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    Clinical Trial Results:
    A phase Ib, multi-center, open-label, dose-escalation study of oral panobinostat (PAN) when administered in combination with oral lenalidomide and dexamethasone in adult patients with multiple myeloma

    Summary
    EudraCT number
    		 2006-007030-35
    Trial protocol
    		 IT  
    Global end of trial date
    08 Nov 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Nov 2018
    First version publication date
    24 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLBH589B2206
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00532675
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    08 Nov 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the maximum tolerated dose (MTD) of panobinostat (PAN) when used in combination with a fixed dose of lenalidomide (Revlimid®) and dexamethasone
    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
    22 Aug 2008
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 18
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Spain: 16
    Worldwide total number of subjects
    46
    EEA total number of subjects
    21
    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)
    32
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 46 patients were enrolled in this study and were assigned treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PAN 5 mg
    Arm description
    		 PAN 5 mg in combination with lenalidomide and dexamethasone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat hard gelatin capsules 5 mg or 20 mg and administered orally at escalating dose for three days per week (i.e., Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 in a 28-day cycle).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlamid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was supplied as 5 mg and 25 mg capsules which was administered at a dose of 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles.

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets was supplied locally by each study site and administered at a dose of 40 mg orally once daily on Days 1-4, 9-12, and 17-20 for the first 4 cycles, then once daily on Days 1-4 every 28 days thereafter.

    Arm title
    		 PAN 10 mg
    Arm description
    		 Pan 10 mg in combination with lenalidomide and dexamethasone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat hard gelatin capsules 5 mg or 20 mg and administered orally at escalating dose for three days per week (i.e., Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 in a 28-day cycle).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlamid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was supplied as 5 mg and 25 mg capsules which was administered at a dose of 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles.

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets was supplied locally by each study site and administered at a dose of 40 mg orally once daily on Days 1-4, 9-12, and 17-20 for the first 4 cycles, then once daily on Days 1-4 every 28 days thereafter.

    Arm title
    		 PAN 20 mg
    Arm description
    		 PAN 20 mg in combination with lenalidomide and dexamethasone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat hard gelatin capsules 5 mg or 20 mg and administered orally at escalating dose for three days per week (i.e., Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 in a 28-day cycle).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlamid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was supplied as 5 mg and 25 mg capsules which was administered at a dose of 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles.

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets was supplied locally by each study site and administered at a dose of 40 mg orally once daily on Days 1-4, 9-12, and 17-20 for the first 4 cycles, then once daily on Days 1-4 every 28 days thereafter.

    Arm title
    		 Pan 25 mg
    Arm description
    		 PAN 25 mg in combination with lenalidomide and dexamethasone
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    LBH589
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Panobinostat hard gelatin capsules 5 mg or 20 mg and administered orally at escalating dose for three days per week (i.e., Days 1, 3, 5, 8, 10, 12, 15, 17, 19, 22, 24 and 26 in a 28-day cycle).

    Investigational medicinal product name
    Lenalidomide
    Investigational medicinal product code
    Other name
    Revlamid
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenalidomide was supplied as 5 mg and 25 mg capsules which was administered at a dose of 25 mg orally once daily on Days 1 to 21 of repeated 28-day cycles.

    Investigational medicinal product name
    dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone tablets was supplied locally by each study site and administered at a dose of 40 mg orally once daily on Days 1-4, 9-12, and 17-20 for the first 4 cycles, then once daily on Days 1-4 every 28 days thereafter.

    Number of subjects in period 1
    		PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Started
    8
    8
    21
    9
    Completed
    0
    0
    0
    0
    Not completed
    8
    8
    21
    9
         Abnormal laboratory value(s)
    -
    1
    -
    -
         Consent withdrawn by subject
    2
    1
    3
    1
         Adverse event, non-fatal
    3
    3
    8
    4
         Death
    -
    -
    4
    -
         Disease Progression
    3
    3
    5
    4
         Protocol deviation
    -
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PAN 5 mg
    Reporting group description
    		 PAN 5 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    PAN 10 mg
    Reporting group description
    		 Pan 10 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    PAN 20 mg
    Reporting group description
    		 PAN 20 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    Pan 25 mg
    Reporting group description
    		 PAN 25 mg in combination with lenalidomide and dexamethasone

    Reporting group values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg Total
    Number of subjects
    		 8 8 21 9 46
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.9 ( 8.54 ) 60.6 ( 5.66 ) 59.1 ( 10.56 ) 56.1 ( 10.84 ) -
    Gender categorical
    Units: Subjects
        Female
    		 1 2 9 5 17
        Male
    		 7 6 12 4 29

    End points

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    End points reporting groups
    Reporting group title
    PAN 5 mg
    Reporting group description
    		 PAN 5 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    PAN 10 mg
    Reporting group description
    		 Pan 10 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    PAN 20 mg
    Reporting group description
    		 PAN 20 mg in combination with lenalidomide and dexamethasone

    Reporting group title
    Pan 25 mg
    Reporting group description
    		 PAN 25 mg in combination with lenalidomide and dexamethasone

    Primary: Maximum Therapeutic Dose (MTD) of Panobinostat in combination with a fixed dose of lenalidomide and dexamethasone

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    End point title
    		 Maximum Therapeutic Dose (MTD) of Panobinostat in combination with a fixed dose of lenalidomide and dexamethasone [1]
    End point description
    After a total of 46 patients had been enrolled into the dose escalation phase, it was concluded that the dosing regimen and schedule needed to be changed for the combination used in this study, based on a review of the accrued safety data and evolution of medical practice on usage of dexamethasone. It was decided that recommended dosing regimen and schedule for this combination would be better implemented in a new study, rather than in a complex protocol amendment. Hence, this study was stopped without determining the MTD, and the dose expansion phase of the study was not initiated.
    End point type
    Primary
    End point timeframe
    24 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: After a total of 46 subjects had been enrolled into the dose escalation phase, it was concluded that the dosing regimen and schedule needed to be changed for the combination used in this study, based on a review of the accrued safety data and evolution of medical practice on usage of dexamethasone. It was decided that recommended dosing regimen and schedule for this combination would be better implemented in a new study, rather than in a complex protocol amendment. The study stopped enrollment.
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    Units: patients
    Notes
    [2] - Study enrolment stopped without determining the MTD, & the dose expansion phase was not initiated
    [3] - Study enrolment stopped without determining the MTD, & the dose expansion phase was not initiated
    [4] - Study enrolment stopped without determining the MTD, & the dose expansion phase was not initiated
    [5] - Study enrolment stopped without determining the MTD, & the dose expansion phase was not initiated
    No statistical analyses for this end point

    Secondary: Overall Response (OR) per investigator's assessment by dose level of Panobinostat

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    End point title
    		 Overall Response (OR) per investigator's assessment by dose level of Panobinostat
    End point description
    Patients with confirmed best overall response = Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR)+ Partial Response (PR) were summarized on the Full Analysis Set (FAS). All 46 enrolled patients received at least one dose of study treatment; they were therefore included in the FAS.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: patients
    6
    1
    8
    4
    No statistical analyses for this end point

    Secondary: OR as per investigator’s assessment for patients with measurable disease at baseline by dose level of Panobinostat

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    End point title
    		 OR as per investigator’s assessment for patients with measurable disease at baseline by dose level of Panobinostat
    End point description
    Patients with confirmed best overall response as per investigator's assessment for patients with measurable disease = Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR)+ Partial Response (PR) were summarized on the Full Analysis Set (FAS). Best confirmed overall response was analyzed by patients with measurable disease at baseline as per the International Myeloma Working Group criteria (IMWG)specified for serum M protein, urine M protein, FLC level and bone marrow plasma cell percentage. All 46 enrolled patients received at least one dose of study treatment; they were therefore included in the FAS.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    7
    8
    19
    8
    Units: patients
    5
    1
    7
    4
    No statistical analyses for this end point

    Secondary: OR as per investigator’s assessment for relapsed-and-refractory patients by dose level of Panobinostat

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    End point title
    		 OR as per investigator’s assessment for relapsed-and-refractory patients by dose level of Panobinostat
    End point description
    Patients with confirmed best overall response (OR) as per investigator's assessment for relapsed and refractory patients = Stringent Complete Response (sCR) + Complete Response (CR) + Very Good Partial Response (VGPR)+ Partial Response (PR) were summarized on the Full Analysis Set (FAS). All 46 enrolled patients received at least one dose of study treatment; they were therefore included in the FAS.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    5
    6
    13
    6
    Units: patients
    4
    0
    4
    2
    No statistical analyses for this end point

    Secondary: Summary statistics of AUCinf for Panobinostat on Day 1

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    End point title
    		 Summary statistics of AUCinf for Panobinostat on Day 1
    End point description
    Area Under the Curve from 0 to infinity (AUCinf) for Panobinostat on Day 1 Pharmacokinetics (PK) set: consisted of all patients with evaluable PK profile on Day 1 and/or steady state PK concentrations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: ng∙h/mL
        arithmetic mean (standard deviation)
    22.79 ( 25.1 )
    37.52 ( 34.1 )
    90.85 ( 44.4 )
    117.55 ( 43.7 )
    No statistical analyses for this end point

    Secondary: Summary statistics of AUClast for Panobinostat on Day 1

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    End point title
    		 Summary statistics of AUClast for Panobinostat on Day 1
    End point description
    Area Under the Curve from 0 to the time of the last quantifiable concentration; Pharmacokinetics (PK) set: consisted of all patients with evaluable PK profile on Day 1 and/or steady state PK concentrations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: ng∙h/mL
        arithmetic mean (standard deviation)
    10.14 ( 8.6 )
    31.38 ( 31.2 )
    75.93 ( 41.9 )
    102.53 ( 38.7 )
    No statistical analyses for this end point

    Secondary: Summary statistics of Cmax for Panobinostat on Day 1

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    End point title
    		 Summary statistics of Cmax for Panobinostat on Day 1
    End point description
    Maximum observed concentration (Cmax) is the peak serum concentration of a therapeutic drug after administration; and is used to determine the rate and extent of drug absorption; Pharmacokinetics (PK) set: consisted of all patients with evaluable PK profile on Day 1 and/or steady state PK concentrations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: ng/mL
        arithmetic mean (standard deviation)
    1.87 ( 0.8 )
    7.89 ( 5.8 )
    13.91 ( 9.2 )
    20.03 ( 10.09 )
    No statistical analyses for this end point

    Secondary: Summary statistics of Tmax for Panobinostat on Day 1

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    End point title
    		 Summary statistics of Tmax for Panobinostat on Day 1
    End point description
    Tmax = Time of occurrence of Cmax, Cmax is the peak serum concentration of a therapeutic drug after administration; and is used to determine the rate and extent of drug absorption; Pharmacokinetics (PK) set: consisted of all patients with evaluable PK profile on Day 1 and/or steady state PK concentrations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: hours
        median (full range (min-max))
    1.26 (0.75 to 4.00)
    1.25 (0.50 to 3.00)
    1.00 (0.42 to 2.50)
    1.00 (0.50 to 3.00)
    No statistical analyses for this end point

    Secondary: Summary statistics of T1/2 for Panobinostat on Day 1

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    End point title
    		 Summary statistics of T1/2 for Panobinostat on Day 1
    End point description
    t 1/2 = Terminal elimination half-life; Pharmacokinetics (PK) set: consisted of all patients with evaluable PK profile on Day 1 and/or steady state PK concentrations.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 PAN 5 mg PAN 10 mg PAN 20 mg Pan 25 mg
    Number of subjects analysed
    8
    8
    21
    9
    Units: hours
        arithmetic mean (standard deviation)
    15.35 ( 27.3 )
    4.40 ( 2.5 )
    11.51 ( 4.7 )
    13.57 ( 5.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    PAN 5 mg
    Reporting group description
    		 PAN 5 mg

    Reporting group title
    PAN 10 mg
    Reporting group description
    		 PAN 10 mg

    Reporting group title
    PAN 20 mg
    Reporting group description
    		 PAN 20 mg

    Reporting group title
    PAN 25 mg
    Reporting group description
    		 PAN 25 mg

    Serious adverse events
    		 PAN 5 mg PAN 10 mg PAN 20 mg PAN 25 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 8 (62.50%)
    18 / 21 (85.71%)
    7 / 9 (77.78%)
         number of deaths (all causes)
    0
    0
    6
    1
         number of deaths resulting from adverse events
    0
    0
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to soft tissue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    4 / 9 (44.44%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 8
    0 / 4
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    4 / 21 (19.05%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 8
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhythm idioventricular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    4 / 21 (19.05%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
    6 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal suppression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteolysis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacterial infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis B
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Listeria sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    2 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
    4 / 6
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic embolus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PAN 5 mg PAN 10 mg PAN 20 mg PAN 25 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    8 / 8 (100.00%)
    21 / 21 (100.00%)
    9 / 9 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    2
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    4
    4
    Orthostatic hypotension
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    3 / 9 (33.33%)
         occurrences all number
    0
    0
    6
    12
    Phlebitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    7 / 21 (33.33%)
    6 / 9 (66.67%)
         occurrences all number
    2
    6
    26
    20
    Chest discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    4
    0
    0
    Chills
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    2
    0
    Discomfort
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 8 (75.00%)
    3 / 8 (37.50%)
    7 / 21 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    14
    8
    14
    12
    Feeling abnormal
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Malaise
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    2 / 9 (22.22%)
         occurrences all number
    2
    0
    4
    4
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    4 / 21 (19.05%)
    5 / 9 (55.56%)
         occurrences all number
    0
    4
    12
    10
    Pyrexia
         subjects affected / exposed
    5 / 8 (62.50%)
    2 / 8 (25.00%)
    7 / 21 (33.33%)
    2 / 9 (22.22%)
         occurrences all number
    10
    8
    30
    10
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Catarrh
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    12
    2
    Cough
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    4
    2
    6
    4
    Dysphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Dyspnoea
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    6
    0
    2
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    4
    4
    Epistaxis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    6
    4
    Hiccups
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    4
    0
    0
    4
    Pleuritic pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Respiratory depression
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Depressed mood
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Depression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    7 / 21 (33.33%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    14
    2
    Libido decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Mania
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    4
    Stress
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    4
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    8
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    6
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Weight decreased
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    5 / 21 (23.81%)
    1 / 9 (11.11%)
         occurrences all number
    6
    6
    10
    2
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    4
    2
    0
    2
    Excoriation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Femur fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Foreign body in eye
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pelvic fracture
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Cardiotoxicity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Coronary artery disease
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Tachycardia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Coordination abnormal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Dizziness
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    5 / 21 (23.81%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    18
    0
    Dizziness postural
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Dysgeusia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    3 / 21 (14.29%)
    3 / 9 (33.33%)
         occurrences all number
    2
    4
    6
    6
    Essential tremor
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Head discomfort
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Headache
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    3 / 21 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    6
    4
    8
    4
    Loss of consciousness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Neuralgia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    6
    2
    4
    2
    Paraesthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Sciatica
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    0
    2
    Syncope
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Tremor
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    13 / 21 (61.90%)
    6 / 9 (66.67%)
         occurrences all number
    10
    18
    126
    36
    Febrile neutropenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    4
    0
    Leukopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    4 / 9 (44.44%)
         occurrences all number
    0
    2
    14
    26
    Lymphopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    2
    4
    Neutropenia
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 8 (50.00%)
    13 / 21 (61.90%)
    8 / 9 (88.89%)
         occurrences all number
    14
    30
    256
    58
    Thrombocytopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 8 (37.50%)
    13 / 21 (61.90%)
    8 / 9 (88.89%)
         occurrences all number
    4
    16
    162
    52
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    4
    4
    Vision blurred
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    0
    2
    Vitreous floaters
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    2
    4
    6
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    8
    4
    Aphthous ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Constipation
         subjects affected / exposed
    4 / 8 (50.00%)
    1 / 8 (12.50%)
    10 / 21 (47.62%)
    3 / 9 (33.33%)
         occurrences all number
    8
    2
    24
    6
    Diarrhoea
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 8 (37.50%)
    13 / 21 (61.90%)
    6 / 9 (66.67%)
         occurrences all number
    12
    12
    66
    36
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Flatulence
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Gingival bleeding
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    6
    0
    Nausea
         subjects affected / exposed
    2 / 8 (25.00%)
    4 / 8 (50.00%)
    11 / 21 (52.38%)
    5 / 9 (55.56%)
         occurrences all number
    4
    8
    28
    12
    Oesophagitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Oral pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Retching
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 8 (25.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    4
    2
    0
    Tooth disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    6 / 21 (28.57%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    20
    4
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    6
    8
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Dermal cyst
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    0
    2
    Ingrowing nail
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Precancerous skin lesion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    2
    0
    2
    2
    Rash
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    2 / 21 (9.52%)
    2 / 9 (22.22%)
         occurrences all number
    6
    6
    4
    4
    Urticaria
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    0
    2
    Micturition disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nephrolithiasis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pollakiuria
         subjects affected / exposed
    2 / 8 (25.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Renal impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Hypothyroidism
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Steroid withdrawal syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    2 / 9 (22.22%)
         occurrences all number
    0
    0
    6
    4
    Back pain
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    8
    2
    10
    6
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Joint swelling
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    6 / 8 (75.00%)
    2 / 8 (25.00%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    20
    4
    6
    4
    Muscular weakness
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 8 (25.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    6
    4
    4
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    0
    4
    Osteoarthritis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pain in extremity
         subjects affected / exposed
    3 / 8 (37.50%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    6
    2
    6
    2
    Infections and infestations
    Campylobacter infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    4
    Gastroenteritis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Laryngitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Localised infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    4
    4
    2
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Oral herpes
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    0
    8
    10
    2
    Sinusitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Subcutaneous abscess
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Tonsillitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    4
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 8 (50.00%)
    2 / 8 (25.00%)
    4 / 21 (19.05%)
    1 / 9 (11.11%)
         occurrences all number
    28
    28
    8
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Vulvitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 8 (25.00%)
    5 / 21 (23.81%)
    6 / 9 (66.67%)
         occurrences all number
    6
    4
    18
    14
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 9 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    0
    2
    Hyperglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 8 (37.50%)
    7 / 21 (33.33%)
    0 / 9 (0.00%)
         occurrences all number
    0
    12
    24
    0
    Hypermagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    4
    2
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    7 / 21 (33.33%)
    4 / 9 (44.44%)
         occurrences all number
    0
    12
    30
    24
    Hypokalaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 8 (62.50%)
    10 / 21 (47.62%)
    3 / 9 (33.33%)
         occurrences all number
    6
    24
    38
    28
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 8 (25.00%)
    3 / 21 (14.29%)
    2 / 9 (22.22%)
         occurrences all number
    0
    14
    10
    10
    Hyponatraemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    1 / 9 (11.11%)
         occurrences all number
    6
    0
    8
    2
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 8 (12.50%)
    4 / 21 (19.05%)
    4 / 9 (44.44%)
         occurrences all number
    2
    4
    8
    20
    Hypoproteinaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2008
    Protocol Amendment 1: Lenalididomide (Revlimid®) is a highly-regulated drug that has been recently approved by only a small number of health authorities around the world. In order for Novartis to use Revlimid® as a combination partner with LBH589 in the CLBH589B2206 trial, the company has entered into a Collaboration Agreement with Celgene Corporation, the manufacturers of Revlimid®. Celgene has agreed to provide Novartis with sufficient supplies of Revlimid® at no cost in exchange for the final study report. However, one of Novartis’ key contractual obligations is to allow Celgene to review and comment on the original CLBH589B2206 Protocol Version 00, dated 18 April 2007. Celgene has completed their review, and the primary purpose of this amendment is to incorporate their comments into a new version of the document. In addition, there have been some adjustments made to the Bayesian statistical model being used in the trial. The details of these changes together with the correction of minor inconsistencies are described below.
    16 May 2011
    Amendment 2 Summary of changes: • Reduce the number of visits and assessments for the ongoing patients: • Reduce from weekly to biweekly the frequency for non labs AE assessments • Reduce ECG monitoring schedule frequency following program wide change • Points updated and / or clarified: • Clarification on the timing and wording for re-assessment of bone lesions • Update of the disease status categories for Investigator’s assessment, introducing the category of Minimal Response (MR) in accordance with the update of IMWG response criteria. • Add definition for “clinical relapse” criterion. • Update the Safety Set definition and define the Fully Analysis set as per updated Novartis standard definitions. • Update to the safety section of the combination partner drug

    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.
    Novartis decided to terminate study enrollment on 08 Sep 2010 as there were complex changes in the dosing schedule required from safety perspective after a protocol defined routine review of safety data.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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