Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43865   clinical trials with a EudraCT protocol, of which   7286   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A multicenter, randomized, double-blind, placebocontrolled phase III study of panobinostat in combination with bortezomib and dexamethasone in patients with relapsed multiple myeloma

    Summary
    EudraCT number
    		 2009-015507-52
    Trial protocol
    		 SE   FI   DE   NL   BE   DK   IT   FR   ES   CZ   PL   GB   AT   GR  
    Global end of trial date
    30 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Aug 2016
    First version publication date
    13 Aug 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLBH589D2308
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH 4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 612341111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 612341111,
    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
    30 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare progression-free survival (PFS) in patients treated with panobinostat (PAN) in combination with bortezomib (BTZ)/dexamethasone (Dex) vs. patients treated with placebo (PBO) in combination with bortezomib/dexamethasone. The key secondary objective was to compare overall survival (OS) between treatment arms.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 28 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 9
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Austria: 8
    Country: Number of subjects enrolled
    Belgium: 12
    Country: Number of subjects enrolled
    Brazil: 37
    Country: Number of subjects enrolled
    Canada: 21
    Country: Number of subjects enrolled
    China: 45
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    Denmark: 16
    Country: Number of subjects enrolled
    Egypt: 16
    Country: Number of subjects enrolled
    Finland: 6
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 63
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Israel: 5
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Japan: 34
    Country: Number of subjects enrolled
    Korea, Republic of: 68
    Country: Number of subjects enrolled
    Lebanon: 5
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Russian Federation: 17
    Country: Number of subjects enrolled
    Singapore: 10
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    Sweden: 25
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Thailand: 45
    Country: Number of subjects enrolled
    Turkey: 21
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    United States: 54
    Worldwide total number of subjects
    768
    EEA total number of subjects
    335
    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)
    445
    From 65 to 84 years
    323
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 768 eligible patients were randomized 1:1 to the panobinostat and control arms. Central randomization was stratified 1) by number of prior lines of anti-myeloma therapy: 1 vs. 2 or 3 and 2) by prior use of bortezomib: Yes vs. No.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Panobinostat + Bortezomib + Dexamethasone
    Arm description
    		 Panobinostat was given 20 mg hard gelatin capsules . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV)injection. Dexamethasone was given as an oral dose of 20 mg/day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat was given 20 mg capsules

    Arm title
    		 Placebo + Bortezomib + Dexamethasone
    Arm description
    		 Placebo was given as a hard gelatin capsule in the image of Panobinostat . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV) injection. Dexamethasone was given as an oral dose of 20 mg/day.
    Arm type
    		 Placebo

    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 hard capsule match of panobinostat

    Number of subjects in period 1
    		Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Started
    387
    381
    Completed
    102
    102
    Not completed
    285
    279
         Adverse event, serious fatal
    21
    17
         Consent withdrawn by subject
    34
    18
         Disease progression
    82
    153
         Adverse event, non-fatal
    130
    66
         New Cancer therapy
    4
    7
         Administrative problems
    2
    1
         Untreated
    5
    5
         Abnormal test proceedure results
    3
    8
         Lost to follow-up
    1
    -
         Protocol deviation
    3
    4

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Panobinostat + Bortezomib + Dexamethasone
    Reporting group description
    		 Panobinostat was given 20 mg hard gelatin capsules . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV)injection. Dexamethasone was given as an oral dose of 20 mg/day.

    Reporting group title
    Placebo + Bortezomib + Dexamethasone
    Reporting group description
    		 Placebo was given as a hard gelatin capsule in the image of Panobinostat . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV) injection. Dexamethasone was given as an oral dose of 20 mg/day.

    Reporting group values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone Total
    Number of subjects
    		 387 381 768
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 225 220 445
        From 65-84 years
    		 162 161 323
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.4 ± 9.34 61.8 ± 9.43 -
    Gender, Male/Female
    Units: participants
        Female
    		 185 176 361
        Male
    		 202 205 407
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 249 250 499
        Asian
    		 128 104 232
        Black
    		 5 17 22
        Other
    		 5 10 15

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Panobinostat + Bortezomib + Dexamethasone
    Reporting group description
    		 Panobinostat was given 20 mg hard gelatin capsules . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV)injection. Dexamethasone was given as an oral dose of 20 mg/day.

    Reporting group title
    Placebo + Bortezomib + Dexamethasone
    Reporting group description
    		 Placebo was given as a hard gelatin capsule in the image of Panobinostat . Bortezomib was given at 1.3 mg/m2 as a 3 to 5 second bolus intravenous (IV) injection. Dexamethasone was given as an oral dose of 20 mg/day.

    Primary: Progression-free survival events in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Progression-free survival events in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    End point type
    Primary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: number of events
    207
    260
    Statistical analysis title
    		 investigator assessment using mEBMT
    Comparison groups
    Panobinostat + Bortezomib + Dexamethasone v Placebo + Bortezomib + Dexamethasone
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.76

    Primary: Progression Free Survival in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Progression Free Survival in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    End point type
    Primary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: months
        median (confidence interval 95%)
    11.99 (10.32 to 12.94)
    8.8 (7.56 to 9.23)
    Statistical analysis title
    		 PFS (investigator’s assessment) overall
    Comparison groups
    Panobinostat + Bortezomib + Dexamethasone v Placebo + Bortezomib + Dexamethasone
    Number of subjects included in analysis
    768
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 0.76

    Secondary: Final analysis of overall survival events in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone

    		 Close Top of page
    End point title
    		 Final analysis of overall survival events in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone
    End point description
    Number of OS events
    End point type
    Secondary
    End point timeframe
    Survival follow-up continued until 415 survival events had occurred. Data cut off was 29-Jun-2015 and the last patient last visit was on 30-Jul-2015.
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: Number of OS events
    204
    211
    No statistical analyses for this end point

    Secondary: Final analysis of overall survival in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone

    		 Close Top of page
    End point title
    		 Final analysis of overall survival in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone
    End point description
    survival time in months
    End point type
    Secondary
    End point timeframe
    Survival follow-up continued until 415 survival events had occurred. Data cut off was 29-Jun-2015 and the last patient last visit was on 30-Jul-2015.
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: months
        median (confidence interval 95%)
    40.28 (35.02 to 44.81)
    35.78 (28.98 to 40.64)
    No statistical analyses for this end point

    Secondary: Overall response rate in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Overall response rate in patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    Best overall response based on mEBMT criteria per investigator assessment
    End point type
    Secondary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: % participants with response
        number (not applicable)
    60.7
    54.6
    No statistical analyses for this end point

    Secondary: Time to response per investigator assessment (mEBMT criteria) of response patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Time to response per investigator assessment (mEBMT criteria) of response patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    End point type
    Secondary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: time to response in months
        median (confidence interval 95%)
    1.51 (1.41 to 1.64)
    2 (1.61 to 2.79)
    No statistical analyses for this end point

    Secondary: Duration of response per investigator assessment (mEBMT criteria) patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Duration of response per investigator assessment (mEBMT criteria) patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    End point type
    Secondary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: duration of response in months
        median (confidence interval 95%)
    13.14 (11.76 to 14.92)
    10.87 (9.23 to 11.76)
    No statistical analyses for this end point

    Secondary: Time to progression/relapse per investigator assessment (mEBMT criteria) patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.

    		 Close Top of page
    End point title
    		 Time to progression/relapse per investigator assessment (mEBMT criteria) patients treated with panobinostat in combination with bortezomib and dexamethasone vs. patients treated by placebo in combination with bortezomib and dexamethasone.
    End point description
    End point type
    Secondary
    End point timeframe
    45 months
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: response in months
        median (confidence interval 95%)
    12.71 (11.3 to 14.06)
    8.54 (7.66 to 9.72)
    No statistical analyses for this end point

    Secondary: EORTC QLQ-MY20-Change from Baseline by treatment group

    		 Close Top of page
    End point title
    		 EORTC QLQ-MY20-Change from Baseline by treatment group
    End point description
    Higher values in the disease symptoms and side effects of treatment scores indicate worsening. Higher scores in the future perspective and body image scores indicate improvement. LS Means and SEM are estimated from the repeated measures model. Following factors and covariates are included in the repeated measurement model: time, treatment, treatment by time interaction, number of prior lines of anti-MM therapy (1/ 2 and 3), prior use of BTZ (Yes/ No), baseline score.
    End point type
    Secondary
    End point timeframe
    12, 24 and 48 weeks
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Disease Symptom wk 12 change baseline (n=215,243)
    -4.795 (-6.76 to -2.83)
    -4.865 (-6.75 to -2.98)
        Disease Symptom wk 24 change baseline (n=148,177)
    -4.401 (-6.53 to -2.27)
    -6.797 (-8.79 to -4.81)
        Disease Symptom wk 48 change baseline (n=37,26)
    -2.836 (-6.76 to -1.084)
    -6.626 (-11.1 to -2.12)
        Side effects of treatment wk 12 chge (n=213,242)
    8.162 (6.51 to 9.814)
    5.524 (3.933 to 7.115)
        Side effects of treatment wk 24 chge (n=148,175)
    9.016 (6.955 to 11.08)
    7.731 (5.795 to 9.668)
        Side effects of treatment wk 48 chge (n=37,26)
    3.357 (0.442 to 6.273)
    3.654 (0.352 to 6.956)
        Future perspective wk 12 chge (n=214,242)
    5.319 (2.893 to 7.744)
    6.194 (3.854 to 8.533)
        Future perspective wk 24 chge (n=148,176)
    3.877 (0.977 to 6.778)
    5.839 (3.103 to 8.575)
        Future perspective wk 48 chge (n=37,26)
    4.331 (-0.142 to 8.804)
    6.951 (1.807 to 12.1)
        Body image wk 12 chge (n=213,240)
    -7.178 (-10.5 to -3.87)
    -6.22 (-9.41 to -3.03)
        Body image wk 24 chge (n=147,175)
    -11.463 (-15.3 to -7.66)
    -7.358 (-10.9 to -3.81)
        Body image wk 48 chge (n=37,26)
    -2.161 (-7.73 to 3.41)
    -4.666 (-11.1 to 1.729)
    No statistical analyses for this end point

    Secondary: EORTC QLQ-C30 - Summary Statistics by treatment group

    		 Close Top of page
    End point title
    		 EORTC QLQ-C30 - Summary Statistics by treatment group
    End point description
    The EORTC QLQ-C30 measures functional dimensions (physical, role, emotional, cognitive, and social), three multi-item symptom scales (fatigue, nausea/vomiting, and pain), six single-item symptom scales (dyspnea, sleep disturbance, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale
    End point type
    Secondary
    End point timeframe
    12, 24 and 48 weeks
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Global health wk 12 change baseline (n=216,239)
    -9.853 (-12.5 to -7.2)
    -4.044 (-6.6 to -1.49)
        Global health wk 24 change baseline (n=150,176)
    -7.867 (-10.7 to -5.08)
    -1.518 (-4.11 to -1.075)
        Global health wk 48 change baseline (n=38,26)
    -2.986 (-7.21 to 1.237)
    4.345 (-0.416 to 9.106)
        Physical functioning wk 12 chge (n=217,242)
    -9.67 (-12 to -7.38)
    -5.393 (-76.3 to -3.16)
        Physical functioning wk 24 chge (n=151,177)
    -9.516 (-12.2 to -7.38)
    -6.456 (-8.98 to -3.93)
        Physical functioning wk 48 chge (n=38,26)
    -2.88 (-6.41 to 0.651)
    2.037 (-2.07 to 6.147)
        Role functioning wk 12 chge (n=215,237)
    -11.159 (-14.6 to -7.74)
    -6.762 (-10.1 to -3.45)
        Role functioning wk 24 chge (n=150,176)
    -11.875 (-15.7 to -8.01)
    -11.263 (-14.9 to -7.61)
        Role functioning wk 48 chge (n=38,26)
    -5.927 (-11.4 to -0.424)
    -0.401 (-6.73 to 5.924)
        Cognitive functioning wk 12 chge (n=216,240)
    -4.464 (-6.89 to -2.04)
    -1.023 (-3.36 to 1.318)
        Cognitive functioning wk 24 chge (n=149,176)
    -6.053 (-8.87 to -3.24)
    -3.542 (-6.22 to -0.865)
        Cognitive functioning wk 48 chge (n=38,26)
    -5.568 (-9.79 to -1.34)
    -4.042 (-8.99 to 0.902)
        Social functioning wk 12 chge (n=216,240)
    -8.502 (-11.6 to -5.44)
    -3.991 (-6.97 to 1.02)
        Social functioning wk 24 chge (n=148,171)
    -8.925 (-12.4 to -5.42)
    -6.338 (-9.66 to -3.02)
        Social functioning wk 48 chge (n=37,26)
    -6.104 (-11 to -1.22)
    4.617 (-0.93 to 10.16)
        Fatigue wk 12 chge (n=217,241)
    15.122 (12.27 to 17.98)
    7.939 (5.174 to 10.7)
        Fatigue wk 24 chge (n=151,176)
    12.677 (9.419 to 15.94)
    9.203 (6.136 to 12.27)
        Fatigue wk 48 chge(n=38,26)
    4.646 (0.086 to 9.206)
    -2.625 (-7.88 to 2.628)
        Dyspnea wk 12 chge (n=217,240)
    13.964 (10.6 to 17.33)
    6.266 (3.012 to 9.521)
        Dyspnea wk 24 chge (n=151,177)
    7.939 (4.639 to 11.24)
    5.308 (2.221 to 8.394)
        Dyspnea wk 48 chge (n=38,26)
    4.118 (-1.58 to 9.813)
    2.82 (-3.88 to 9.523)
        Insomnia wk 12 chge (n=216,239)
    6.283 (2.851 to 9.715)
    7.625 (4.331 to 10.92)
        Insomnia wk 24 chge (n=149,176)
    10.023 (6.038 to 14.01)
    6.104 (2.381 to 9.827)
        Insomnia wk 48 chge (n=38,26)
    -2.464 (-8.74 to 3.811)
    -3.442 (-10.9 to 4.017)
        Appetite loss wk 12 chge (n=217,239)
    15.167 (11.6 to 18.74)
    5.383 (1.925 to 8.841)
        Appetite loss wk 24 chge (n=151,176)
    16.574 (12.39 to 20.76)
    5.861 (1.918 to 9.804)
        Appetite loss wk 48 chge (n=38,26)
    3.999 (-2.08 to 10.07)
    -2.963 (-9.99 to 4.061)
        Constipation wk 12 chge (n=215,240)
    4.135 (0.667 to 7.603)
    6.42 (3.104 to 9.735)
        Constipation wk 24 chge (n=151,177)
    -0.153 (-3.64 to 3.337)
    0.524 (-2.73 to 5.782)
        Constipation wk 48 chge (n=38,25)
    -0.358 (-5.57 to 4.851)
    -0.946 (-7.26 to 5.373)
        Diarrhea wk 12 chge (n=217,241)
    18.888 (15.04 to 22.74)
    10.206 (6.452 to 13.96)
        Diarrhea wk 24 chge (n=150,177)
    23.163 (18.46 to 27.87)
    16.406 (11.98 to 20.83)
        Diarrhea wk 48 chge (n=38,26)
    20.48 (14.02 to 26.94)
    10.996 (3.422 to 18.57)
    No statistical analyses for this end point

    Secondary: Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-NTX) Change from Baseline by treatment group

    		 Close Top of page
    End point title
    		 Functional Assessment of Cancer Therapy/Gynecologic Oncology Group- Neurotoxicity (FACT/GOG-NTX) Change from Baseline by treatment group
    End point description
    The FACT/GOG-NTX was developed from the Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System and focuses on four general quality of life domains for physical well being, functional wellbeing, social/family well-being, and emotional well-being, and includes additional items to characterize treatment-related neurotoxicity. Higher subscales/total scores represent higher QOL. In the case of the neurotoxicity subscale, lower scores correspond to higher neurotoxicity. The recall period referenced in the questionnaire is the past 7 days.Ranges for FACT-G subscales are as follows:.PWB, SWB and FWB scale 0 -28, EWB scale 0-24, NtxS scale 0-44, FACT/GOG-Ntx trial outcome index scale is 0-100 and FACT-G scale is also scaled 0-100. An increase from baseline in these scores indicate improvement.
    End point type
    Secondary
    End point timeframe
    12, 24 and 48 weeks
    End point values
    		 Panobinostat + Bortezomib + Dexamethasone Placebo + Bortezomib + Dexamethasone
    Number of subjects analysed
    387
    381
    Units: score on a scale
    least squares mean (confidence interval 95%)
        Neurotoxicity wk 12 change baseline (n=212,240)
    -4.481 (-5.33 to -3.63)
    -3.337 (-4.17 to -2.5)
        Neurotoxicity wk 24 change baseline (n=148,174)
    -4.564 (-5.49 to -3.64)
    -4.739 (-5.61 to -3.86)
        Neurotoxicity wk 48 change baseline (n=35,26)
    -3.158 (-4.52 to -1.79)
    -2.133 (-3.64 to -0.627)
        Physical wellbeing wk 12 chge (n=215,240)
    -3.29 (-3.94 to -2.64)
    -1.952 (-2.58 to -1.32)
        Physical wellbeingwk 24 chge (n=150,176)
    -3.044 (-3.74 to -2.35)
    -2.259 (-2.92 to -1.6)
        Physical wellbeing wk 48 chge (n=38,26)
    -2.037 (-3.08 to -0.992)
    0.203 (-1.03 to 1.439)
        Trial Outcomes wk 12 chge (n=209,236)
    -10.573 (-12.2 to -8.86)
    -6.874 (-8.55 to -5.19)
        Trial Outcomes wk 24 chge (n=148,173)
    -9.84 (-11.7 to -7.98)
    -8.894 (-10.7 to -7.13)
        Trial Outcomes wk 48 chge (n=35,26)
    -6.633 (-9.28 to -3.98)
    -2.821 (-5.76 to 0.122)
        FACT-G Total wk 12 chge (n=213,240)
    -6.658 (-8.23 to -5.09)
    -4.106 (-5.64 to -2.57)
        FACT-G Totalwk 24 chge (n=147,175)
    -6.076 (-7.84 to -4.31)
    -4.609 (-6.3 to -2.92)
        FACT-G Total wk 48 chge (n=37,26)
    -2.704 (-5.29 to -0.118)
    -1.435 (-4.42 to 1.547)
        FACT/GOGNTX Total wk 12 chge (n=206,230)
    -11.176 (-13.3 to -9.03)
    -7.524 (-9.64 to -5.41)
        FACT/GOGNTX Total wk 24 chge (n=146,172)
    -10.581 (-12.9 to -8.23)
    -9.179 (-9.64 to -5.41)
        FACT/GOGNTX Total wk 48 chge (n=35,26)
    -5.871 (-9.24 to -2.5)
    -3.151 (-6.92 to 0.614)
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    PAN+BTZ+Dex
    Reporting group description
    		 PAN+BTZ+Dex

    Reporting group title
    PBO+BTZ+Dex
    Reporting group description
    		 PBO+BTZ+Dex

    Serious adverse events
    		 PAN+BTZ+Dex PBO+BTZ+Dex
    Total subjects affected by serious adverse events
         subjects affected / exposed
    228 / 381 (59.84%)
    157 / 377 (41.64%)
         number of deaths (all causes)
    30
    18
         number of deaths resulting from adverse events
    7
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal cancer
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 381 (0.52%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 381 (1.31%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    9 / 381 (2.36%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    7 / 9
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 381 (3.94%)
    6 / 377 (1.59%)
         occurrences causally related to treatment / all
    6 / 18
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    11 / 381 (2.89%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    10 / 12
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 381 (0.26%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    16 / 381 (4.20%)
    11 / 377 (2.92%)
         occurrences causally related to treatment / all
    5 / 17
    4 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (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
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 381 (0.79%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Aspiration
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    4 / 381 (1.05%)
    7 / 377 (1.86%)
         occurrences causally related to treatment / all
    1 / 4
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthopnoea
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 381 (1.05%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 381 (0.26%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 381 (1.31%)
    4 / 377 (1.06%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    5 / 381 (1.31%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Tachypnoea
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomania
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental disorder
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure decreased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    4 / 381 (1.05%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transfusion reaction
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 381 (0.52%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 381 (1.05%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 381 (0.52%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autonomic neuropathy
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain compression
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Brain oedema
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system haemorrhage
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central nervous system necrosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    Cerebrovascular accident
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Coma
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cranial nerve paralysis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    5 / 381 (1.31%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperreflexia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lacunar infarction
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    5 / 381 (1.31%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    3 / 381 (0.79%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraparesis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sensory loss
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Speech disorder
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    5 / 381 (1.31%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VIIth nerve paralysis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 381 (3.67%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    10 / 15
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 381 (0.79%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperviscosity syndrome
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monocytosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    28 / 381 (7.35%)
    8 / 377 (2.12%)
         occurrences causally related to treatment / all
    28 / 35
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exophthalmos
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic ischaemic neuropathy
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 381 (0.79%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    3 / 381 (0.79%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 381 (0.79%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    2 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    43 / 381 (11.29%)
    9 / 377 (2.39%)
         occurrences causally related to treatment / all
    35 / 54
    7 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 381 (0.52%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    5 / 381 (1.31%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    7 / 381 (1.84%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    6 / 7
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising oesophagitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal necrosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    12 / 381 (3.15%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    11 / 12
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Biliary dyskinesia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Swelling face
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 381 (1.84%)
    9 / 377 (2.39%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Azotaemia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    4 / 381 (1.05%)
    5 / 377 (1.33%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 381 (0.79%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspergillus infection
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteriuria
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 381 (0.79%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus colitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated tuberculosis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 381 (1.57%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemophilus sepsis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    3 / 381 (0.79%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    4 / 381 (1.05%)
    5 / 377 (1.33%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    5 / 381 (1.31%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 381 (0.79%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    3 / 381 (0.79%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Neutropenic sepsis
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Oral candidiasis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (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
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal sepsis
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    56 / 381 (14.70%)
    40 / 377 (10.61%)
         occurrences causally related to treatment / all
    35 / 66
    16 / 47
         deaths causally related to treatment / all
    2 / 2
    1 / 3
    Pneumonia bacterial
         subjects affected / exposed
    0 / 381 (0.00%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia influenzal
         subjects affected / exposed
    2 / 381 (0.52%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pneumococcal
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia respiratory syncytial viral
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal bacteraemia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    4 / 381 (1.05%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    2 / 4
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salmonellosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    9 / 381 (2.36%)
    7 / 377 (1.86%)
         occurrences causally related to treatment / all
    3 / 9
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    9 / 381 (2.36%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 381 (0.26%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal sepsis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 381 (0.79%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    8 / 381 (2.10%)
    4 / 377 (1.06%)
         occurrences causally related to treatment / all
    2 / 11
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral haemorrhagic cystitis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         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
    4 / 381 (1.05%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    3 / 5
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    11 / 381 (2.89%)
    5 / 377 (1.33%)
         occurrences causally related to treatment / all
    4 / 12
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 381 (0.26%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 381 (0.52%)
    3 / 377 (0.80%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochloraemia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 381 (0.26%)
    2 / 377 (0.53%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    8 / 381 (2.10%)
    4 / 377 (1.06%)
         occurrences causally related to treatment / all
    7 / 11
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 381 (1.05%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophagia
         subjects affected / exposed
    2 / 381 (0.52%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 381 (0.00%)
    1 / 377 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 381 (0.26%)
    0 / 377 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PAN+BTZ+Dex PBO+BTZ+Dex
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    379 / 381 (99.48%)
    366 / 377 (97.08%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    28 / 381 (7.35%)
    23 / 377 (6.10%)
         occurrences all number
    33
    36
    Hypotension
         subjects affected / exposed
    49 / 381 (12.86%)
    34 / 377 (9.02%)
         occurrences all number
    62
    38
    Orthostatic hypotension
         subjects affected / exposed
    22 / 381 (5.77%)
    11 / 377 (2.92%)
         occurrences all number
    28
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    77 / 381 (20.21%)
    51 / 377 (13.53%)
         occurrences all number
    132
    70
    Fatigue
         subjects affected / exposed
    155 / 381 (40.68%)
    109 / 377 (28.91%)
         occurrences all number
    217
    161
    Oedema peripheral
         subjects affected / exposed
    104 / 381 (27.30%)
    69 / 377 (18.30%)
         occurrences all number
    147
    88
    Pyrexia
         subjects affected / exposed
    90 / 381 (23.62%)
    48 / 377 (12.73%)
         occurrences all number
    137
    60
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    81 / 381 (21.26%)
    70 / 377 (18.57%)
         occurrences all number
    110
    96
    Dyspnoea
         subjects affected / exposed
    53 / 381 (13.91%)
    40 / 377 (10.61%)
         occurrences all number
    59
    51
    Productive cough
         subjects affected / exposed
    18 / 381 (4.72%)
    19 / 377 (5.04%)
         occurrences all number
    25
    27
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    73 / 381 (19.16%)
    61 / 377 (16.18%)
         occurrences all number
    89
    64
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    22 / 381 (5.77%)
    19 / 377 (5.04%)
         occurrences all number
    30
    36
    Blood creatinine increased
         subjects affected / exposed
    37 / 381 (9.71%)
    21 / 377 (5.57%)
         occurrences all number
    71
    29
    Blood urea increased
         subjects affected / exposed
    20 / 381 (5.25%)
    10 / 377 (2.65%)
         occurrences all number
    46
    21
    Platelet count decreased
         subjects affected / exposed
    44 / 381 (11.55%)
    17 / 377 (4.51%)
         occurrences all number
    82
    31
    Weight decreased
         subjects affected / exposed
    44 / 381 (11.55%)
    17 / 377 (4.51%)
         occurrences all number
    49
    17
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    66 / 381 (17.32%)
    61 / 377 (16.18%)
         occurrences all number
    84
    95
    Dysgeusia
         subjects affected / exposed
    36 / 381 (9.45%)
    26 / 377 (6.90%)
         occurrences all number
    39
    27
    Headache
         subjects affected / exposed
    51 / 381 (13.39%)
    40 / 377 (10.61%)
         occurrences all number
    67
    65
    Hypoaesthesia
         subjects affected / exposed
    29 / 381 (7.61%)
    34 / 377 (9.02%)
         occurrences all number
    33
    39
    Neuralgia
         subjects affected / exposed
    38 / 381 (9.97%)
    44 / 377 (11.67%)
         occurrences all number
    51
    57
    Neuropathy peripheral
         subjects affected / exposed
    117 / 381 (30.71%)
    133 / 377 (35.28%)
         occurrences all number
    145
    178
    Paraesthesia
         subjects affected / exposed
    24 / 381 (6.30%)
    27 / 377 (7.16%)
         occurrences all number
    29
    37
    Peripheral sensory neuropathy
         subjects affected / exposed
    42 / 381 (11.02%)
    46 / 377 (12.20%)
         occurrences all number
    49
    64
    Polyneuropathy
         subjects affected / exposed
    28 / 381 (7.35%)
    28 / 377 (7.43%)
         occurrences all number
    35
    36
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    155 / 381 (40.68%)
    125 / 377 (33.16%)
         occurrences all number
    305
    231
    Leukopenia
         subjects affected / exposed
    61 / 381 (16.01%)
    31 / 377 (8.22%)
         occurrences all number
    173
    77
    Lymphopenia
         subjects affected / exposed
    52 / 381 (13.65%)
    35 / 377 (9.28%)
         occurrences all number
    149
    113
    Neutropenia
         subjects affected / exposed
    112 / 381 (29.40%)
    40 / 377 (10.61%)
         occurrences all number
    296
    102
    Thrombocytopenia
         subjects affected / exposed
    238 / 381 (62.47%)
    150 / 377 (39.79%)
         occurrences all number
    697
    342
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    28 / 381 (7.35%)
    31 / 377 (8.22%)
         occurrences all number
    32
    36
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    30 / 381 (7.87%)
    26 / 377 (6.90%)
         occurrences all number
    32
    31
    Abdominal pain
         subjects affected / exposed
    50 / 381 (13.12%)
    38 / 377 (10.08%)
         occurrences all number
    76
    44
    Abdominal pain upper
         subjects affected / exposed
    43 / 381 (11.29%)
    36 / 377 (9.55%)
         occurrences all number
    54
    51
    Constipation
         subjects affected / exposed
    102 / 381 (26.77%)
    122 / 377 (32.36%)
         occurrences all number
    135
    159
    Diarrhoea
         subjects affected / exposed
    254 / 381 (66.67%)
    157 / 377 (41.64%)
         occurrences all number
    655
    342
    Dyspepsia
         subjects affected / exposed
    47 / 381 (12.34%)
    43 / 377 (11.41%)
         occurrences all number
    52
    54
    Nausea
         subjects affected / exposed
    138 / 381 (36.22%)
    78 / 377 (20.69%)
         occurrences all number
    212
    118
    Vomiting
         subjects affected / exposed
    91 / 381 (23.88%)
    47 / 377 (12.47%)
         occurrences all number
    141
    54
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    33 / 381 (8.66%)
    23 / 377 (6.10%)
         occurrences all number
    40
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    25 / 381 (6.56%)
    26 / 377 (6.90%)
         occurrences all number
    28
    35
    Back pain
         subjects affected / exposed
    45 / 381 (11.81%)
    46 / 377 (12.20%)
         occurrences all number
    51
    51
    Bone pain
         subjects affected / exposed
    21 / 381 (5.51%)
    31 / 377 (8.22%)
         occurrences all number
    24
    37
    Muscle spasms
         subjects affected / exposed
    23 / 381 (6.04%)
    21 / 377 (5.57%)
         occurrences all number
    29
    25
    Muscular weakness
         subjects affected / exposed
    24 / 381 (6.30%)
    20 / 377 (5.31%)
         occurrences all number
    26
    21
    Myalgia
         subjects affected / exposed
    24 / 381 (6.30%)
    24 / 377 (6.37%)
         occurrences all number
    32
    30
    Pain in extremity
         subjects affected / exposed
    40 / 381 (10.50%)
    54 / 377 (14.32%)
         occurrences all number
    47
    61
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    20 / 381 (5.25%)
    25 / 377 (6.63%)
         occurrences all number
    23
    28
    Herpes zoster
         subjects affected / exposed
    15 / 381 (3.94%)
    36 / 377 (9.55%)
         occurrences all number
    16
    42
    Nasopharyngitis
         subjects affected / exposed
    49 / 381 (12.86%)
    43 / 377 (11.41%)
         occurrences all number
    59
    60
    Respiratory tract infection
         subjects affected / exposed
    17 / 381 (4.46%)
    20 / 377 (5.31%)
         occurrences all number
    27
    39
    Upper respiratory tract infection
         subjects affected / exposed
    66 / 381 (17.32%)
    54 / 377 (14.32%)
         occurrences all number
    104
    84
    Urinary tract infection
         subjects affected / exposed
    23 / 381 (6.04%)
    15 / 377 (3.98%)
         occurrences all number
    30
    19
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    106 / 381 (27.82%)
    46 / 377 (12.20%)
         occurrences all number
    152
    58
    Hyperglycaemia
         subjects affected / exposed
    30 / 381 (7.87%)
    25 / 377 (6.63%)
         occurrences all number
    53
    46
    Hypoalbuminaemia
         subjects affected / exposed
    21 / 381 (5.51%)
    8 / 377 (2.12%)
         occurrences all number
    32
    8
    Hypocalcaemia
         subjects affected / exposed
    35 / 381 (9.19%)
    32 / 377 (8.49%)
         occurrences all number
    60
    46
    Hypokalaemia
         subjects affected / exposed
    100 / 381 (26.25%)
    53 / 377 (14.06%)
         occurrences all number
    197
    91
    Hyponatraemia
         subjects affected / exposed
    48 / 381 (12.60%)
    18 / 377 (4.77%)
         occurrences all number
    77
    29
    Hypophosphataemia
         subjects affected / exposed
    42 / 381 (11.02%)
    32 / 377 (8.49%)
         occurrences all number
    91
    98

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jun 2010
    This amendment was a local, country-specific amendment for Japan whose main purpose was to include hospitalization of Japanese patients during the first cycle of treatment in order to comply with the local bortezomib label. Secondly, this amendment included PK sampling on Cycle 1 Day 1 and Cycle 1 Day 8 in Japanese patients. Thirdly, this amendment added the commercially available dosage form of bortezomib available in Japan as part of the global protocol. As of the release date of this amendment, 34 patients had been randomized worldwide
    22 Dec 2011
    As of 17-Nov-2011, 668 patients had been randomized worldwide. This amendment was a global amendment to adjust the sample size to compensate for a higher than expected drop-out rate in the absence of any safety concerns. The study design was based on the best available information from the literature, other ongoing panobinostat trials, historical data and expert opinion. A review of blinded data concluded that the drop-out rate was higher than originally assumed. The main reason for the drop-out rate was that patients who discontinued treatment withdrew their consent to be followed for response assessment as per protocol. As a consequence, the expected drop-out rate as written in the statistical section of the original protocol needed to be updated. The sample size was therefore recalculated in order to attain the targeted number of PFS events while maintaining the original statistical assumptions. In addition to the increased sample size, an operational action plan for new and ongoing patients was put into place to follow patients for disease assessment after treatment discontinuation
    07 Mar 2012
    This amendment is a global amendment to enhance robustness of analysis at the second interim analysis (IA2), in order to provide a more precise estimate of the treatment effect and to increase probability of detecting a treatment effect at IA2. Consequently, this amendment increases the event (PFS) fraction for IA2 from 67% to 80% (306 to 368 events). In case the study is stopped at IA2 with higher fraction of the planned PFS events, the risk of an overestimation of the treatment effect would be reduced. As outlined in the statistical design, the group-sequential plan of the original CLBH589D2308 protocol stipulated two interim analyses corresponding to the time point when 33% (IA1:153 PFS events) and 67% (IA2:306 PFS events) of the total planned 460 PFS events have occurred. These time points were expected 13 months after start of randomization for IA1, 20 months for IA2, and 29 months for the final PFS analysis, respectively under the assumption of 30 patients / month accrual and 10% dropout rate. In this amendment the assumptions on the treatment effect (HR 0.74) are unchanged. The power to detect the treatment effect and to stop the study at IA2 for efficacy is increased from 53% to 71%. The cumulative type I error is unchanged (less than 5 %, two-sided).
    02 Oct 2012
    The main aim of this global amendment is to clarify that the collection of serum calcium variables (ionized serum calcium and/or total serum calcium and serum albumin for the derivation of albumin-adjusted serum calcium) should continue after the end of treatment until the end of follow-up for disease evaluations. The collection of these variables is already described in the Novartis Guidelines for response assessment in Multiple Myeloma (Post-text supplement 2), and is mandatory to identify hypercalcemia as part of progressive disease and relapse criteria, during treatment phase and for all patients who have entered or will enter post-treatment disease evaluations.
    06 May 2013
    For efficacy assessments, the study protocol requires measurement of the monoclonal protein (M-protein) spike by protein electrophoresis (PEP) in serum and urine as per modified EBMT criteria. Sites participating in the study used their local laboratories to perform the M-protein assessments. However, it was recently identified, that some study patients were monitored using either PEP without specific measurement of the M-protein spike (e.g. globulin gamma fraction was used as indicator for M-component IgG) or by alternative methods, other than PEP (e.g. nephelometric quantification of immunoglobulin levels). Although these methods are used in routine clinical practice, they are not a part of mEBMT criteria. The objective of this protocol amendment is: a. to document use of PEP results without specific measurement of the M-protein spike. b. to document use of measurement methods other than PEP (e.g. nephelometry) Regardless of the method used before this amendment, patients should continue to be followed with the same method throughout the study to ensure intra-patient consistency. The primary PFS analysis remains based on the Investigator’s response assessment following the ITT principle. The newly collected data will be used in sensitivity analyses of PFS and other efficacy related endpoints, including an analysis using independent response assessment in patients for whom M-protein was not measured by electrophoresis or electrophoresis was used without measurement of M-protein spike. This specific assessment will be done by an Independent Review Committee (IRC). Detailed instructions on the independent review process will be included in the IRC Charter. Additional sensitivity analyses will be presented in detail in the Report Analysis Plan.
    21 Aug 2014
    Based on the trial’s positive outcome for the final analysis of the primary endpoint PFS, Novartis has submitted the study results to several health authorities seeking regulatory approval of panobinostat in multiple myeloma. Overall survival (OS) is a key secondary endpoint in this study. The final analysis of OS is planned to be performed when approximately 415 survival events have been documented. The main purpose of this amendment is to introduce an additional (fourth) OS interim analysis when approximately 90% of the targeted number of OS events have been reached, in order to support the benefit/risk assessment of the studied investigational treatment prior to the final OS analysis, as agreed with the FDA. The OS alpha spending function for the additional IA and the final analysis will be adjusted to ensure control of the overall type I error.

    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
    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.

    European Medicines Agency © 1995-Sun Apr 28 19:54:53 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA