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    Clinical Trial Results:
    iNNOVATE Study: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Ibrutinib or Placebo in Combination with Rituximab in Subjects with Waldenstrom’s Macroglobulinemia

    Summary
    EudraCT number
    		 2013-005478-22
    Trial protocol
    		 IT   DE   ES   GR   GB  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    24 Feb 2019
    First version publication date
    24 Feb 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    PCYC-1127-CA
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02165397
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pharmacyclics
    Sponsor organisation address
    995 East Arques Avenue, Sunnyvale, United States, 94085-4521
    Public contact
    Medical Monitor, Pharmacyclics, Incorporated Lori Styles 995 East Arques Avenue Sunnyvale CA 94085-4521 US, 001 4082153770, lstyles@pcyc.com
    Scientific contact
    Medical Monitor, Pharmacyclics, Incorporated Lori Styles 995 East Arques Avenue Sunnyvale CA 94085-4521 US, 001 4082153770, lstyles@pcyc.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    17 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Oct 2017
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effect of the addition of ibrutinib to rituximab on progression-free survival (PFS) assessed by an independent review committee (IRC) in subjects with Waldenstrom`s Macroglobulinemia WM. Efficacy evaluations will be based on the modified Consensus Response Criteria from the VIth International Workshop for WM (NCCN 2014).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements, with the exception of the issues discussed in Section 4.4 of the CSR. These issues/non-conformances did not have an impact on the overall conclusions of this study
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jul 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Greece: 29
    Country: Number of subjects enrolled
    Italy: 25
    Country: Number of subjects enrolled
    United States: 26
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    Australia: 27
    Worldwide total number of subjects
    181
    EEA total number of subjects
    110
    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)
    72
    From 65 to 84 years
    99
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 Multi-center, randomized in 1:1 ibrutinib and rituximab or placebo and rituximab. Phase 3 study conducted at a total of 48 sites, 10 sites in the US, 30 sites in Europe, 4 sites in Canada and 4 sites in Australia

    Pre-assignment
    Screening details
    		 Eligible subjects were ≥ 18 years of age with untreated WM or previously treated WM.During the screening phase, the subjects’ eligibility was to be determined. Eligible subjects must have had clinicopathological diagnosis of WM confirmed by central pathology review and in accordance with the consensus panel of the Second IWWM.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Double-blind study: subjects, investigators, and the Sponsor’s study team members were blinded to treatment assignment. Data that could potentially unblind the treatment assignment (ie, study drug plasma concentrations) was to be handled with special care to ensure that the integrity of the blind was maintained and the potential for bias minimized. This included making special provisions, such as segregating the data in question from view by the investigators and the team involved in the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ibrutinib and Rituximab
    Arm description
    		 subjects who received ibrutinib and rituximab in combination
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Rituximab 375 mg/m2 IV was administered per package insert instructions weekly for 4 consecutive weeks, followed by a second 4-week rituximab course after a 3-month interval (Day 1 of Weeks 1-4 and Weeks 17-20 (total of 8 infusions of rituximab).

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered daily at a dose of 420 mg (3 capsules of 140 mg) until progression, discontinuation due to toxicity or other reasons to discontinue treatment.

    Arm title
    		 Placebo and Rituximab
    Arm description
    		 Subjects receiving placebo and rituximab in combination.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Rituximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intravenous drip use
    Dosage and administration details
    Rituximab 375 mg/m2 IV was administered per package insert instructions weekly for 4 consecutive weeks, followed by a second 4-week rituximab course after a 3-month interval (Day 1 of Weeks 1-4 and Weeks 17-20 (total of 8 infusions of rituximab).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as capsules identical to ibrutinib until progression, discontinuation due to toxicity or other reasons for discontinuation of treatment.

    Arm title
    		 Open-label ritux refractory arm
    Arm description
    		 Subject in this arm were treated with ibrutinib 420 mg monotherapy in an open-labeled substudy independently of the 2 randomized main treatment arm (R+I and R+P)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Ibrutinib was administered daily at a dose of 420 mg (3 capsules of 140 mg) until disease progression, discontinuation due to toxicity or other reasons to discontinue treatment.

    Number of subjects in period 1
    		Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm
    Started
    75
    75
    31
    Completed
    13
    42
    12
    Not completed
    62
    33
    19
         Consent withdrawn by subject
    6
    7
    2
         treatment ongoing
    56
    26
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ibrutinib and Rituximab
    Reporting group description
    		 subjects who received ibrutinib and rituximab in combination

    Reporting group title
    Placebo and Rituximab
    Reporting group description
    		 Subjects receiving placebo and rituximab in combination.

    Reporting group title
    Open-label ritux refractory arm
    Reporting group description
    		 Subject in this arm were treated with ibrutinib 420 mg monotherapy in an open-labeled substudy independently of the 2 randomized main treatment arm (R+I and R+P)

    Reporting group values
    		 Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm Total
    Number of subjects
    		 75 75 31 181
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 28 30 14 72
        From 65-84 years
    		 42 43 14 99
        85 years and over
    		 5 2 3 10
    Age continuous
    Mean age of subjects incl. standard deviation
    Units: years
        arithmetic mean (standard deviation)
    		 69.2 ( 10.90 ) 66.1 ( 11.10 ) 66.4 ( 10.76 ) -
    Gender categorical
    Units: Subjects
        Female
    		 30 21 11 62
        Male
    		 45 54 20 119

    End points

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    End points reporting groups
    Reporting group title
    Ibrutinib and Rituximab
    Reporting group description
    		 subjects who received ibrutinib and rituximab in combination

    Reporting group title
    Placebo and Rituximab
    Reporting group description
    		 Subjects receiving placebo and rituximab in combination.

    Reporting group title
    Open-label ritux refractory arm
    Reporting group description
    		 Subject in this arm were treated with ibrutinib 420 mg monotherapy in an open-labeled substudy independently of the 2 randomized main treatment arm (R+I and R+P)

    Primary: Progression free survival (30 month landmark)

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    End point title
    		 Progression free survival (30 month landmark)
    End point description
    KM point estimates of the PFS rate per IRC assessment at 30 months. PFS is defined as time from the date of randomization to the date of first IRC-confirmed disease progression (PD) or date of death due to any cause, whichever occurs first, regardless of the use of subsequent antineoplastic therapy prior to documented PD or death. As the median PFS was not reached in the Ibr+R and the open-label ritux refractory arm (20.3 months in the Pbo+R arm), PFS rates at 30 months are presented.
    End point type
    Primary
    End point timeframe
    Results at a median time on study of 26.5 months for Ibr+R and Pbo+R and 34.4 months for the open-label ritux refractory arm.
    End point values
    		 Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm
    Number of subjects analysed
    75
    75
    31
    Units: percentage
        number (confidence interval 95%)
    81.6 (70.5 to 88.9)
    27.5 (12.8 to 44.4)
    57.5 (38.2 to 72.7)
    Statistical analysis title
    		 Progression free survival (PFS)
    Statistical analysis description
    The treatment effect was tested with a stratified log rank test. The hazard ratio and its 95% confidence interval were based on a Cox regression model stratified by the randomization stratification factors.
    Comparison groups
    Ibrutinib and Rituximab v Placebo and Rituximab
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.202
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.107
         upper limit
    		 0.38

    Secondary: Response rate (CR, VGPR, PR)

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    End point title
    		 Response rate (CR, VGPR, PR)
    End point description
    Response rate is defined as proportion of subjects achieving a best overall response of confirmed CR, VGPR, or PR per the IRC assessment.
    End point type
    Secondary
    End point timeframe
    Response rate at a median time on study of 26.5 months for Ibr+R and Pbo+R and 34.4 months for the open-label ritux refractory arm
    End point values
    		 Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm
    Number of subjects analysed
    75
    75
    31
    Units: percentage
        number (not applicable)
    72
    32
    71
    Statistical analysis title
    		 Response Rate
    Statistical analysis description
    Response rate was compared using Cochran-Mantel-Haenszel (CMH) chi-square test.
    Comparison groups
    Ibrutinib and Rituximab v Placebo and Rituximab
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Rate ratio
    Point estimate
    2.299
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.592
         upper limit
    		 3.319

    Secondary: Time to next treatment (30 month landmark)

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    End point title
    		 Time to next treatment (30 month landmark)
    End point description
    TTnT is defined as time from the date of randomization to the start date of any subsequent WM treatment. As the median TTnT was not reached in the Ibr+R and the open-label ritux refractory arm (18.1 months in the Pbo+R arm), TTnT rates at 30 months are presented.
    End point type
    Secondary
    End point timeframe
    Results at a median time on study of 26.5 months for Ibr+R and Pbo+R and 34.4 months for the open-label ritux refractory arm.
    End point values
    		 Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm
    Number of subjects analysed
    75
    75
    31
    Units: percentage
        number (confidence interval 95%)
    91.5 (82.0 to 96.1)
    41.4 (29.1 to 53.3)
    82.9 (63.7 to 92.5)
    Statistical analysis title
    		 Time to next treatment (TTnT)
    Comparison groups
    Ibrutinib and Rituximab v Placebo and Rituximab
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.096
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.04
         upper limit
    		 0.227

    Secondary: Sustained improvement in hemoglobin

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    End point title
    		 Sustained improvement in hemoglobin
    End point description
    Sustained hemoglobin improvement is defined as hemoglobin improvement that sustained continuously for ≥ 56 days without blood transfusion or growth factors which includes hemoglobin > 110 g/L with at least a 5 g/L improvement if baseline ≤ 110 g/L or increase ≥ 20 g/L over baseline.
    End point type
    Secondary
    End point timeframe
    Sustained improvement in hemoglobin at a median time on study of 26.5 months for Ibr+R and Pbo+R and 34.4 months for the open-label ritux refractory arm
    End point values
    		 Ibrutinib and Rituximab Placebo and Rituximab Open-label ritux refractory arm
    Number of subjects analysed
    75
    75
    31
    Units: percent
        number (not applicable)
    73.3
    41.3
    71.0
    Statistical analysis title
    		 Sustained improvement in hemoglobin
    Comparison groups
    Ibrutinib and Rituximab v Placebo and Rituximab
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Chi-squared
    Parameter type
    		 Rate ratio
    Point estimate
    1.774
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.311
         upper limit
    		 2.4

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 30 days after the last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    ibrutinib and rituximab
    Reporting group description
    		 subjects who received ibrutinib and rituximab in combination

    Reporting group title
    Placebo and Rituximab
    Reporting group description
    		 subjects who received placebo and rituximab in combination

    Reporting group title
    Open-label ritux refractory arm
    Reporting group description
    		 Subject in this arm were treated with ibrutinib 420 mg monotherapy in an open-labeled substudy independently of the 2 randomized main treatment arm (R+I and R+P)

    Serious adverse events
    		 ibrutinib and rituximab Placebo and Rituximab Open-label ritux refractory arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 75 (42.67%)
    25 / 75 (33.33%)
    11 / 31 (35.48%)
         number of deaths (all causes)
    0
    3
    0
         number of deaths resulting from adverse events
    0
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Breast mass
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopneumopathy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 75 (0.00%)
    5 / 75 (6.67%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    9 / 31 (29.03%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune thrombocytopenic purpura
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Ulcerative keratitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecalith
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psoriatic arthropathy
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Synovial cyst
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendonitis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 75 (8.00%)
    2 / 75 (2.67%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 75 (0.00%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ibrutinib and rituximab Placebo and Rituximab Open-label ritux refractory arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 75 (100.00%)
    73 / 75 (97.33%)
    30 / 31 (96.77%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour flare
         subjects affected / exposed
    6 / 75 (8.00%)
    35 / 75 (46.67%)
    0 / 31 (0.00%)
         occurrences all number
    7
    50
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    13 / 75 (17.33%)
    3 / 75 (4.00%)
    7 / 31 (22.58%)
         occurrences all number
    21
    4
    10
    Hypotension
         subjects affected / exposed
    1 / 75 (1.33%)
    3 / 75 (4.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    3
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    13 / 75 (17.33%)
    9 / 75 (12.00%)
    5 / 31 (16.13%)
         occurrences all number
    17
    12
    8
    Asthenia
         subjects affected / exposed
    12 / 75 (16.00%)
    19 / 75 (25.33%)
    4 / 31 (12.90%)
         occurrences all number
    13
    26
    5
    Fatigue
         subjects affected / exposed
    10 / 75 (13.33%)
    20 / 75 (26.67%)
    5 / 31 (16.13%)
         occurrences all number
    20
    27
    7
    Pyrexia
         subjects affected / exposed
    10 / 75 (13.33%)
    12 / 75 (16.00%)
    7 / 31 (22.58%)
         occurrences all number
    11
    18
    9
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    13 / 75 (17.33%)
    8 / 75 (10.67%)
    4 / 31 (12.90%)
         occurrences all number
    19
    9
    4
    Dyspnoea
         subjects affected / exposed
    7 / 75 (9.33%)
    10 / 75 (13.33%)
    2 / 31 (6.45%)
         occurrences all number
    8
    13
    4
    Epistaxis
         subjects affected / exposed
    7 / 75 (9.33%)
    5 / 75 (6.67%)
    3 / 31 (9.68%)
         occurrences all number
    8
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 75 (6.67%)
    1 / 31 (3.23%)
         occurrences all number
    4
    5
    1
    Productive cough
         subjects affected / exposed
    3 / 75 (4.00%)
    4 / 75 (5.33%)
    1 / 31 (3.23%)
         occurrences all number
    3
    7
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    3
    2
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 75 (10.67%)
    3 / 75 (4.00%)
    2 / 31 (6.45%)
         occurrences all number
    9
    3
    2
    Depression
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 75 (1.33%)
    3 / 75 (4.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    2
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    32 / 75 (42.67%)
    43 / 75 (57.33%)
    0 / 31 (0.00%)
         occurrences all number
    60
    122
    0
    Contusion
         subjects affected / exposed
    6 / 75 (8.00%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences all number
    7
    2
    1
    Traumatic haematoma
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Fall
         subjects affected / exposed
    2 / 75 (2.67%)
    3 / 75 (4.00%)
    3 / 31 (9.68%)
         occurrences all number
    2
    4
    4
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    10 / 75 (13.33%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences all number
    15
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 75 (13.33%)
    17 / 75 (22.67%)
    5 / 31 (16.13%)
         occurrences all number
    14
    18
    6
    Dizziness
         subjects affected / exposed
    8 / 75 (10.67%)
    5 / 75 (6.67%)
    3 / 31 (9.68%)
         occurrences all number
    8
    5
    3
    Dysgeusia
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences all number
    4
    1
    1
    Paraesthesia
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 75 (5.33%)
    2 / 31 (6.45%)
         occurrences all number
    4
    4
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 75 (5.33%)
    2 / 31 (6.45%)
         occurrences all number
    5
    5
    2
    Sciatica
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 75 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    4
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    13 / 75 (17.33%)
    22 / 75 (29.33%)
    4 / 31 (12.90%)
         occurrences all number
    18
    40
    4
    Neutropenia
         subjects affected / exposed
    10 / 75 (13.33%)
    7 / 75 (9.33%)
    9 / 31 (29.03%)
         occurrences all number
    15
    7
    14
    Increased tendency to bruise
         subjects affected / exposed
    7 / 75 (9.33%)
    2 / 75 (2.67%)
    7 / 31 (22.58%)
         occurrences all number
    7
    2
    7
    Thrombocytopenia
         subjects affected / exposed
    4 / 75 (5.33%)
    8 / 75 (10.67%)
    6 / 31 (19.35%)
         occurrences all number
    5
    17
    12
    Spontaneous haematoma
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    6
    0
    2
    Lymphadenopathy
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 75 (0.00%)
    3 / 75 (4.00%)
    4 / 31 (12.90%)
         occurrences all number
    0
    3
    4
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    6 / 75 (8.00%)
    3 / 75 (4.00%)
    0 / 31 (0.00%)
         occurrences all number
    7
    3
    0
    Cataract
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 75 (1.33%)
    4 / 31 (12.90%)
         occurrences all number
    5
    1
    4
    Eye irritation
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences all number
    5
    1
    0
    Dry eye
         subjects affected / exposed
    4 / 75 (5.33%)
    5 / 75 (6.67%)
    2 / 31 (6.45%)
         occurrences all number
    5
    7
    2
    Lacrimation increased
         subjects affected / exposed
    4 / 75 (5.33%)
    3 / 75 (4.00%)
    1 / 31 (3.23%)
         occurrences all number
    4
    4
    1
    Photophobia
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 75 (2.67%)
    0 / 31 (0.00%)
         occurrences all number
    4
    2
    0
    Vision blurred
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    5
    3
    2
    Diplopia
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    0
    2
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    21 / 75 (28.00%)
    11 / 75 (14.67%)
    12 / 31 (38.71%)
         occurrences all number
    26
    13
    20
    Nausea
         subjects affected / exposed
    16 / 75 (21.33%)
    9 / 75 (12.00%)
    7 / 31 (22.58%)
         occurrences all number
    20
    14
    8
    Dyspepsia
         subjects affected / exposed
    12 / 75 (16.00%)
    1 / 75 (1.33%)
    2 / 31 (6.45%)
         occurrences all number
    13
    1
    2
    Constipation
         subjects affected / exposed
    9 / 75 (12.00%)
    8 / 75 (10.67%)
    5 / 31 (16.13%)
         occurrences all number
    11
    11
    10
    Abdominal pain upper
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 75 (2.67%)
    1 / 31 (3.23%)
         occurrences all number
    9
    2
    1
    Dry mouth
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    4
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 75 (2.67%)
    8 / 75 (10.67%)
    1 / 31 (3.23%)
         occurrences all number
    5
    10
    1
    Abdominal pain
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 75 (2.67%)
    3 / 31 (9.68%)
         occurrences all number
    3
    2
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 75 (1.33%)
    3 / 31 (9.68%)
         occurrences all number
    2
    1
    3
    Abdominal discomfort
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    4
    Abdominal distension
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    2
    Gingival bleeding
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    2
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    8 / 75 (10.67%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    10
    0
    0
    Petechiae
         subjects affected / exposed
    7 / 75 (9.33%)
    0 / 75 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    8
    0
    4
    Pruritus
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 75 (5.33%)
    2 / 31 (6.45%)
         occurrences all number
    6
    4
    2
    Rash erythematous
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    4
    4
    2
    Rash maculo-papular
         subjects affected / exposed
    3 / 75 (4.00%)
    3 / 75 (4.00%)
    2 / 31 (6.45%)
         occurrences all number
    3
    4
    6
    Dry skin
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    4 / 31 (12.90%)
         occurrences all number
    2
    0
    4
    Actinic keratosis
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 75 (1.33%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    4
    Onychoclasis
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    1
    0
    3
    Onycholysis
         subjects affected / exposed
    0 / 75 (0.00%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    0
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 75 (4.00%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    3
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 75 (22.67%)
    8 / 75 (10.67%)
    5 / 31 (16.13%)
         occurrences all number
    24
    9
    9
    Muscle spasms
         subjects affected / exposed
    13 / 75 (17.33%)
    9 / 75 (12.00%)
    5 / 31 (16.13%)
         occurrences all number
    19
    10
    6
    Pain in extremity
         subjects affected / exposed
    9 / 75 (12.00%)
    5 / 75 (6.67%)
    4 / 31 (12.90%)
         occurrences all number
    10
    5
    4
    Back pain
         subjects affected / exposed
    8 / 75 (10.67%)
    6 / 75 (8.00%)
    8 / 31 (25.81%)
         occurrences all number
    11
    6
    12
    Myalgia
         subjects affected / exposed
    5 / 75 (6.67%)
    3 / 75 (4.00%)
    2 / 31 (6.45%)
         occurrences all number
    8
    8
    2
    Osteoarthritis
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 75 (1.33%)
    0 / 31 (0.00%)
         occurrences all number
    5
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 75 (2.67%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    2
    0
    2
    Muscular weakness
         subjects affected / exposed
    1 / 75 (1.33%)
    1 / 75 (1.33%)
    2 / 31 (6.45%)
         occurrences all number
    2
    1
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    10 / 75 (13.33%)
    0 / 75 (0.00%)
    3 / 31 (9.68%)
         occurrences all number
    16
    0
    5
    Bronchitis
         subjects affected / exposed
    9 / 75 (12.00%)
    5 / 75 (6.67%)
    3 / 31 (9.68%)
         occurrences all number
    11
    8
    4
    Influenza
         subjects affected / exposed
    9 / 75 (12.00%)
    5 / 75 (6.67%)
    2 / 31 (6.45%)
         occurrences all number
    9
    5
    2
    Viral upper respiratory tract infection
         subjects affected / exposed
    8 / 75 (10.67%)
    5 / 75 (6.67%)
    2 / 31 (6.45%)
         occurrences all number
    11
    7
    2
    Upper respiratory tract infection
         subjects affected / exposed
    6 / 75 (8.00%)
    3 / 75 (4.00%)
    6 / 31 (19.35%)
         occurrences all number
    9
    6
    15
    Herpes zoster
         subjects affected / exposed
    5 / 75 (6.67%)
    1 / 75 (1.33%)
    2 / 31 (6.45%)
         occurrences all number
    6
    1
    2
    Oral herpes
         subjects affected / exposed
    4 / 75 (5.33%)
    0 / 75 (0.00%)
    0 / 31 (0.00%)
         occurrences all number
    5
    0
    0
    Pneumonia
         subjects affected / exposed
    4 / 75 (5.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    5
    2
    3
    Rhinitis
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences all number
    4
    3
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 75 (4.00%)
    2 / 75 (2.67%)
    5 / 31 (16.13%)
         occurrences all number
    4
    3
    7
    Cellulitis
         subjects affected / exposed
    2 / 75 (2.67%)
    1 / 75 (1.33%)
    3 / 31 (9.68%)
         occurrences all number
    2
    1
    3
    Conjunctivitis
         subjects affected / exposed
    2 / 75 (2.67%)
    3 / 75 (4.00%)
    4 / 31 (12.90%)
         occurrences all number
    2
    4
    5
    Paronychia
         subjects affected / exposed
    1 / 75 (1.33%)
    0 / 75 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    1
    0
    2
    Sinusitis
         subjects affected / exposed
    1 / 75 (1.33%)
    2 / 75 (2.67%)
    2 / 31 (6.45%)
         occurrences all number
    1
    3
    2
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    8 / 75 (10.67%)
    1 / 75 (1.33%)
    2 / 31 (6.45%)
         occurrences all number
    11
    2
    2
    Gout
         subjects affected / exposed
    4 / 75 (5.33%)
    1 / 75 (1.33%)
    1 / 31 (3.23%)
         occurrences all number
    5
    1
    1
    Hyperuricaemia
         subjects affected / exposed
    4 / 75 (5.33%)
    4 / 75 (5.33%)
    2 / 31 (6.45%)
         occurrences all number
    5
    4
    2
    Decreased appetite
         subjects affected / exposed
    1 / 75 (1.33%)
    7 / 75 (9.33%)
    3 / 31 (9.68%)
         occurrences all number
    1
    7
    3

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Mar 2014
    Added open-label substudy treatment arm for subjects refractory to the last prior rituximab-containing therapy in alignment with the scientific advice received from the European Medicines Agency (subjects not suitable for Ibr+R or Pbo+R treatment in the randomized study may be enrolled into the substudy to received single-agent ibrutinib), with efficacy and safety to be descriptively summarized and analyzed separately from the randomized treatment arms. • Revised inclusion criteria to allow ECOG PS status of 2. • Changed a randomization factor from prior rituximab exposure (yes vs. no) to ECOG PS (0-1 vs. 2) to ensure treatment balance for subjects with ECOG PS of 2. • Changed FACT-An from a secondary to an exploratory objective.
    09 Feb 2015
    • Allowed inclusion of subjects with untreated WM. • Updated the number of prior systemic treatment regimens for stratification from 1-2 vs. ≥3 to 0 vs. 1-2 vs. ≥3 to maintain balance between the 2 randomized treatment arms with regard to the addition of previously untreated subjects. • Revised the O’Brien-Fleming boundary from 60% (~42 PFS events) to 70% (~50 PFS events) for the interim analysis for the randomized arms. • Added new or additional guidance or information on the use of anticoagulants, antiplatelets, prednisone or equivalent, P-glycoprotein substrates, dose modifications for subjects with hepatic impairment, and major hemorrhage.
    09 Oct 2015
    • Updated enrollment criteria to allow for the inclusion of subjects with abnormal coagulation results unrelated to coagulopathy or bleeding disorders due to interfering substances. • Clarified enrollment criteria abstinence language. • Updated enrollment criteria for next-line ibrutinib therapy to allow involvement of CNS by WM. • Added planned subgroup analyses to be conducted for the PFS primary efficacy endpoint. • Updated risk sections and CYP3A section to align with current version of IB.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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