5 single-item dimensions which ask subjects to rate their health in terms of mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5 single items can be summed and expressed as a single global index of health-related quality of life. For each of the 5 items subjects must choose between 3 levels of difficulty in accomplishing tasks in that dimension. The VAS is then used in combination with the dimension scores to generate a subject profile. 1 response exists per dimension: Level 1 (no problem) is coded as “1”; Level 2 (some or moderate problems) is coded as “2”; Level 3 (unable, or extreme problems) is coded as “3”.
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    120
    119
    Units: scores on a scale
    arithmetic mean (standard deviation)
        EQ5D01-EQ VAS Score C5D1(n=85,76)
    5.5 ± 19.25
    -6.5 ± 18.83
        EQ5D01-EQ VAS Score C11D1(n=69,47)
    12.9 ± 19.88
    1.1 ± 20.87
        EQ5D01-EQ VAS Score D252 (n=1,2)
    0.00 ± 999
    -7.5 ± 31.82
        EQ5D01-EQ VAS Score 12M post-D252(n=46,29)
    14.2 ± 21.47
    6.7 ± 20.77
        EQ5D01-EQ VAS Score Withdrawal (n=6,11)
    -18.5 ± 13.35
    5.4 ± 37.78
        EuroQoL Tariffs C5D1(n=84, 76)
    0.0 ± 0.24
    0.0 ± 0.23
        EuroQoL Tariffs C11D1(n=70, 47))
    0.1 ± 0.22
    0.0 ± 0.20
        EuroQoL Tariffs D252 (n=1, 2)
    0.0 ± 999
    0.4 ± 0.53
        EuroQoL Tariffs 12M post-D252(n=46,28)
    0.0 ± 0.22
    0.0 ± 0.16
        EuroQoL Tariffs Withdrawal (n=6,11)
    -0.1 ± 0.16
    0.1 ± 0.36
    No statistical analyses for this end point

    Secondary: PRO - Change in health treatment in HRQL measures in all participants: The Health Change Questionnaire (HCQ)

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    End point title
    		 PRO - Change in health treatment in HRQL measures in all participants: The Health Change Questionnaire (HCQ)
    End point description
    The Health Change Questionnaire, (HCQ) used is a nine item scale that asks the patient to rate change in status since beginning treatment on this study. Subject response provides an ongoing evaluation of perceived progress and satisfaction with treatment services.
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change in health treatment C5D1(n=124, 118)
    2.8 ± 1.81
    3.8 ± 2.29
        Change in health treatment C11D1(n=105, 77)
    2.6 ± 1.73
    2.5 ± 1.74
        Change in health treatment D252(n=3, 6)
    5.3 ± 2.52
    4.8 ± 2.56
        Change in health treatment 12M post D252(n=66, 50)
    2.4 ± 1.95
    2.6 ± 1.99
        Change in health treatment Withdrawal (n=11, 15)
    5.4 ± 3.32
    4.3 ± 2.63
    No statistical analyses for this end point

    Secondary: PRO - Change in health treatment in HRQL measures in participants with FL: The Health Change Questionnaire (HCQ)

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    End point title
    		 PRO - Change in health treatment in HRQL measures in participants with FL: The Health Change Questionnaire (HCQ)
    End point description
    The Health Change Questionnaire, (HCQ) used is a nine item scale that asks the patient to rate change in status since beginning treatment on this study. Subject response provides an ongoing evaluation of perceived progress and satisfaction with treatment services.
    End point type
    Secondary
    End point timeframe
    administered at the Screening visit and at all post-baseline, up to 67.5 months (presented at particular clinically relevant time points)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    120
    119
    Units: scores on a scale
    arithmetic mean (standard deviation)
        Change in health treatment C5D1(n=86, 78)
    2.9 ± 1.93
    3.9 ± 2.25
        Change in health treatment C11D1(n=73, 46)
    2.7 ± 1.73
    2.4 ± 1.56
        Change in health treatment D252(n=1, 2)
    3.0 ± 999
    4.5 ± 3.54
        Change in health treatment 12M post D252(n=47,27)
    2.7 ± 2.11
    2.1 ± 1.54
        Change in health treatment Withdrawal (n=5,11)
    7.2 ± 1.79
    4.2 ± 2.96
    No statistical analyses for this end point

    Secondary: Reduction in tumor size

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    End point title
    		 Reduction in tumor size
    End point description
    Tumor size was measured by the mean change in the sum of the products of the greatest diameter (SPD) of the largest abnormal nodes from baseline to post-baseline by CT Scan.
    End point type
    Secondary
    End point timeframe
    baseline, post-baseline (up to 55 months)
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: mm^2
        arithmetic mean (standard deviation)
    -33.2 ± 44.08
    -32.8 ± 36.83
    No statistical analyses for this end point

    Secondary: Improvement in Eastern Cooperative Oncology Group (ECOG) Performance status

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    End point title
    		 Improvement in Eastern Cooperative Oncology Group (ECOG) Performance status
    End point description
    Improvement was defined as decrease from baseline by at least one step on the ECOG performance status scale (improvement categorized as yes or no).
    End point type
    Secondary
    End point timeframe
    from baseline to End of study up to 67.5 months
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: participants
        C5D1 (n= 142, 134): Deteriorated
    18
    24
        C5D1 (n= 142, 134): Improved
    30
    22
        C5D1 (n= 142, 134): No Change
    94
    88
        C11D1 (n= 115, 90): Deteriorated
    13
    9
        C11D1 (n= 115, 90): Improved
    27
    23
        C11D1 (n= 115, 90): No Change
    75
    58
        12M post D252 (n= 70, 56): Deteriorated
    9
    6
        12M post-D252 (n= 70, 56): Improved
    17
    12
        12M post-D252 (n= 70, 56): No Change
    44
    38
        Withdrawal (n= 17, 21): Deteriorated
    7
    8
        Withdrawal (n= 17, 21): Improved
    2
    2
        Withdrawal (n= 17, 21): No Change
    8
    11
    No statistical analyses for this end point

    Secondary: Summary of number of participants with Human Anti-Human Antibodies (HAHA)

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    End point title
    		 Summary of number of participants with Human Anti-Human Antibodies (HAHA) [1]
    End point description
    A summary by responders and non-responders
    End point type
    Secondary
    End point timeframe
    From randomization up to about 67.5 months
    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: No statistical analysis was planned for this endpoint.
    End point values
    		 Ofa + benda (Arm A)
    Number of subjects analysed
    172
    Units: Participants
        with Post-Ofatumumab HAHA results
    151
        with at least 1 conf. +ve post-Ofa HAHA result
    1
        -ve post-Ofa HAHA results, no Ofa conc. <200 ug/mL
    6
        -ve post-Ofa HAHA, at least 1 Ofa conc<200ug/mL
    144
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) to optional ofatumumab monotherapy in subjects who progressed during or following single-agent bendamustine

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    End point title
    		 Overall response rate (ORR) to optional ofatumumab monotherapy in subjects who progressed during or following single-agent bendamustine
    End point description
    Percentage of subjects achieving a CR or PR from the start of randomization until disease progression or the start of new anti-cancer therapy, including the optional ofatumumab for subjects in Arm B. Based on responses from the IRC assessment of best overall response using the Revised Response Criteria for Malignant Lymophoma (RRCML) with response criteria defined as CR, PR, SD, PD or NE
    End point type
    Secondary
    End point timeframe
    From randomization until the 217th PFS event occurred, up to about 67.8 months
    End point values
    		 Optional Ofa
    Number of subjects analysed
    30
    Units: Percentage of participants
    17
    No statistical analyses for this end point

    Secondary: Quantitative assessments of immunoglobulins A, G and M (IgA, IgG, IgM)

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    End point title
    		 Quantitative assessments of immunoglobulins A, G and M (IgA, IgG, IgM) [2]
    End point description
    at scheduled visits for actual values as well as for change from baseline
    End point type
    Secondary
    End point timeframe
    prior to receiving ofatumumab, at first monthly dose, and at 1, 3, and 6 months post last infusion of ofatumumab
    Notes
    [2] - 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: No statistical analysis was planned for this endpoint.
    End point values
    		 Ofa + benda (Arm A)
    Number of subjects analysed
    173
    Units: g/L
    arithmetic mean (standard deviation)
        IgA @ screening (BL) (n=1)
    0.7 ± 999
        IgG @ screening (n=1)
    4.7 ± 999
        IgM @ screening (n=1)
    0.6 ± 999
        IgA @ C1D1 (n=134)
    1.3 ± 0.78
        IgG @ C1D1 (n=153)
    7.7 ± 3.96
        IgM @ C1D1 (n=120)
    1.4 ± 4.15
        IgA @ 1M post-D252 (n=77)
    1.1 ± 0.74
        IgG @ 1M post-D252 (n=90)
    7.1 ± 2.90
        IgM @ 1M post-D252 (n=50)
    0.6 ± 0.68
        IgA @ 6M post D252 (n=65)
    1.1 ± 0.59
        IgG @ 6M post D252 (n=75)
    7.3 ± 2.97
        IgM @ 6M post D252 (n=41)
    0.7 ± 0.97
        IgA @ 12M post D252 (n=53)
    1.1 ± 1.2
        IgG @12M post D252 (n=63)
    7.1 ± 3.31
        IgM @ 12M post D252 (n=41)
    0.7 ± 0.66
    No statistical analyses for this end point

    Secondary: Plasma ofatumumab concentrations

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    End point title
    		 Plasma ofatumumab concentrations [3]
    End point description
    Concentrations of ofatumumab in plasma listed by actual relative time and summarized by nominal time.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 up to 12 months follow up
    Notes
    [3] - 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: No statistical analysis was planned for this endpoint.
    End point values
    		 Ofa + benda (Arm A)
    Number of subjects analysed
    173
    Units: ug/mL
    arithmetic mean (standard deviation)
        C1D1 End of infusion (EOI) (n=64
    262.0 ± 83.97
        C1D1 1h post-EOI (n=61
    283.2 ± 227.11
        C7D1 pre-dose (n=128)
    153.6 ± 74.45
        C7D1 EOI (n=42)
    402.2 ± 148.78
        C7D1 1h post-EOI (n=39)
    419.1 ± 167.44
        C12D1 pre-dose (n=101)
    143.5 ± 75.58
        C12D1 EOI (n=27)
    392.0 ± 130.64
        12M post-D252 (n=43)
    0.9 ± 2.53
        Withdrawal (n=13)
    29.6 ± 42.58
    No statistical analyses for this end point

    Secondary: Participants with complete B-cell depletion and near-complete B-cell depletion: B-cell monitoring (CD19+, CD20+)

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    End point title
    		 Participants with complete B-cell depletion and near-complete B-cell depletion: B-cell monitoring (CD19+, CD20+)
    End point description
    The percent change of CD5+CD19+ and CD5-CD19+ from baseline was summarized to assess the treatment effect, to monitor the normal B-cell population, and to follow their recovery. Complete B-cell depletion is defined as the absolute value of CD5+CD19+ and CD5-CD19+ both equal to zero cells/uL.
    End point type
    Secondary
    End point timeframe
    From Baseline up to 18 months follow up
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: percentage change from baseline
    arithmetic mean (standard deviation)
        C5D1: CD45+CD19+ (n=18, 1)
    -94.0 ± 16.6
    -97.0 ± 999
        1M post-D252: CD45+CD19+ (n=27, 0)
    -82.0 ± 77.0
    999 ± 999
        9M post-D252: CD45+CD19+ (n=15, 0)
    1421.0 ± 5721.6
    999 ± 999
        C1D1: CD45+CD20+ (n=17,1)
    -100.0 ± 0.0
    -98.0 ± 999
        1M post-D252: CD45+CD20+ (n=26, 0)
    -100.0 ± 0.0
    999 ± 999
        9M post-D252: CD45+CD20+ (n=15, 0)
    925.0 ± 3803.1
    999 ± 999
    No statistical analyses for this end point

    Secondary: Human Anti-chimeric Antibodies (HACA) Over Time

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    End point title
    		 Human Anti-chimeric Antibodies (HACA) Over Time
    End point description
    The percentage of participants with positive and negative baseline HACA results
    End point type
    Secondary
    End point timeframe
    At Baselone and Cycle 1 day 1
    End point values
    		 Ofa + benda (Arm A) Benda (Arm B)
    Number of subjects analysed
    173
    173
    Units: paercentage of participants
        Baseline: Negative (n = 172, 170)
    86
    70
        Baseline: Positive (n = 172, 170)
    13
    14
        C1D1: Negative (n=170, 142)
    87
    84
        C1D1:Positive (n=170, 142)
    13
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Total
    Reporting group description
    		 Total

    Reporting group title
    OFA + BENDA
    Reporting group description
    		 OFA + BENDA

    Reporting group title
    BENDA
    Reporting group description
    		 BENDA

    Reporting group title
    Optional OFA
    Reporting group description
    		 Optional OFA

    Serious adverse events
    		 Total OFA + BENDA BENDA Optional OFA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    160 / 342 (46.78%)
    72 / 172 (41.86%)
    84 / 170 (49.41%)
    8 / 32 (25.00%)
         number of deaths (all causes)
    137
    66
    71
    15
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute myeloid leukaemia
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign ovarian tumour
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Brain neoplasm
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Burkitt's lymphoma
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer metastatic
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    0 / 170 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Lung adenocarcinoma
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    3 / 342 (0.88%)
    2 / 172 (1.16%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    Myelofibrosis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    2 / 342 (0.58%)
    2 / 172 (1.16%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    0 / 170 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    4 / 342 (1.17%)
    3 / 172 (1.74%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 1
    Fatigue
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Malaise
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Pyrexia
         subjects affected / exposed
    16 / 342 (4.68%)
    7 / 172 (4.07%)
    9 / 170 (5.29%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
    6 / 10
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type IV hypersensitivity reaction
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    0 / 170 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Social circumstances
    Loss of personal independence in daily activities
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiectasis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    5 / 342 (1.46%)
    1 / 172 (0.58%)
    4 / 170 (2.35%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 342 (1.17%)
    3 / 172 (1.74%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Cytomegalovirus test positive
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 342 (0.58%)
    2 / 172 (1.16%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    2 / 342 (0.58%)
    2 / 172 (1.16%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular encephalopathy
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 342 (3.51%)
    2 / 172 (1.16%)
    10 / 170 (5.88%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    9 / 11
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aplastic anaemia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autoimmune haemolytic anaemia
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    15 / 342 (4.39%)
    8 / 172 (4.65%)
    5 / 170 (2.94%)
    2 / 32 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
    6 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemolytic anaemia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 342 (1.17%)
    1 / 172 (0.58%)
    3 / 170 (1.76%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    14 / 342 (4.09%)
    6 / 172 (3.49%)
    8 / 170 (4.71%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 9
    9 / 9
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    8 / 342 (2.34%)
    2 / 172 (1.16%)
    6 / 170 (3.53%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    5 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Thrombocytopenic purpura
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Optic atrophy
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal haemorrhage
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal perforation
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Faecalith
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 342 (0.88%)
    2 / 172 (1.16%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Drug-induced liver injury
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraneoplastic pemphigus
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson syndrome
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Toxic epidermal necrolysis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Urinary tract inflammation
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal sepsis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Candida infection
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus chorioretinitis
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysentery
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes ophthalmic
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    5 / 342 (1.46%)
    1 / 172 (0.58%)
    4 / 170 (2.35%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster disseminated
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Lung infection
         subjects affected / exposed
    5 / 342 (1.46%)
    3 / 172 (1.74%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic infection
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii pneumonia
         subjects affected / exposed
    3 / 342 (0.88%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Pneumonia
         subjects affected / exposed
    25 / 342 (7.31%)
    10 / 172 (5.81%)
    14 / 170 (8.24%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 10
    6 / 15
    0 / 1
         deaths causally related to treatment / all
    0 / 8
    0 / 2
    0 / 6
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Progressive multifocal leukoencephalopathy
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 342 (0.88%)
    2 / 172 (1.16%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
    0 / 0
    Sinusitis
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord infection
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal skin infection
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    0 / 170 (0.00%)
    1 / 32 (3.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 342 (0.58%)
    0 / 172 (0.00%)
    2 / 170 (1.18%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 342 (0.58%)
    2 / 172 (1.16%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    2 / 342 (0.58%)
    1 / 172 (0.58%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 342 (0.29%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 342 (0.88%)
    0 / 172 (0.00%)
    3 / 170 (1.76%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 342 (0.29%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 342 (0.58%)
    2 / 172 (1.16%)
    0 / 170 (0.00%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 342 (0.88%)
    0 / 172 (0.00%)
    3 / 170 (1.76%)
    0 / 32 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Total OFA + BENDA BENDA Optional OFA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    320 / 342 (93.57%)
    158 / 172 (91.86%)
    162 / 170 (95.29%)
    21 / 32 (65.63%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 342 (6.14%)
    10 / 172 (5.81%)
    6 / 170 (3.53%)
    5 / 32 (15.63%)
         occurrences all number
    0
    10
    6
    6
    Hypotension
         subjects affected / exposed
    16 / 342 (4.68%)
    9 / 172 (5.23%)
    6 / 170 (3.53%)
    1 / 32 (3.13%)
         occurrences all number
    0
    9
    7
    1
    Phlebitis
         subjects affected / exposed
    16 / 342 (4.68%)
    6 / 172 (3.49%)
    10 / 170 (5.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    6
    12
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    44 / 342 (12.87%)
    17 / 172 (9.88%)
    27 / 170 (15.88%)
    0 / 32 (0.00%)
         occurrences all number
    0
    26
    31
    0
    Chills
         subjects affected / exposed
    25 / 342 (7.31%)
    9 / 172 (5.23%)
    15 / 170 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    0
    12
    19
    1
    Fatigue
         subjects affected / exposed
    101 / 342 (29.53%)
    41 / 172 (23.84%)
    59 / 170 (34.71%)
    5 / 32 (15.63%)
         occurrences all number
    0
    53
    69
    5
    Influenza like illness
         subjects affected / exposed
    13 / 342 (3.80%)
    9 / 172 (5.23%)
    4 / 170 (2.35%)
    0 / 32 (0.00%)
         occurrences all number
    0
    9
    6
    0
    Malaise
         subjects affected / exposed
    15 / 342 (4.39%)
    3 / 172 (1.74%)
    12 / 170 (7.06%)
    0 / 32 (0.00%)
         occurrences all number
    0
    3
    16
    0
    Mucosal inflammation
         subjects affected / exposed
    24 / 342 (7.02%)
    9 / 172 (5.23%)
    14 / 170 (8.24%)
    1 / 32 (3.13%)
         occurrences all number
    0
    10
    16
    2
    Oedema peripheral
         subjects affected / exposed
    23 / 342 (6.73%)
    9 / 172 (5.23%)
    14 / 170 (8.24%)
    0 / 32 (0.00%)
         occurrences all number
    0
    15
    15
    0
    Pyrexia
         subjects affected / exposed
    78 / 342 (22.81%)
    33 / 172 (19.19%)
    44 / 170 (25.88%)
    2 / 32 (6.25%)
         occurrences all number
    0
    54
    62
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    68 / 342 (19.88%)
    38 / 172 (22.09%)
    27 / 170 (15.88%)
    6 / 32 (18.75%)
         occurrences all number
    0
    42
    31
    8
    Dyspnoea
         subjects affected / exposed
    38 / 342 (11.11%)
    14 / 172 (8.14%)
    21 / 170 (12.35%)
    4 / 32 (12.50%)
         occurrences all number
    0
    16
    23
    5
    Oropharyngeal pain
         subjects affected / exposed
    14 / 342 (4.09%)
    10 / 172 (5.81%)
    3 / 170 (1.76%)
    1 / 32 (3.13%)
         occurrences all number
    0
    11
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    26 / 342 (7.60%)
    15 / 172 (8.72%)
    8 / 170 (4.71%)
    3 / 32 (9.38%)
         occurrences all number
    0
    18
    8
    3
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    26 / 342 (7.60%)
    13 / 172 (7.56%)
    13 / 170 (7.65%)
    0 / 32 (0.00%)
         occurrences all number
    0
    27
    24
    0
    Platelet count decreased
         subjects affected / exposed
    26 / 342 (7.60%)
    12 / 172 (6.98%)
    14 / 170 (8.24%)
    0 / 32 (0.00%)
         occurrences all number
    0
    15
    18
    0
    Weight decreased
         subjects affected / exposed
    31 / 342 (9.06%)
    11 / 172 (6.40%)
    20 / 170 (11.76%)
    0 / 32 (0.00%)
         occurrences all number
    0
    11
    20
    0
    White blood cell count decreased
         subjects affected / exposed
    20 / 342 (5.85%)
    11 / 172 (6.40%)
    9 / 170 (5.29%)
    0 / 32 (0.00%)
         occurrences all number
    0
    17
    15
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    25 / 342 (7.31%)
    19 / 172 (11.05%)
    2 / 170 (1.18%)
    4 / 32 (12.50%)
         occurrences all number
    0
    27
    2
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 342 (6.43%)
    14 / 172 (8.14%)
    7 / 170 (4.12%)
    1 / 32 (3.13%)
         occurrences all number
    0
    16
    7
    1
    Dysgeusia
         subjects affected / exposed
    29 / 342 (8.48%)
    9 / 172 (5.23%)
    20 / 170 (11.76%)
    0 / 32 (0.00%)
         occurrences all number
    0
    9
    20
    0
    Headache
         subjects affected / exposed
    56 / 342 (16.37%)
    31 / 172 (18.02%)
    21 / 170 (12.35%)
    4 / 32 (12.50%)
         occurrences all number
    0
    40
    27
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    77 / 342 (22.51%)
    31 / 172 (18.02%)
    46 / 170 (27.06%)
    0 / 32 (0.00%)
         occurrences all number
    0
    41
    65
    0
    Leukopenia
         subjects affected / exposed
    46 / 342 (13.45%)
    25 / 172 (14.53%)
    21 / 170 (12.35%)
    1 / 32 (3.13%)
         occurrences all number
    0
    43
    31
    1
    Lymphopenia
         subjects affected / exposed
    34 / 342 (9.94%)
    17 / 172 (9.88%)
    17 / 170 (10.00%)
    0 / 32 (0.00%)
         occurrences all number
    0
    25
    18
    0
    Neutropenia
         subjects affected / exposed
    141 / 342 (41.23%)
    66 / 172 (38.37%)
    74 / 170 (43.53%)
    3 / 32 (9.38%)
         occurrences all number
    0
    132
    145
    4
    Thrombocytopenia
         subjects affected / exposed
    77 / 342 (22.51%)
    30 / 172 (17.44%)
    46 / 170 (27.06%)
    1 / 32 (3.13%)
         occurrences all number
    0
    37
    74
    1
    Eye disorders
    Vitreous floaters
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    20 / 342 (5.85%)
    9 / 172 (5.23%)
    11 / 170 (6.47%)
    1 / 32 (3.13%)
         occurrences all number
    0
    10
    12
    1
    Constipation
         subjects affected / exposed
    72 / 342 (21.05%)
    29 / 172 (16.86%)
    40 / 170 (23.53%)
    4 / 32 (12.50%)
         occurrences all number
    0
    39
    46
    4
    Diarrhoea
         subjects affected / exposed
    75 / 342 (21.93%)
    35 / 172 (20.35%)
    40 / 170 (23.53%)
    3 / 32 (9.38%)
         occurrences all number
    0
    56
    53
    3
    Dry mouth
         subjects affected / exposed
    16 / 342 (4.68%)
    7 / 172 (4.07%)
    9 / 170 (5.29%)
    0 / 32 (0.00%)
         occurrences all number
    0
    9
    10
    0
    Dyspepsia
         subjects affected / exposed
    16 / 342 (4.68%)
    9 / 172 (5.23%)
    7 / 170 (4.12%)
    0 / 32 (0.00%)
         occurrences all number
    0
    10
    7
    0
    Nausea
         subjects affected / exposed
    155 / 342 (45.32%)
    62 / 172 (36.05%)
    93 / 170 (54.71%)
    5 / 32 (15.63%)
         occurrences all number
    0
    101
    151
    6
    Stomatitis
         subjects affected / exposed
    19 / 342 (5.56%)
    6 / 172 (3.49%)
    12 / 170 (7.06%)
    1 / 32 (3.13%)
         occurrences all number
    0
    7
    13
    1
    Vomiting
         subjects affected / exposed
    66 / 342 (19.30%)
    25 / 172 (14.53%)
    40 / 170 (23.53%)
    2 / 32 (6.25%)
         occurrences all number
    0
    36
    58
    3
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    10 / 342 (2.92%)
    4 / 172 (2.33%)
    4 / 170 (2.35%)
    2 / 32 (6.25%)
         occurrences all number
    0
    4
    4
    2
    Erythema
         subjects affected / exposed
    12 / 342 (3.51%)
    7 / 172 (4.07%)
    4 / 170 (2.35%)
    2 / 32 (6.25%)
         occurrences all number
    0
    11
    4
    2
    Pruritus
         subjects affected / exposed
    40 / 342 (11.70%)
    24 / 172 (13.95%)
    12 / 170 (7.06%)
    4 / 32 (12.50%)
         occurrences all number
    0
    32
    19
    4
    Rash
         subjects affected / exposed
    50 / 342 (14.62%)
    33 / 172 (19.19%)
    15 / 170 (8.82%)
    2 / 32 (6.25%)
         occurrences all number
    0
    47
    16
    2
    Urticaria
         subjects affected / exposed
    18 / 342 (5.26%)
    13 / 172 (7.56%)
    1 / 170 (0.59%)
    4 / 32 (12.50%)
         occurrences all number
    0
    14
    1
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 342 (7.31%)
    13 / 172 (7.56%)
    12 / 170 (7.06%)
    0 / 32 (0.00%)
         occurrences all number
    0
    14
    13
    0
    Back pain
         subjects affected / exposed
    20 / 342 (5.85%)
    13 / 172 (7.56%)
    5 / 170 (2.94%)
    2 / 32 (6.25%)
         occurrences all number
    0
    13
    5
    2
    Musculoskeletal pain
         subjects affected / exposed
    7 / 342 (2.05%)
    0 / 172 (0.00%)
    5 / 170 (2.94%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    5
    2
    Myalgia
         subjects affected / exposed
    15 / 342 (4.39%)
    4 / 172 (2.33%)
    9 / 170 (5.29%)
    2 / 32 (6.25%)
         occurrences all number
    0
    4
    10
    2
    Pain in extremity
         subjects affected / exposed
    19 / 342 (5.56%)
    11 / 172 (6.40%)
    8 / 170 (4.71%)
    0 / 32 (0.00%)
         occurrences all number
    0
    14
    10
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    30 / 342 (8.77%)
    19 / 172 (11.05%)
    11 / 170 (6.47%)
    0 / 32 (0.00%)
         occurrences all number
    0
    23
    13
    0
    Herpes zoster
         subjects affected / exposed
    20 / 342 (5.85%)
    9 / 172 (5.23%)
    10 / 170 (5.88%)
    1 / 32 (3.13%)
         occurrences all number
    0
    9
    11
    1
    Nasopharyngitis
         subjects affected / exposed
    42 / 342 (12.28%)
    27 / 172 (15.70%)
    14 / 170 (8.24%)
    1 / 32 (3.13%)
         occurrences all number
    0
    36
    17
    1
    Oral herpes
         subjects affected / exposed
    19 / 342 (5.56%)
    9 / 172 (5.23%)
    10 / 170 (5.88%)
    1 / 32 (3.13%)
         occurrences all number
    0
    9
    10
    1
    Sinusitis
         subjects affected / exposed
    17 / 342 (4.97%)
    10 / 172 (5.81%)
    7 / 170 (4.12%)
    0 / 32 (0.00%)
         occurrences all number
    0
    11
    7
    0
    Upper respiratory tract infection
         subjects affected / exposed
    29 / 342 (8.48%)
    12 / 172 (6.98%)
    15 / 170 (8.82%)
    5 / 32 (15.63%)
         occurrences all number
    0
    17
    16
    5
    Urinary tract infection
         subjects affected / exposed
    21 / 342 (6.14%)
    11 / 172 (6.40%)
    7 / 170 (4.12%)
    3 / 32 (9.38%)
         occurrences all number
    0
    11
    9
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    69 / 342 (20.18%)
    24 / 172 (13.95%)
    44 / 170 (25.88%)
    2 / 32 (6.25%)
         occurrences all number
    0
    28
    53
    3
    Diabetes mellitus
         subjects affected / exposed
    3 / 342 (0.88%)
    1 / 172 (0.58%)
    0 / 170 (0.00%)
    2 / 32 (6.25%)
         occurrences all number
    0
    1
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    17 / 342 (4.97%)
    9 / 172 (5.23%)
    8 / 170 (4.71%)
    0 / 32 (0.00%)
         occurrences all number
    0
    11
    9
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 342 (0.88%)
    0 / 172 (0.00%)
    1 / 170 (0.59%)
    2 / 32 (6.25%)
         occurrences all number
    0
    0
    1
    3
    Hypokalaemia
         subjects affected / exposed
    27 / 342 (7.89%)
    11 / 172 (6.40%)
    15 / 170 (8.82%)
    1 / 32 (3.13%)
         occurrences all number
    0
    14
    20
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Nov 2009
    Logo updated to describe meaning of COMPLEMENT. Sponsor information page: Medical Monitor contact information updated. Addition of secondary endpoint: Overall response rate to optional ofatumumab monotherapy in subjects in Arm B who progress during or following single-agent bendamustine. Spelling correction in the Exclusion Criteria: fludaranine replaced by fludarabine and addition of criteria excluding prior treatment with anti-CD20 mAb within 3 months of randomization. Administered bendamustine therapy as monotherapy or in combination with ofatumumab for up to 8 cycles. There were a total of 12 ofatumumab infusions in Arm A. Ofatumumab was given on day 1 of each cycle of bendamustine as long as subjects in Arm A received bendamustine. Once subjects in Arm A completed bendamustine therapy, the remaining doses of ofatumumab were be given monthly until all 12 doses were completed.
    12 May 2010
    Introduction includes additional rationale for infusion of 1000 mg dose upon first infusion in and 2000 mg dose upon 2nd infusion (for those who receive ofatumumab following PD in Arm B) at protocol defined rate. Inclusion criterion #1 updated: Removed reference to bulky stage. Clarified screening procedures. Inclusion criterion #2 updated: to allow CT imaging performed at least 60 days after the last dose of rituximab-based therapy. Modified text for prior rituximab infusions. Exclusion criterion #3 updated timeframe from previous autologous stem cell transplant, or fludarabine therapy, or radioimmunotherapy from past 12 months to last 6 months. Exclusion criterion #5 updated timeframe for high dose steroids (7 consecutive days) and dose of prednisone before randomization (100 mg). Exclusion criterion #7 update to exclude prior use of any monoclonal antibody (other than anti- CD20) within 3 months of randomization and anti-CD20 therapy first dose was administered 60 days prior to randomization. Exclusion criteria #15 updated: specifies liver metastases related to indolent NHL. Exclusion criterion #18 updated to include hypersensitivity to bendamustine and mannitol. Removed exclusion criterion #20 since it duplicated criterion #7. Subjects in Arm B who chose to receive optional ofatumumab monotherapy received ofatumumab 1000 mg for the first dose. CT scans, lymphoma symptoms, and response assessments will be done Days 84, 168, and 252 (±7 days). Whole body CT scan (contrast imaging of neck when lesion is palpable, thorax, abdomen, pelvis). Rmoved mention of physical examination as part of CR assessment. Updated FACT-Lym Version 4, removed FACT-G Patient Reported Outcomes (PRO) questionnaire. HACA test done before first dose of ofatumumab.
    19 Jan 2012
    CT scans may be whole body or done according to local practice. No required bone marrow aspirate Known and exploratory prognostic markers and exploratory pharmacogenetic research objectives clarified. Inclusion Criterion #1: Type of previous biopsy changed from “lymph node” to “tissue” biopsy. Inclusion Criterion #1 clarified. Tumor verified to be CD20+ positive from a previous or current tissue biopsy. No longer excluded fludarabine and radioimmunotherapy. No longer excluded external beam radiation therapy to pelvis and to bony disease to the cranium, mediastinum, and axilla, or > 3 vertebral bodies. Removed Exclusion criterion restricting anti-CD20 antibody within the last 60 days. Copy of documentation confirming PD (for example, an imaging report, clinical documentation) after subject deemed unresponsive or relapsed to rituximab-based regimen was required. Follow-up visits begin 2 months after PD is confirmed by CT scan. For all other responses, follow-up visits begin on Day 336 (this is 3 months after Day 252) for both arms. Withdrawal Criteria: If a subject withdrew from study drug but did not withdraw from the study, the subject was expected to complete all scheduled visits without study drug. The subject may then enter follow-up.
    07 Feb 2013
    Edited text due to updates found in Investigator Brochure update. Correction in footnotes to Time and Events Table (Appendix 1): baseline CT scans required ≤1 month of randomization. Correct reference for Table updated. High dose steroids ≥ 25 mg prednisolone/day (or equivalent) for 7 consecutive days were excluded. Updated from excluding ≥ 100 mg prednisolone/day (or equivalent). All SAEs regardless of causality were reported from 61 days after the last dose of investigational product to the end of the follow-up period or until initiation of subsequent antilymphoma therapy is initiated. Any SAE brought to the investigator's attention after the start of subsequent anti-lymphoma therapy and considered by the investigator as possibly related to either ofatumumab or bendamustine were to be reported to GSK. Additional biochemistry testing added to time and events table for ofatumumab monotherapy following progression in Arm B. For Japan only: additional directions for Hepatitis monitoring added to an Appendix. Investigator Brochure reference updated.
    07 Feb 2013
    At the request of the French regulatory agency, safety related information from the Study Procedures Manual (SPM) was added.
    02 Dec 2013
    Added additional instructions for monitoring subjects who were HBsAg negative, anti-HBc positive and HBV DNA negative. This instruction was added to the relevant Time and Events tables. Exclusion criteria now specified that physician experienced in care and management of subjects with Hepatitis B manage/treat subjects who were anti-HBc positive must be consulted. Changes for countries using Amendment 4 included specific details on how to manage AEs and SAEs such as infusion reactions, tumor lysis syndrome, progressive multifocal leukoencephalopathy and hepatitis were described.
    07 Jul 2015
    Authors and Sponsor Contact Information Updated Table of Contents updated to include Appendix 15: Protocol Changes for Amendment #7 from Amendment #6. Total number of events increased to 259 events. Total study duration increased to 77 months. Total accrual rate decreased to 5.1pt/month. Clarification of randomization strategy. An Interim Analysis added for efficacy when two thirds of IRR events occurred. Details of a further Independent Data Monitoring Committee (IDMC) added to review the safety, efficacy, and futility data and recommended whether the study should continue without any changes, be stopped to further enrollment, or be terminated. Liver stopping criteria updated to reflect stopping criteria applies to all patients on study, regardless of Arm assignment. Clarification of instructions regarding how patients moved into Survival Follow-Up. Amendment Republished due to typographical error.
    18 Mar 2016
    The purpose of this protocol amendment was to: - Delete or replace references to GSK or its staff with that of Novartis and its authorized agents to align with the change of sponsorship - Make administrative changes to align with Novartis processes and procedures
    13 Apr 2017
    The purpose of amendment 9 was to revise the total number of events required for the primary analysis of the primary end point PFS. The primary analysis was planned after reaching 259 PFS events as determined by an Independent Review Committee (IRC). Based on the current status of the study and PFS event count by IRC, it was highly unlikely that the 259 PFS events wiould be achieved.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    For support, Contact us.
    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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