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    Clinical Trial Results:
    A Randomized, Controlled, Open-Label, Multicenter Phase 3 Study of the Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib, versus Temsirolimus in Subjects with Relapsed or Refractory Mantle Cell Lymphoma Who Have Received at Least One Prior Therapy

    Summary
    EudraCT number
    		 2012-000601-74
    Trial protocol
    		 SE   BE   DE   GB   IE   HU   PT   CZ   NL   ES   IT  
    Global end of trial date
    15 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Dec 2017
    First version publication date
    31 Dec 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PCI-32765MCL3001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01646021
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen-Cilag International NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, B-2340
    Public contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen-Cilag International NV, ClinicalTrialsEU@its.jnj.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
    15 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate whether treatment with ibrutinib compared with temsirolimus would result in prolongation of progression-free survival (PFS) in subjects with relapsed or refractory mantle cell lymphoma (MCL) who have received at least 1 prior rituximab-containing chemotherapy regimen.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included monitoring of adverse events, clinical laboratory tests, physical examinations, Eastern Cooperative Oncology Group (ECOG) criteria for performance status, and concomitant medication usage.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Dec 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    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
    Belgium: 17
    Country: Number of subjects enrolled
    Brazil: 15
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Colombia: 7
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Germany: 23
    Country: Number of subjects enrolled
    Spain: 19
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    United Kingdom: 27
    Country: Number of subjects enrolled
    Hungary: 12
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 14
    Country: Number of subjects enrolled
    Korea, Republic of: 14
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Russian Federation: 29
    Country: Number of subjects enrolled
    Sweden: 18
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    Ukraine: 10
    Worldwide total number of subjects
    280
    EEA total number of subjects
    188
    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)
    107
    From 65 to 84 years
    170
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 280 subjects were enrolled in this study. 139 subjects were randomized and treated in the ibrutinib arm. 141 subjects were randomized to the temsirolimus arm and 139 were treated, 2 subjects were randomized but did not receive treatment.

    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
    		 Treatment Arm A: Ibrutinib
    Arm description
    		 Subjects received 560 milligram (mg) ibrutinib (4*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment during the 21 day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ibrutinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 560 mg ibrutinib (4*140 mg capsules) once daily continuously during the 21-day cycle.

    Arm title
    		 Treatment Arm B: Temsirolimus
    Arm description
    		 Subjects received temsirolimus intravenous (IV) infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Each temsirolimus dose is infused over a 30 to 60 minute period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Temsirolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received temsirolimus intravenous infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle.

    Number of subjects in period 1
    		Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Started
    139
    141
    Treated
    139
    139
    Completed
    0
    0
    Not completed
    139
    141
         Consent withdrawn by subject
    10
    15
         Death
    77
    83
         Study terminated by sponsor
    50
    41
         Lost to follow-up
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Arm A: Ibrutinib
    Reporting group description
    		 Subjects received 560 milligram (mg) ibrutinib (4*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment during the 21 day cycle.

    Reporting group title
    Treatment Arm B: Temsirolimus
    Reporting group description
    		 Subjects received temsirolimus intravenous (IV) infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Each temsirolimus dose is infused over a 30 to 60 minute period.

    Reporting group values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus Total
    Number of subjects
    		 139 141 280
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    		 53 54 107
        From 65 to 84 years
    		 86 84 170
        85 years and over
    		 0 3 3
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.7 ( 8.68 ) 67.1 ( 9.83 ) -
    Title for Gender
    Units: subjects
        Female
    		 39 33 72
        Male
    		 100 108 208

    End points

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    End points reporting groups
    Reporting group title
    Treatment Arm A: Ibrutinib
    Reporting group description
    		 Subjects received 560 milligram (mg) ibrutinib (4*140-mg capsules) by mouth once daily continuous (without interruption) self-administered home treatment during the 21 day cycle.

    Reporting group title
    Treatment Arm B: Temsirolimus
    Reporting group description
    		 Subjects received temsirolimus intravenous (IV) infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Each temsirolimus dose is infused over a 30 to 60 minute period.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS is defined as the duration in months from the date of randomization to the date of progression disease (PD) or relapse from complete response (CR) or death whichever was reported first and was assessed based on the investigator assessment. Revised Response Criteria for Malignant Lymphoma categorizes the response of the treatment of a patient's tumour to CR (the disappearance of all evidence of disease), Relapsed Disease or PD (Any new lesion or increase by greater than or equal to [>=] 50 percent [%] of previously involved sites from nadir). The Intent-to-Treat (ITT) population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Primary
    End point timeframe
    Time from the date of randomization until the date of first documented evidence of progressive disease (or relapse for subjects who experience CR during the study) or death, whichever occurred first (approximately 48 months)
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Months
        median (confidence interval 95%)
    15.6 (10.6 to 25.1)
    6.2 (4.2 to 7.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Treatment Arm A: Ibrutinib v Treatment Arm B: Temsirolimus
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.35
         upper limit
    		 0.6

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR is defined as the percentage of participants who achieved either CR or PR as best overall response based on the investigator assessment where CR is defined as disappearance of all target lesions, PR is defined as greater than or equal to 30 % decrease in the sum of the longest diameter of target lesions and Overall Response (OR) is the sum of CR and PR. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Approximately 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Percentage of Subjects
        number (not applicable)
    77.0
    46.8
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response was defined as the interval between the date of initial documentation of a response and the date of the first documented evidence of progressive disease or death, whichever event occurred first. The analysis was based on the investigator assessment. The ITT population included all subjects randomized into the study regardless of treatment actually received. Here 'N' signifies number of subjects analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Approximately 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    107
    66
    Units: Months
        median (confidence interval 95%)
    23.1 (16.2 to 28.1)
    6.3 (4.7 to 8.6)
    No statistical analyses for this end point

    Secondary: Time to Next Treatment (TTNT)

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    End point title
    		 Time to Next Treatment (TTNT)
    End point description
    Time to next treatment was measured from the date of randomization to the start date of any anti-neoplastic treatment subsequent to study treatment. Here, for Upper 95% CI '99999' indicates median TTNT that was not estimable at primary analysis due to in less than 50% patients event had occurred. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Approximately 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Months
        median (confidence interval 95%)
    31.8 (23.3 to 99999)
    11.6 (8.0 to 13.3)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival (OS) was defined as the interval between the date of randomization and the date of death from any cause. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Approximately 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Months
        median (confidence interval 95%)
    30.3 (19.1 to 42.1)
    23.5 (13.0 to 30.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Treatment Arm A: Ibrutinib v Treatment Arm B: Temsirolimus
    Number of subjects included in analysis
    280
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0621
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.54
         upper limit
    		 1.02

    Secondary: Progression-Free Survival 2

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    End point title
    		 Progression-Free Survival 2
    End point description
    Progression-free survival 2 defined as the time interval between the date of randomization and date of event, defined as progressive disease as assessed by investigator that started after the next line of subsequent antineoplastic therapy (including cross-over to ibrutinib), death from any cause, or the start of the second subsequent antineoplastic therapy if no progressive disease was recorded after the first subsequent antineoplastic therapy. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Approximately 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Months
        median (confidence interval 95%)
    26.2 (17.2 to 32.4)
    15.4 (10.2 to 21.3)
    No statistical analyses for this end point

    Secondary: Time to Worsening in the Lymphoma Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)

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    End point title
    		 Time to Worsening in the Lymphoma Subscale of the Functional Assessment of Cancer Therapy-Lymphoma (FACT-Lym)
    End point description
    Time to worsening in the Lym subscale of the FACT-Lym, defined as the interval from the date of randomization to the start date of worsening. Worsening was defined by a 5-point decrease from baseline. The FACT-Lym PRO questionnaires were administered to assess functional status and well-being and lymphoma symptoms over time. FACT-Lym Lymphoma subscale contains 15 questions, scores from 0 to 4 for each question (higher the worse). Lymphoma subscale score is the total of reverse scores, range 0 to 60. Here, 99999 indicates median and upper limit of CI of FACT-Lym that was not estimable at final analysis due to less than 50% patients had events occurred. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Secondary
    End point timeframe
    Approximately up to 48 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Weeks
        median (confidence interval 95%)
    99999 (81.4 to 99999)
    10.6 (6.6 to 15.3)
    No statistical analyses for this end point

    Secondary: Number of Subjects Affected With Treatment-emergent Adverse Events

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    End point title
    		 Number of Subjects Affected With Treatment-emergent Adverse Events
    End point description
    An AE is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all randomized subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Time from first dose of study drug until the last dose date + 30 days or the start of a subsequent anti-neoplastic therapy, whichever occur earlier
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    139
    Units: Subjects
    139
    138
    No statistical analyses for this end point

    Other pre-specified: Time to Response

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    End point title
    		 Time to Response
    End point description
    Time to response for subjects with CR/PR, defined as the interval between the date of randomization and date of initial documentation of response. The Intent ­to ­Treat population included all subjects randomized into the study. The 'N' signifies the number of subjects responded for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Approximately 2.8 years
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    100
    57
    Units: Months
        median (full range (min-max))
    2.15 (0.5 to 10.4)
    2.14 (0.9 to 12.0)
    No statistical analyses for this end point

    Other pre-specified: Extent of Exposure of Time

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    End point title
    		 Extent of Exposure of Time
    End point description
    Extent of exposure is defined as the duration of the treatment administered during the study. Duration of exposure is calculated as the number of months between the start and end of treatment. Safety Analysis Set (SAS) population includes all the randomized subjects who received at least 1 dose of study agent (ibrutinib or temsirolimus) during the treatment phase.
    End point type
    Other pre-specified
    End point timeframe
    Approximately up to 46.8 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    139
    Units: Months
        median (full range (min-max))
    14.39 (0.0 to 46.8)
    3.02 (0.0 to 31.4)
    No statistical analyses for this end point

    Other pre-specified: Area Under the Plasma Concentration of Ibrutinib during Steady State (AUC-ss)

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    End point title
    		 Area Under the Plasma Concentration of Ibrutinib during Steady State (AUC-ss) [1]
    End point description
    The AUC-ss is the area under the plasma concentration time curve observed during steady state. The pharmacokinetics population was included in the study.
    End point type
    Other pre-specified
    End point timeframe
    Cycle 1 and 2 (Day 1): Predose, 1, 2, 4 hr postdose; Cycle 3 (day 1): Predose
    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: Endpoint was planned to be reported for the specified arms only.
    End point values
    		 Treatment Arm A: Ibrutinib
    Number of subjects analysed
    139
    Units: nanogram*hour per milliliter (ng*h/mL)
        arithmetic mean (standard deviation)
    561.6 ( 448 )
    No statistical analyses for this end point

    Other pre-specified: Number of Subjects With Bio markers That Alter B-cell Receptor (BCR) signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib

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    End point title
    		 Number of Subjects With Bio markers That Alter B-cell Receptor (BCR) signaling or Activate Alternative Signaling Pathways and to Explore Their Association With Response or Resistance to Ibrutinib
    End point description
    Next-generation sequencing at baseline identifies possible primary resistance mutations and those found only at progression are acquired mutations on therapy.
    End point type
    Other pre-specified
    End point timeframe
    Approximately up to 28.2 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Subjects
        number (not applicable)
    61
    53
    No statistical analyses for this end point

    Other pre-specified: Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI)

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    End point title
    		 Number of Hospitalizations Reported Related Medical Resource Utilization Information (MRUI)
    End point description
    Medical resource utilization data associated with medical encounters related to disease was reported for all subjects throughout the study. The Intent-­to ­Treat population included subjects randomized into the study. The 'N' signifies the number of subjects responded for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Approximately up to 28.2 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    83
    91
    Units: Hospitalizations
        arithmetic mean (standard deviation)
    3.1 ( 4.6 )
    2.8 ( 4.3 )
    No statistical analyses for this end point

    Other pre-specified: Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)

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    End point title
    		 Number of Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
    End point description
    Medical resource utilization data associated with medical encounters related to disease was reported for all subjects throughout the study. The Intent-to--Treat population included subjects randomized into the study. The 'N' signifies the number of subjects responded for this outcome measure.
    End point type
    Other pre-specified
    End point timeframe
    Approximately up to 28.2 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    5
    5
    Units: Emergency room visits
        arithmetic mean (standard deviation)
    1.2 ( 0.4 )
    1.2 ( 0.4 )
    No statistical analyses for this end point

    Other pre-specified: Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)

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    End point title
    		 Days of Hospitalization and Emergency Room Visits Reported Related Medical Resource Utilization Information (MRUI)
    End point description
    Medical resource utilization data associated with medical encounters related to disease was reported for all subjects throughout the study. The Intent-­to-­Treat population included subjects randomized into the study. The 'n' signifies the number of subjects analyzed at this time point.
    End point type
    Other pre-specified
    End point timeframe
    Approximately up to 28.2 months
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    139
    141
    Units: Days
    arithmetic mean (standard deviation)
        Mean days of hospitalization (n=83, 91)
    19.7 ( 20.5 )
    20.3 ( 22.4 )
        Mean days of emergency room visits (n=5, 5)
    1.8 ( 1.3 )
    1.6 ( 1.3 )
    No statistical analyses for this end point

    Other pre-specified: The Mean Change From Baseline in the EuroQol-5 Dimension 5-Level Instrument (EQ-5D-5L) Scores for Each Post Baseline Assessment

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    End point title
    		 The Mean Change From Baseline in the EuroQol-5 Dimension 5-Level Instrument (EQ-5D-5L) Scores for Each Post Baseline Assessment
    End point description
    The EQ-5D is a subject rated questionnaire to assess health-related quality of life in terms of a single utility score. Health State Profile component assesses level of current health for 5 domains: mobility, self-care, usual activities, pain and discomfort, and anxiety and depression, using 5 levels (1=no problems, 2=slight problems, 3=moderate problems, 4=severe problems, and 5=extreme problems). Scoring formula developed by EuroQol Group assigns a utility value for each domain in the profile. Score is transformed and possible total score range -0.594 to 1; higher score indicates a better health state. Here, number of subjects analyzed ‘N’ signifies number of subjects evaluable for this endpoint. 'n' signifies the number of subjects analyzed at specified time point. The ITT population included all subjects randomized into the study regardless of treatment actually received.
    End point type
    Other pre-specified
    End point timeframe
    Baseline, Cycle 2, 3, 4, 5, 6, 7, 8, 11, 14, 17, 20, 28, 36 and End of treatment (approximately 23 months)
    End point values
    		 Treatment Arm A: Ibrutinib Treatment Arm B: Temsirolimus
    Number of subjects analysed
    138
    130
    Units: Unit on a Scale
    arithmetic mean (standard deviation)
        Baseline (n= 130, 120)
    0.7 ( 0.2 )
    0.7 ( 0.2 )
        Change at Cycle 2 (n= 113, 95)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 3 (n=115, 85)
    0.1 ( 0.2 )
    -0.1 ( 0.2 )
        Change at Cycle 4 (n=103, 70)
    0.0 ( 0.2 )
    0.0 ( 0.3 )
        Change at Cycle 5 (n=102, 57)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 6 (n=99, 49)
    0.1 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 7 (n=98, 39)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 8 (n=90, 37)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 11 (n=88, 33)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 14 (n=72, 26)
    0.0 ( 0.2 )
    0.0 ( 0.1 )
        Change at Cycle 17 (n=69, 19)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 20 (n=64, 16)
    0.0 ( 0.2 )
    0.0 ( 0.2 )
        Change at Cycle 28 (n=22, 6)
    -0.1 ( 0.2 )
    0.1 ( 0.2 )
        Change at Cycle 36 (n=10, 4)
    0.0 ( 0.3 )
    -0.1 ( 0.2 )
        End of treatment (n= 23, 65)
    0.0 ( 0.2 )
    -0.1 ( 0.3 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Approximately up to 48 months
    Adverse event reporting additional description
    Safety population included all randomized subjects who received at least 1 dose of study agent (ibrutinib or temsirolimus) during the treatment phase.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Temsirolimus
    Reporting group description
    		 Subjects in Treatment Arm B received temsirolimus intravenous (IV) infusion 175 mg on Days 1, 8, 15 of the first cycle followed by 75 mg on Days 1, 8, 15 of each subsequent 21-day cycle. Each temsirolimus dose is infused over a 30 to 60 minute period.

    Reporting group title
    Ibrutinib
    Reporting group description
    		 Subjects in Treatment Arm A received 560 milligram (mg) oral ibrutinib (4*140-mg capsules) once daily continuously (self-administration at home) during the 21-day cycle.

    Serious adverse events
    		 Temsirolimus Ibrutinib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    83 / 139 (59.71%)
    79 / 139 (56.83%)
         number of deaths (all causes)
    82
    77
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma Gastric
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal Cell Carcinoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal Cancer Metastatic
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salivary Gland Cancer
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous Cell Carcinoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thymoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional Cell Carcinoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic Hypotension
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 139 (2.16%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    5 / 139 (3.60%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal Inflammation
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-Organ Failure
         subjects affected / exposed
    0 / 139 (0.00%)
    4 / 139 (2.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Oedema
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 139 (5.04%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    5 / 11
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    5 / 139 (3.60%)
    6 / 139 (4.32%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Disorder
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infiltration
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 139 (0.00%)
    6 / 139 (4.32%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 139 (2.16%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pulmonary Oedema
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Psychiatric disorders
    Confusional State
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Disorder
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil Count Decreased
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet Count Decreased
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula Fracture
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foreign Body
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post Procedural Swelling
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic Rupture
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Subdural Haematoma
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Toxicity to Various Agents
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 139 (1.44%)
    7 / 139 (5.04%)
         occurrences causally related to treatment / all
    1 / 3
    8 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coronary Artery Insufficiency
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary Artery Stenosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular Tachycardia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cognitive Disorder
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial Paresis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Memory Impairment
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 139 (3.60%)
    4 / 139 (2.88%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune Haemolytic Anaemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 139 (0.00%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic Infarction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    3 / 139 (2.16%)
    5 / 139 (3.60%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Retinopathy
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous Haemorrhage
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 139 (0.72%)
    5 / 139 (3.60%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 139 (2.88%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    6 / 6
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal Stenosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis Haemorrhagic
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Haemorrhoids
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal Haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small Intestinal Obstruction
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    3 / 139 (2.16%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis Toxic
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Guttate Psoriasis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panniculitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Ulcer
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis Haemorrhagic
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    4 / 139 (2.88%)
    3 / 139 (2.16%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Renal Impairment
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis Pyrophosphate
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral Disc Compression
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in Extremity
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess Limb
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical Pneumonia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes Zoster
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 139 (1.44%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious Colitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis Fungal
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver Abscess
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    2 / 2
    9 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    2 / 139 (1.44%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral Candidiasis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    1 / 139 (0.72%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 139 (8.63%)
    16 / 139 (11.51%)
         occurrences causally related to treatment / all
    9 / 15
    15 / 21
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumonia Escherichia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 139 (3.60%)
    6 / 139 (4.32%)
         occurrences causally related to treatment / all
    6 / 8
    3 / 10
         deaths causally related to treatment / all
    1 / 1
    1 / 4
    Septic Shock
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sinusitis
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis Aspergillus
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft Tissue Infection
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth Infection
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    3 / 139 (2.16%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary Tract Infection Bacterial
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased Appetite
         subjects affected / exposed
    2 / 139 (1.44%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 139 (0.72%)
    2 / 139 (1.44%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes Mellitus
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic Ketoacidosis
         subjects affected / exposed
    0 / 139 (0.00%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 139 (0.72%)
    0 / 139 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour Lysis Syndrome
         subjects affected / exposed
    3 / 139 (2.16%)
    1 / 139 (0.72%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Temsirolimus Ibrutinib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    137 / 139 (98.56%)
    130 / 139 (93.53%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    3 / 139 (2.16%)
    11 / 139 (7.91%)
         occurrences all number
    4
    18
    Hypertension
         subjects affected / exposed
    5 / 139 (3.60%)
    16 / 139 (11.51%)
         occurrences all number
    5
    22
    Hypotension
         subjects affected / exposed
    3 / 139 (2.16%)
    7 / 139 (5.04%)
         occurrences all number
    3
    10
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    26 / 139 (18.71%)
    12 / 139 (8.63%)
         occurrences all number
    48
    15
    Fatigue
         subjects affected / exposed
    40 / 139 (28.78%)
    31 / 139 (22.30%)
         occurrences all number
    71
    57
    Mucosal Inflammation
         subjects affected / exposed
    21 / 139 (15.11%)
    2 / 139 (1.44%)
         occurrences all number
    44
    3
    Oedema Peripheral
         subjects affected / exposed
    33 / 139 (23.74%)
    19 / 139 (13.67%)
         occurrences all number
    60
    22
    Pyrexia
         subjects affected / exposed
    26 / 139 (18.71%)
    24 / 139 (17.27%)
         occurrences all number
    32
    46
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    31 / 139 (22.30%)
    31 / 139 (22.30%)
         occurrences all number
    55
    50
    Dyspnoea
         subjects affected / exposed
    13 / 139 (9.35%)
    12 / 139 (8.63%)
         occurrences all number
    13
    18
    Epistaxis
         subjects affected / exposed
    31 / 139 (22.30%)
    13 / 139 (9.35%)
         occurrences all number
    42
    23
    Oropharyngeal Pain
         subjects affected / exposed
    8 / 139 (5.76%)
    8 / 139 (5.76%)
         occurrences all number
    11
    10
    Pleural Effusion
         subjects affected / exposed
    5 / 139 (3.60%)
    10 / 139 (7.19%)
         occurrences all number
    5
    12
    Pneumonitis
         subjects affected / exposed
    7 / 139 (5.04%)
    0 / 139 (0.00%)
         occurrences all number
    16
    0
    Productive Cough
         subjects affected / exposed
    5 / 139 (3.60%)
    7 / 139 (5.04%)
         occurrences all number
    5
    8
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 139 (10.79%)
    7 / 139 (5.04%)
         occurrences all number
    18
    11
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    9 / 139 (6.47%)
    4 / 139 (2.88%)
         occurrences all number
    15
    4
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    10 / 139 (7.19%)
    5 / 139 (3.60%)
         occurrences all number
    25
    6
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    9 / 139 (6.47%)
    4 / 139 (2.88%)
         occurrences all number
    30
    5
    Blood Creatinine Increased
         subjects affected / exposed
    18 / 139 (12.95%)
    16 / 139 (11.51%)
         occurrences all number
    32
    36
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    7 / 139 (5.04%)
    2 / 139 (1.44%)
         occurrences all number
    9
    2
    Neutrophil Count Decreased
         subjects affected / exposed
    10 / 139 (7.19%)
    7 / 139 (5.04%)
         occurrences all number
    40
    20
    Platelet Count Decreased
         subjects affected / exposed
    23 / 139 (16.55%)
    11 / 139 (7.91%)
         occurrences all number
    165
    18
    Weight Decreased
         subjects affected / exposed
    18 / 139 (12.95%)
    9 / 139 (6.47%)
         occurrences all number
    24
    10
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    3 / 139 (2.16%)
    10 / 139 (7.19%)
         occurrences all number
    3
    13
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 139 (0.72%)
    8 / 139 (5.76%)
         occurrences all number
    1
    10
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    7 / 139 (5.04%)
    1 / 139 (0.72%)
         occurrences all number
    9
    1
    Headache
         subjects affected / exposed
    17 / 139 (12.23%)
    13 / 139 (9.35%)
         occurrences all number
    20
    20
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    57 / 139 (41.01%)
    27 / 139 (19.42%)
         occurrences all number
    196
    70
    Neutropenia
         subjects affected / exposed
    36 / 139 (25.90%)
    21 / 139 (15.11%)
         occurrences all number
    94
    47
    Thrombocytopenia
         subjects affected / exposed
    77 / 139 (55.40%)
    25 / 139 (17.99%)
         occurrences all number
    323
    83
    Eye disorders
    Cataract
         subjects affected / exposed
    7 / 139 (5.04%)
    2 / 139 (1.44%)
         occurrences all number
    9
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    11 / 139 (7.91%)
    8 / 139 (5.76%)
         occurrences all number
    14
    16
    Abdominal Pain Upper
         subjects affected / exposed
    3 / 139 (2.16%)
    8 / 139 (5.76%)
         occurrences all number
    4
    27
    Constipation
         subjects affected / exposed
    21 / 139 (15.11%)
    13 / 139 (9.35%)
         occurrences all number
    25
    15
    Diarrhoea
         subjects affected / exposed
    42 / 139 (30.22%)
    45 / 139 (32.37%)
         occurrences all number
    94
    113
    Dyspepsia
         subjects affected / exposed
    1 / 139 (0.72%)
    9 / 139 (6.47%)
         occurrences all number
    1
    14
    Mouth Ulceration
         subjects affected / exposed
    8 / 139 (5.76%)
    0 / 139 (0.00%)
         occurrences all number
    10
    0
    Nausea
         subjects affected / exposed
    30 / 139 (21.58%)
    20 / 139 (14.39%)
         occurrences all number
    37
    22
    Oral Pain
         subjects affected / exposed
    9 / 139 (6.47%)
    1 / 139 (0.72%)
         occurrences all number
    16
    1
    Stomatitis
         subjects affected / exposed
    28 / 139 (20.14%)
    4 / 139 (2.88%)
         occurrences all number
    43
    5
    Vomiting
         subjects affected / exposed
    9 / 139 (6.47%)
    17 / 139 (12.23%)
         occurrences all number
    18
    17
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    18 / 139 (12.95%)
    12 / 139 (8.63%)
         occurrences all number
    28
    13
    Rash
         subjects affected / exposed
    25 / 139 (17.99%)
    18 / 139 (12.95%)
         occurrences all number
    37
    25
    Rash Generalised
         subjects affected / exposed
    7 / 139 (5.04%)
    1 / 139 (0.72%)
         occurrences all number
    10
    1
    Rash Maculo-Papular
         subjects affected / exposed
    7 / 139 (5.04%)
    5 / 139 (3.60%)
         occurrences all number
    11
    7
    Skin Lesion
         subjects affected / exposed
    8 / 139 (5.76%)
    6 / 139 (4.32%)
         occurrences all number
    13
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    9 / 139 (6.47%)
    10 / 139 (7.19%)
         occurrences all number
    15
    16
    Back Pain
         subjects affected / exposed
    14 / 139 (10.07%)
    15 / 139 (10.79%)
         occurrences all number
    15
    23
    Muscle Spasms
         subjects affected / exposed
    4 / 139 (2.88%)
    26 / 139 (18.71%)
         occurrences all number
    5
    36
    Pain in Extremity
         subjects affected / exposed
    12 / 139 (8.63%)
    5 / 139 (3.60%)
         occurrences all number
    14
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    8 / 139 (5.76%)
    8 / 139 (5.76%)
         occurrences all number
    8
    8
    Conjunctivitis
         subjects affected / exposed
    9 / 139 (6.47%)
    17 / 139 (12.23%)
         occurrences all number
    12
    21
    Herpes Zoster
         subjects affected / exposed
    5 / 139 (3.60%)
    10 / 139 (7.19%)
         occurrences all number
    5
    10
    Nasopharyngitis
         subjects affected / exposed
    16 / 139 (11.51%)
    16 / 139 (11.51%)
         occurrences all number
    25
    25
    Oral Herpes
         subjects affected / exposed
    15 / 139 (10.79%)
    4 / 139 (2.88%)
         occurrences all number
    18
    9
    Paronychia
         subjects affected / exposed
    5 / 139 (3.60%)
    9 / 139 (6.47%)
         occurrences all number
    10
    12
    Pneumonia
         subjects affected / exposed
    14 / 139 (10.07%)
    6 / 139 (4.32%)
         occurrences all number
    18
    8
    Respiratory Tract Infection
         subjects affected / exposed
    14 / 139 (10.07%)
    9 / 139 (6.47%)
         occurrences all number
    31
    13
    Rhinitis
         subjects affected / exposed
    5 / 139 (3.60%)
    8 / 139 (5.76%)
         occurrences all number
    7
    11
    Sinusitis
         subjects affected / exposed
    6 / 139 (4.32%)
    11 / 139 (7.91%)
         occurrences all number
    9
    12
    Upper Respiratory Tract Infection
         subjects affected / exposed
    15 / 139 (10.79%)
    28 / 139 (20.14%)
         occurrences all number
    25
    45
    Urinary Tract Infection
         subjects affected / exposed
    7 / 139 (5.04%)
    10 / 139 (7.19%)
         occurrences all number
    10
    12
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    25 / 139 (17.99%)
    26 / 139 (18.71%)
         occurrences all number
    43
    30
    Diabetes Mellitus
         subjects affected / exposed
    7 / 139 (5.04%)
    1 / 139 (0.72%)
         occurrences all number
    61
    3
    Hypercholesterolaemia
         subjects affected / exposed
    18 / 139 (12.95%)
    2 / 139 (1.44%)
         occurrences all number
    46
    2
    Hyperglycaemia
         subjects affected / exposed
    26 / 139 (18.71%)
    4 / 139 (2.88%)
         occurrences all number
    93
    17
    Hyperkalaemia
         subjects affected / exposed
    3 / 139 (2.16%)
    9 / 139 (6.47%)
         occurrences all number
    3
    25
    Hypertriglyceridaemia
         subjects affected / exposed
    25 / 139 (17.99%)
    1 / 139 (0.72%)
         occurrences all number
    77
    1
    Hypokalaemia
         subjects affected / exposed
    24 / 139 (17.27%)
    12 / 139 (8.63%)
         occurrences all number
    52
    23
    Hypomagnesaemia
         subjects affected / exposed
    4 / 139 (2.88%)
    9 / 139 (6.47%)
         occurrences all number
    5
    22
    Hyponatraemia
         subjects affected / exposed
    7 / 139 (5.04%)
    1 / 139 (0.72%)
         occurrences all number
    14
    23

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Dec 2012
    This amendment was implemented to clarify management of ibrutinib with CYP3A4/5 inhibitors/inducers and anticoagulants, including warfarin, and to clarify perioperative management of study medication.
    30 Jul 2014
    This amendment was implemented to introduce crossover treatment for subjects randomized to temsirolimus who have IRC-confirmed disease progression; and to update the protocol with new safety-related information and safety instructions, minor revisions to operational aspects of the study, provide updates based on new information, and perform minor modifications and formatting changes.
    04 Aug 2015
    This amendment was implemented to include the information on the conduct of the study after the clinical cutoff for the primary analysis occurs, and to include the new safety-related information and safety instructions.

    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.
    Within this context, there were no notable study limitations identified by the Sponsor.
    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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