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    Clinical Trial Results:
    A phase Ib, multi-center, open-label, dose-escalation study of oral LBH589 and IV bortezomib in adult patients with multiple myeloma

    Summary
    EudraCT number
    		 2006-006638-16
    Trial protocol
    		 IT  
    Global end of trial date
    07 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    13 Aug 2015
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLBH589B2207
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00532389
    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
    07 Oct 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2013
    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) and bortezomib (BTZ) when administered in combination.
    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. In the dose escalation phase of the study, Investigators could use their discretion to add Dexamethasone to the study treatment of subjects who in their opinion could benefit from its addition after the completion of Cycle 1.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Oct 2007
    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
    United States: 14
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Canada: 7
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Italy: 3
    Worldwide total number of subjects
    62
    EEA total number of subjects
    39
    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)
    44
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects were screened for eligibility over a period of 2 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg capsules for a total dose of 10 mg daily on Days 1, 3, 5, 8, 10, 12, 15, 17, 19, and 21 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.0 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Arm title
    		 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for Bortezomib (BTZ) and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg or 20 mg capsules for a total dose of 20 mg daily on Days 1, 3, 5, 8, 10, 12, 15, 17, 19, and 21 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.0 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Arm title
    		 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg or 20 mg capsules for a total dose of 20 mg daily on Days 1, 3, 5, 8, 10, 12, 15, 17, 19, and 21 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Arm title
    		 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg and 20 mg capsules for a total dose of 30 mg daily on Days 1, 3, 5, 8, 10, 12, 15, 17, 19, and 21 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Arm title
    		 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg and 20 mg capsules for a total dose of 25 mg daily on Days 1, 3, 5, 8, 10, 12, 15, 17, 19, and 21 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.3 mg/m2 on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Arm title
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Arm description
    		 Subjects received Panobinostat (PAN) three days per week for two weeks, Bortezomib (BTZ) four times over the first eleven days, and Dexamethasone (DEX) four times per week for two weeks (Cycle 2 onwards), for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. The maximum duration for BTZ and DEX treatment was eight cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Panobinostat
    Investigational medicinal product code
    Other name
    LBH589
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered a combination of 5 mg or 20 mg capsules for a total dose of 20 mg on Days 1, 3, 5, 8, 10, and 12 of each 21-day treatment cycle until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion.

    Investigational medicinal product name
    Bortezomib
    Investigational medicinal product code
    Other name
    Velcade
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects were administered a 3 to 5-second bolus intravenous (IV) injection for a total dose of 1.3 mg/m2 twice weekly on Days 1, 4, 8, and 11 of each 21-day cycle, followed by a 10-day treatment holiday. The maximum duration for Bortezomib (BTZ) treatment was eight cycles.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 20 mg of DEX on Days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day treatment cycle starting with Cycle 2.

    Number of subjects in period 1
    		Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Started
    7
    7
    17
    7
    9
    15
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    7
    7
    17
    7
    9
    15
         Adverse event, serious fatal
    -
    -
    -
    -
    -
    1
         Subject withdrew consent
    1
    -
    2
    1
    1
    2
         Disease progression
    3
    4
    5
    2
    4
    6
         Adverse event, non-fatal
    1
    2
    8
    4
    3
    5
         Administrative problems
    1
    1
    2
    -
    1
    1
         Abnormal laboratory values
    1
    -
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose escalation PAN 10 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 20 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for Bortezomib (BTZ) and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 20 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 30 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week for two weeks, Bortezomib (BTZ) four times over the first eleven days, and Dexamethasone (DEX) four times per week for two weeks (Cycle 2 onwards), for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg Total
    Number of subjects
    		 7 7 17 7 9 15 62
    Age categorical
    Units: Subjects
        < 65 years
    		 4 6 10 6 6 12 44
        >/= 65 years
    		 3 1 7 1 3 3 18
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.1 ( 10.67 ) 57.6 ( 10.49 ) 64.4 ( 8.8 ) 60 ( 7.16 ) 60.3 ( 8.62 ) 60.8 ( 6.32 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 1 6 3 2 4 19
        Male
    		 4 6 11 4 7 11 43

    End points

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    End points reporting groups
    Reporting group title
    Dose escalation PAN 10 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 20 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for Bortezomib (BTZ) and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 20 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 30 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week and Bortezomib (BTZ) four times over the first eleven days, for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. Dexamethasone (DEX; 20 mg oral) could be administered on the day of and the day after BTZ treatment from Cycle 2 onward at the Investigator’s discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Reporting group title
    Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Reporting group description
    		 Subjects received Panobinostat (PAN) three days per week for two weeks, Bortezomib (BTZ) four times over the first eleven days, and Dexamethasone (DEX) four times per week for two weeks (Cycle 2 onwards), for at least one 21-day cycle. Subjects were permitted to remain on PAN until disease progression, unacceptable toxicity, subject refusal and/or at Investigator’s own discretion. The maximum duration for BTZ and DEX treatment was eight cycles.

    Primary: Number of Subjects With Dose-Limiting Toxicities

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    End point title
    		 Number of Subjects With Dose-Limiting Toxicities [1] [2]
    End point description
    A dose limiting toxicity (DLT) was defined as an adverse event (AE) or abnormal laboratory value assessed as clinically relevant and occurring ≤ 21 days following the first dose of study treatment in Cycle 1. This endpoint analyzed the Maximum Tolerated Dose Determining Set (MTD Determining Set), defined as
    End point type
    Primary
    End point timeframe
    Up to 21 days after the start of treatment
    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: No statistical analysis was planned for this primary outcome measure.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for dose-limiting toxicities were not collected from subjects in the dose-expansion arm of the study.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    6
    5
    15
    6
    6
    Units: subjects
    0
    0
    3
    4
    2
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Area Under The Concentration-Time Curve From Time Zero to 48 Hours (AUC0-48) of Panobinostat During Cycle 1 of Dose Escalation [3]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [4]
    16 [5]
    6 [6]
    8 [7]
    Units: ng.h/mL
    geometric mean (geometric coefficient of variation)
        Day 8
    27.8 ( 38.6 )
    111.4 ( 95.6 )
    107.8 ( 64.6 )
    134.6 ( 38.4 )
    134.7 ( 36.9 )
        Day 15
    25.5 ( 39 )
    82.6 ( 61.4 )
    91.9 ( 91.9 )
    171.3 ( 85.7 )
    95.1 ( 142.4 )
    Notes
    [4] - n = 6, 4
    [5] - n = 15, 14
    [6] - n = 5, 4
    [7] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Maximum Observed Concentration (Cmax) of Panobinostat During Cycle 1 of Dose Escalation [8]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [9]
    16 [10]
    6 [11]
    8 [12]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 8
    3.5 ( 10.8 )
    10.8 ( 125.5 )
    15.8 ( 63.2 )
    14.5 ( 74.8 )
    18 ( 47.6 )
        Day 15
    4.8 ( 68.8 )
    7.6 ( 50.6 )
    12.2 ( 103.3 )
    19.8 ( 109.6 )
    12 ( 105.4 )
    Notes
    [9] - n = 6, 4
    [10] - n = 15, 14
    [11] - n = 5, 4
    [12] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Last Measurable Concentration (Clast) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Last Measurable Concentration (Clast) of Panobinostat During Cycle 1 of Dose Escalation [13]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [14]
    16 [15]
    6 [16]
    8 [17]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Day 8
    0.7 ( 24.8 )
    1.3 ( 63.1 )
    0.9 ( 31.8 )
    1.1 ( 61.1 )
    1 ( 26 )
        Day 15
    0.8 ( 18.2 )
    1.1 ( 159.4 )
    0.8 ( 44.2 )
    0.9 ( 53.6 )
    1 ( 51.6 )
    Notes
    [14] - n = 6, 4
    [15] - n = 15, 14
    [16] - n = 5, 4
    [17] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Time to Maximum Concentration (Tmax) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Time to Maximum Concentration (Tmax) of Panobinostat During Cycle 1 of Dose Escalation [18]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [19]
    16 [20]
    6 [21]
    8 [22]
    Units: hours
    median (full range (min-max))
        Day 8
    2 (1 to 2)
    2.4 (1 to 3)
    1 (0.1 to 6)
    1 (1 to 3)
    2 (0.5 to 3)
        Day 15
    1 (0.5 to 2.8)
    2 (1 to 3.9)
    1.8 (0.5 to 3)
    1.8 (0.5 to 3.5)
    2 (0.9 to 6)
    Notes
    [19] - n = 6, 4
    [20] - n = 15, 14
    [21] - n = 5, 4
    [22] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Time to Elimination Half-life (T1/2) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Time to Elimination Half-life (T1/2) of Panobinostat During Cycle 1 of Dose Escalation [23]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [24]
    16 [25]
    6 [26]
    8 [27]
    Units: hours
    geometric mean (geometric coefficient of variation)
        Day 8
    7.4 ( 90 )
    13.8 ( 3.3 )
    13.2 ( 65.6 )
    18.7 ( 41.4 )
    15.1 ( 26.4 )
        Day 15
    6.2 ( 68.1 )
    14.4 ( 56.7 )
    14.1 ( 62.3 )
    14.9 ( 23.4 )
    10.8 ( 60.5 )
    Notes
    [24] - n = 5, 4
    [25] - n = 15, 14
    [26] - n = 5, 4
    [27] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Time to Last Measurable Concentration (Tlast) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Time to Last Measurable Concentration (Tlast) of Panobinostat During Cycle 1 of Dose Escalation [28]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [29]
    16 [30]
    6 [31]
    8 [32]
    Units: hours
    median (full range (min-max))
        Day 8
    16 (8 to 24.5)
    24.5 (22.8 to 48)
    46 (8 to 48.8)
    47.1 (24 to 48)
    46.5 (23.9 to 49.2)
        Day 15
    8 (7.8 to 24.1)
    48 (23.5 to 49.8)
    47 (8 to 51.1)
    47.7 (46.8 to 48.2)
    46.3 (5.3 to 48.8)
    Notes
    [29] - n = 6, 4
    [30] - n = 15, 14
    [31] - n = 5, 4
    [32] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Total Body Clearance of Drug From The Plasma (CL/F) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Total Body Clearance of Drug From The Plasma (CL/F) of Panobinostat During Cycle 1 of Dose Escalation [33]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [34]
    16 [35]
    6 [36]
    8 [37]
    Units: L/h
    geometric mean (geometric coefficient of variation)
        Day 8
    358.4 ( 55.3 )
    150.6 ( 108.5 )
    167.1 ( 71.8 )
    184 ( 34.2 )
    166.3 ( 40.6 )
        Day 15
    418.5 ( 54.7 )
    191.9 ( 74.5 )
    193.3 ( 103.7 )
    156.2 ( 81.1 )
    245.5 ( 166 )
    Notes
    [34] - n = 5, 4
    [35] - n = 15, 14
    [36] - n = 5, 4
    [37] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During The Terminal Phase (Associated With λz) (Vz/F) of Panobinostat During Cycle 1 of Dose Escalation

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    End point title
    		 Apparent Volume of Distribution During The Terminal Phase (Associated With λz) (Vz/F) of Panobinostat During Cycle 1 of Dose Escalation [38]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 and 15 of Cycle 1
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    6 [39]
    16 [40]
    6 [41]
    8 [42]
    Units: Litres
    geometric mean (geometric coefficient of variation)
        Day 8
    3815.5 ( 28.3 )
    2990.8 ( 113.1 )
    3175.2 ( 54 )
    4962.7 ( 58.2 )
    3624.2 ( 31.2 )
        Day 15
    3722.4 ( 11.4 )
    3989.3 ( 105.9 )
    3930 ( 56.6 )
    3360.5 ( 106.2 )
    3833.6 ( 81.9 )
    Notes
    [39] - n = 5, 4
    [40] - n = 15, 14
    [41] - n = 5, 4
    [42] - n = 7, 7
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24), 48 Hours (AUC0-48), Time of Last Measurable Concentration (AUC0-tlast), and Infinity (AUC0-inf) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation

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    End point title
    		 Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24), 48 Hours (AUC0-48), Time of Last Measurable Concentration (AUC0-tlast), and Infinity (AUC0-inf) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation [43]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    7
    14
    5
    4
    Units: ng.h/mL
    geometric mean (geometric coefficient of variation)
        AUC0-inf
    160.4 ( 59.1 )
    256.2 ( 48.7 )
    247.3 ( 59.9 )
    192.9 ( 37.8 )
    196.9 ( 74.8 )
        AUC0-tlast
    79 ( 27.2 )
    132.6 ( 58.6 )
    155.4 ( 49.7 )
    109 ( 16.8 )
    123.3 ( 45.5 )
        AUC0-24
    55.9 ( 29.3 )
    95.9 ( 74.1 )
    117.2 ( 58.8 )
    77.1 ( 16.4 )
    88.6 ( 38.9 )
        AUC0-48
    79.4 ( 26.8 )
    132.6 ( 59 )
    158.2 ( 51.6 )
    109.7 ( 16.8 )
    123.9 ( 44.5 )
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) and Last Measurable Concentration (Clast) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation

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    End point title
    		 Maximum Observed Concentration (Cmax) and Last Measurable Concentration (Clast) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation [44]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    7
    14
    5
    4
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmax
    72.7 ( 49.5 )
    179.5 ( 223.3 )
    157.9 ( 65.5 )
    76.8 ( 43.1 )
    101.9 ( 26.5 )
        Clast
    0.9 ( 36.5 )
    1.1 ( 35.1 )
    1.3 ( 55.1 )
    1.2 ( 25.7 )
    1.2 ( 73.3 )
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration (Tmax) and Last Measurable Concentration (Tlast) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation

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    End point title
    		 Time to Maximum Observed Concentration (Tmax) and Last Measurable Concentration (Tlast) of Bortezomib on Day 8 of Cycle 1 of Dose Escalation [45]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    7
    14
    5
    4
    Units: hours
    median (full range (min-max))
        Tmax
    0.1 (0.1 to 0.2)
    0.1 (0 to 0.1)
    0.1 (0 to 1.3)
    0.1 (0.1 to 0.1)
    0.1 (0.1 to 0.1)
        Tlast
    47.5 (47 to 48.1)
    48 (46.8 to 49)
    47.9 (24 to 49)
    47.3 (46.5 to 48)
    47.4 (46.3 to 49.2)
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [46]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [47]
    Units: ng.h/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    61.8 ( 60.9 )
        Cycle 2
    47.5 ( 76.8 )
    Notes
    [47] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Maximum Observed Concentration (Cmax) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [48]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [49]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    9.5 ( 60.4 )
        Cycle 2
    8.1 ( 90.3 )
    Notes
    [49] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Last Measurable Concentration (Clast) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Last Measurable Concentration (Clast) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [50]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [51]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    0.8 ( 52.5 )
        Cycle 2
    0.7 ( 81.2 )
    Notes
    [51] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration (Tmax) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Time to Maximum Observed Concentration (Tmax) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [52]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [53]
    Units: hours
    median (full range (min-max))
        Cycle 1
    2 (0.5 to 3)
        Cycle 2
    1 (0.5 to 6.3)
    Notes
    [53] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Time to Elimination Half-life (T1/2) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Time to Elimination Half-life (T1/2) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [54]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [55]
    Units: hours
    geometric mean (geometric coefficient of variation)
        Cycle 1
    13.3 ( 34.7 )
        Cycle 2
    15.9 ( 29.2 )
    Notes
    [55] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Time to Last Measurable Concentration (Tlast) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Time to Last Measurable Concentration (Tlast) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [56]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [57]
    Units: hours
    median (full range (min-max))
        Cycle 1
    28 (23.9 to 47.7)
        Cycle 2
    28 (25.6 to 28.5)
    Notes
    [57] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Total Body Clearance of Drug From The Plasma (CL/F) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Total Body Clearance of Drug From The Plasma (CL/F) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [58]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [59]
    Units: L/h
    geometric mean (geometric coefficient of variation)
        Cycle 1
    241.5 ( 60.8 )
        Cycle 2
    285.2 ( 79.4 )
    Notes
    [59] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Apparent Volume of Distribution During The Terminal Phase (Associated With λz) (Vz/F) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Apparent Volume of Distribution During The Terminal Phase (Associated With λz) (Vz/F) of Panobinostat on Day 8 of Cycles 1 and 2 of Dose Expansion [60]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for panobinostat (PK set-panobinostat), defined as subjects with at least one evaluable PK profile of panobinostat.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [61]
    Units: Litres
    geometric mean (geometric coefficient of variation)
        Cycle 1
    4632.6 ( 71.5 )
        Cycle 2
    6539 ( 81 )
    Notes
    [61] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Area Under The Concentration-Time Curve From Time Zero to 24 Hours (AUC0-24) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion [62]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [63]
    Units: ng.h/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    91.7 ( 87.5 )
        Cycle 2
    94.3 ( 40 )
    Notes
    [63] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Maximum Observed Concentration (Cmax) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Maximum Observed Concentration (Cmax) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion [64]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib.
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [64] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [65]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    107.9 ( 114.6 )
        Cycle 2
    81.4 ( 87.7 )
    Notes
    [65] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Time to Maximum Observed Concentration (Tmax) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Time to Maximum Observed Concentration (Tmax) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion [66]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [67]
    Units: hours
    median (full range (min-max))
        Cycle 1
    0.1 (0.1 to 0.5)
        Cycle 2
    0.1 (0.1 to 1)
    Notes
    [67] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Last Measurable Concentration (Clast) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Last Measurable Concentration (Clast) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion [68]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [69]
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1
    1.4 ( 52.1 )
        Cycle 2
    2.1 ( 92.2 )
    Notes
    [69] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Time to Last Measurable Concentration (Tlast) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion

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    End point title
    		 Time to Last Measurable Concentration (Tlast) of Bortezomib on Day 8 of Cycles 1 and 2 of Dose Expansion [70]
    End point description
    This endpoint analyzed the Pharmacokinetic Set for bortezomib (PK set-bortezomib), defined as subjects with at least one evaluable PK profile of bortezomib
    End point type
    Secondary
    End point timeframe
    Up to 48 hours post-dose on Days 8 of Cycle 1 and 2
    Notes
    [70] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15 [71]
    Units: hours
    median (full range (min-max))
        Cycle 1
    28.1 (23.9 to 47.7)
        Cycle 2
    28 (25.9 to 28.5)
    Notes
    [71] - n = 15, 12
    No statistical analyses for this end point

    Secondary: Percent of Subjects Who Responded to Treatment During The Dose Escalation Phase

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    End point title
    		 Percent of Subjects Who Responded to Treatment During The Dose Escalation Phase [72]
    End point description
    Response was defined as the overall response rate (rate of stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]). This endpoint analyzed the Full Analysis Set, defined as all subjects who received one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of treatment through the end of the dose escalation phase
    Notes
    [72] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 30 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    7
    7
    17
    7
    9
    Units: percent of subjects
        number (confidence interval 95%)
    14.3 (0.4 to 57.9)
    28.6 (3.7 to 71)
    52.9 (27.8 to 77)
    57.1 (18.4 to 90.1)
    55.6 (21.2 to 86.3)
    No statistical analyses for this end point

    Secondary: Percent of Subjects Who Responded to Treatment During The Dose Expansion Phase

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    End point title
    		 Percent of Subjects Who Responded to Treatment During The Dose Expansion Phase [73]
    End point description
    Response was defined as the overall response rate (rate of stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]). This endpoint analyzed the Full Analysis Set, defined as all subjects who received one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of treatment through the end of the dose escalation phase
    Notes
    [73] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    15
    Units: percent of subjects
        number (confidence interval 95%)
    73.3 (44.9 to 92.2)
    No statistical analyses for this end point

    Secondary: Percent of Subjects Who Responded to Treatment During The Dose Escalation Phase - Investigator's Assessment of Bortezomib-Refractory Subjects

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    End point title
    		 Percent of Subjects Who Responded to Treatment During The Dose Escalation Phase - Investigator's Assessment of Bortezomib-Refractory Subjects [74]
    End point description
    Response was defined as the overall response rate (rate of stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]). This endpoint analyzed the Full Analysis Set, defined as all subjects who received one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of treatment through the end of the dose escalation phase
    Notes
    [74] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose escalation PAN 10 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.0 mg/m2 Dose escalation PAN 20 mg + BTZ 1.3 mg/m2 Dose escalation PAN 25 mg + BTZ 1.3 mg/m2
    Number of subjects analysed
    4
    5
    4
    2
    Units: percent of subjects
        number (not applicable)
    0
    20
    0
    100
    No statistical analyses for this end point

    Secondary: Percent of Subjects Who Responded to Treatment During The Dose Expansion Phase - Investigator's Assessment of Bortezomib-Refractory Subjects

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    End point title
    		 Percent of Subjects Who Responded to Treatment During The Dose Expansion Phase - Investigator's Assessment of Bortezomib-Refractory Subjects [75]
    End point description
    Response was defined as the overall response rate (rate of stringent complete response [sCR] + complete response [CR] + very good partial response [VGPR] + partial response [PR]). This endpoint analyzed the Full Analysis Set, defined as all subjects who received one dose of study treatment.
    End point type
    Secondary
    End point timeframe
    From the start of treatment through the end of the dose escalation phase
    Notes
    [75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point is not reporting statistics for all the arms; only arms defined.
    End point values
    		 Dose expansion PAN 20 mg + BTZ 1.3 mg/m2 + DEX 20 mg
    Number of subjects analysed
    4
    Units: percent of subjects
        number (not applicable)
    50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All other adverse events are monitored from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    PAN 20 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 PAN 20 mg + BTZ 1.0 mg/m2

    Reporting group title
    PAN 10 mg + BTZ 1.0 mg/m2
    Reporting group description
    		 PAN 10 mg + BTZ 1.0 mg/m2

    Reporting group title
    PAN 20 mg + BTZ 1.3 mg/m2 (MTD)
    Reporting group description
    		 PAN 20 mg + BTZ 1.3 mg/m2 (MTD)

    Reporting group title
    PAN 30 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 PAN 30 mg + BTZ 1.3 mg/m2

    Reporting group title
    PAN 25 mg + BTZ 1.3 mg/m2
    Reporting group description
    		 PAN 25 mg + BTZ 1.3 mg/m2

    Reporting group title
    PAN 20 mg (2 weeks on/ 1 week off) + BTZ 1.3 mg/m2 + DEX 20 mg
    Reporting group description
    		 PAN 20 mg (2 weeks on/ 1 week off) + BTZ 1.3 mg/m2 + DEX 20 mg

    Serious adverse events
    		 PAN 20 mg + BTZ 1.0 mg/m2 PAN 10 mg + BTZ 1.0 mg/m2 PAN 20 mg + BTZ 1.3 mg/m2 (MTD) PAN 30 mg + BTZ 1.3 mg/m2 PAN 25 mg + BTZ 1.3 mg/m2 PAN 20 mg (2 weeks on/ 1 week off) + BTZ 1.3 mg/m2 + DEX 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 7 (57.14%)
    13 / 17 (76.47%)
    3 / 7 (42.86%)
    7 / 9 (77.78%)
    6 / 15 (40.00%)
         number of deaths (all causes)
    1
    1
    0
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    1 / 4
    1 / 1
    1 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung consolidation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood urea increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Rib fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Autonomic neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stupor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    4 / 15 (26.67%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    2 / 2
    1 / 1
    2 / 2
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Alpha haemolytic streptococcal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis jirovecii infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 6
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PAN 20 mg + BTZ 1.0 mg/m2 PAN 10 mg + BTZ 1.0 mg/m2 PAN 20 mg + BTZ 1.3 mg/m2 (MTD) PAN 30 mg + BTZ 1.3 mg/m2 PAN 25 mg + BTZ 1.3 mg/m2 PAN 20 mg (2 weeks on/ 1 week off) + BTZ 1.3 mg/m2 + DEX 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    17 / 17 (100.00%)
    7 / 7 (100.00%)
    9 / 9 (100.00%)
    15 / 15 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hot flush
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haematoma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    Hypertension
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    3 / 7 (42.86%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    2
    8
    1
    2
    Hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    2 / 9 (22.22%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    4
    4
    5
    3
    Orthostatic hypotension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    1
    2
    2
    Phlebitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Shock
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Thrombophlebitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    8 / 17 (47.06%)
    5 / 7 (71.43%)
    5 / 9 (55.56%)
    7 / 15 (46.67%)
         occurrences all number
    1
    1
    12
    8
    12
    9
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    3
    1
    0
    4
    Chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Exercise tolerance decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    4 / 7 (57.14%)
    4 / 7 (57.14%)
    7 / 17 (41.18%)
    4 / 7 (57.14%)
    3 / 9 (33.33%)
    11 / 15 (73.33%)
         occurrences all number
    4
    4
    13
    6
    4
    14
    Face oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Feeling cold
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    4
    Gait disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Generalised oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Irritability
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Local swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Oedema peripheral
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    4 / 17 (23.53%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    5 / 15 (33.33%)
         occurrences all number
    2
    0
    7
    1
    5
    6
    Pyrexia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    7 / 17 (41.18%)
    4 / 7 (57.14%)
    5 / 9 (55.56%)
    6 / 15 (40.00%)
         occurrences all number
    2
    1
    15
    5
    7
    6
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Sensation of foreign body
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Suprapubic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Temperature intolerance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Thirst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pruritus genital
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Scrotal oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    1
    1
    2
    0
    1
    3
    Cough
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    5 / 17 (29.41%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    6 / 15 (40.00%)
         occurrences all number
    1
    1
    7
    1
    1
    7
    Dyspnoea
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    3 / 7 (42.86%)
    1 / 9 (11.11%)
    4 / 15 (26.67%)
         occurrences all number
    0
    3
    4
    5
    2
    8
    Dyspnoea exertional
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    6
    2
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Lung infiltration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Nasal cyst
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    0
    1
    4
    Productive cough
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Rhinalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Respiratory tract irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    1
    0
    1
    Sneezing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    1
    0
    0
    3
    Throat irritation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Apathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Depressed mood
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Disorientation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    1
    0
    Insomnia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    4 / 15 (26.67%)
         occurrences all number
    2
    1
    2
    0
    2
    6
    Mental status changes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Mood altered
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Nightmare
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sleep disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    2
    2
    2
    Tearfulness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    1
    1
    4
    Amylase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    2
    2
    1
    2
    Beta 2 microglobulin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Band neutrophil percentage increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Blood chloride increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    5
    4
    0
    3
    Blood fibrinogen increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    4 / 15 (26.67%)
         occurrences all number
    2
    0
    3
    2
    4
    6
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    4
    7
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    2
    0
    Blood urea increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    4
    1
    5
    Blood uric acid increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Body temperature increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    4
    0
    4
    10
    Calcium ionised increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Foetal haemoglobin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    2
    0
    5
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Glutamate dehydrogenase increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    1
    7
    Monocyte count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Neutrophil count increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Serum ferritin increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Rubulavirus test positive
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    5 / 15 (33.33%)
         occurrences all number
    0
    2
    3
    1
    4
    10
    White blood cell count decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Arthropod bite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Eye injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Post-traumatic pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Limb injury
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Procedural pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Spinal compression fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Thermal burn
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    2
    0
    0
    0
    Atrial fibrillation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Bradycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Myocardial infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Areflexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Depressed level of consciousness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Coma
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    7 / 17 (41.18%)
    3 / 7 (42.86%)
    1 / 9 (11.11%)
    7 / 15 (46.67%)
         occurrences all number
    0
    1
    8
    6
    3
    15
    Dizziness postural
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    6 / 15 (40.00%)
         occurrences all number
    1
    1
    4
    0
    2
    7
    Head discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    3 / 7 (42.86%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    4
    4
    0
    3
    Hypoaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Intercostal neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Mental impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Motor dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Myoclonus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    4 / 17 (23.53%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    7 / 15 (46.67%)
         occurrences all number
    0
    0
    6
    2
    4
    9
    Orthostatic intolerance
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    2 / 7 (28.57%)
    2 / 9 (22.22%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    3
    3
    1
    Parosmia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    2
    0
    1
    3
    Polyneuropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    1
    0
    0
    Post herpetic neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    1
    0
    0
    Syncope
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 7 (85.71%)
    3 / 7 (42.86%)
    10 / 17 (58.82%)
    5 / 7 (71.43%)
    5 / 9 (55.56%)
    5 / 15 (33.33%)
         occurrences all number
    13
    8
    29
    12
    9
    14
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Febrile neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Leukopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    6 / 17 (35.29%)
    3 / 7 (42.86%)
    1 / 9 (11.11%)
    6 / 15 (40.00%)
         occurrences all number
    0
    0
    17
    8
    4
    22
    Lymphopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    5 / 15 (33.33%)
         occurrences all number
    0
    0
    7
    4
    4
    29
    Monocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    0
    0
    13
    Neutropenia
         subjects affected / exposed
    4 / 7 (57.14%)
    4 / 7 (57.14%)
    14 / 17 (82.35%)
    6 / 7 (85.71%)
    5 / 9 (55.56%)
    8 / 15 (53.33%)
         occurrences all number
    8
    12
    51
    37
    68
    30
    Neutrophilia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    6 / 7 (85.71%)
    6 / 7 (85.71%)
    16 / 17 (94.12%)
    7 / 7 (100.00%)
    8 / 9 (88.89%)
    9 / 15 (60.00%)
         occurrences all number
    17
    16
    55
    22
    29
    41
    Thrombocytosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Cataract
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    4
    1
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Eye pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Eye swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Eyelid oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ocular surface disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    6 / 15 (40.00%)
         occurrences all number
    0
    0
    2
    0
    1
    7
    Abdominal distension
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    7 / 15 (46.67%)
         occurrences all number
    0
    0
    3
    0
    3
    10
    Abdominal pain upper
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    4 / 17 (23.53%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    4 / 15 (26.67%)
         occurrences all number
    0
    0
    5
    0
    2
    8
    Aerophagia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    1
    1
    1
    0
    1
    0
    Anal fissure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 7 (57.14%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    8 / 15 (53.33%)
         occurrences all number
    0
    4
    7
    3
    2
    8
    Diarrhoea
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 7 (42.86%)
    14 / 17 (82.35%)
    7 / 7 (100.00%)
    6 / 9 (66.67%)
    13 / 15 (86.67%)
         occurrences all number
    6
    3
    47
    17
    27
    34
    Dry mouth
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    1 / 17 (5.88%)
    2 / 7 (28.57%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    1
    2
    1
    2
    0
    4
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Faecal incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Faeces discoloured
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    5 / 17 (29.41%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    6
    0
    1
    2
    Gastric disorder
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    1
    0
    1
    Gingival bleeding
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    1
    0
    Haematemesis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Mouth haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 7 (42.86%)
    13 / 17 (76.47%)
    5 / 7 (71.43%)
    6 / 9 (66.67%)
    10 / 15 (66.67%)
         occurrences all number
    2
    5
    27
    11
    17
    17
    Mouth ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Odynophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    3
    0
    1
    2
    Oesophagitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oral discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Oral mucosal erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oral pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Pancreatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Vomiting
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    7 / 17 (41.18%)
    4 / 7 (57.14%)
    4 / 9 (44.44%)
    7 / 15 (46.67%)
         occurrences all number
    1
    2
    17
    8
    6
    11
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Blister
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Cutaneous lupus erythematosus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Dermatitis allergic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dry skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Dyshidrotic eczema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    Ecchymosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Leukocytoclastic vasculitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Nail disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Night sweats
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    0
    0
    2
    Pain of skin
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Papule
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Petechiae
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Photosensitivity reaction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Rash
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    4 / 17 (23.53%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    2
    0
    4
    1
    1
    6
    Rash papular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Urticaria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Dysuria
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    1
    0
    1
    0
    0
    1
    Bladder spasm
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Enuresis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Incontinence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    Micturition disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Nephropathy toxic
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Micturition urgency
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Pollakiuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Pyelocaliectasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    13
    2
    1
    0
    Renal impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Ureteric stenosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    2
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    4 / 15 (26.67%)
         occurrences all number
    1
    1
    2
    1
    2
    4
    Back pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    0
    2
    5
    1
    1
    4
    Bone pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    1
    2
    5
    Flank pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    0
    0
    2
    Limb discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Muscle tightness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    1
    2
    0
    0
    3
    Muscular weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    3
    0
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    Myalgia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    4 / 15 (26.67%)
         occurrences all number
    1
    0
    2
    0
    1
    5
    Pain in extremity
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    4 / 15 (26.67%)
         occurrences all number
    1
    2
    5
    0
    0
    4
    Pain in jaw
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Rhabdomyolysis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    4
    0
    0
    0
    Infections and infestations
    Acute tonsillitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bacterial disease carrier
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Arthritis infective
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Candida infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Device related infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Eye infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Gastrointestinal candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    1
    0
    2
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Herpes zoster
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Lobar pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    3 / 15 (20.00%)
         occurrences all number
    2
    0
    13
    0
    4
    4
    Neutropenic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    2
    0
    1
    1
    Oral herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    1
    4
    0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    4 / 17 (23.53%)
    3 / 7 (42.86%)
    2 / 9 (22.22%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    8
    6
    2
    8
    Rhinitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    2 / 15 (13.33%)
         occurrences all number
    0
    0
    1
    0
    1
    2
    Sinusitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Skin candida
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Tinea pedis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Tooth infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    6 / 15 (40.00%)
         occurrences all number
    0
    1
    3
    0
    1
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    1 / 15 (6.67%)
         occurrences all number
    0
    2
    3
    3
    1
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    10 / 17 (58.82%)
    3 / 7 (42.86%)
    5 / 9 (55.56%)
    9 / 15 (60.00%)
         occurrences all number
    2
    0
    14
    4
    8
    14
    Hypercalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    3
    0
    0
    1
    0
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    3 / 15 (20.00%)
         occurrences all number
    0
    1
    0
    0
    0
    4
    Hyperglycaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    4 / 17 (23.53%)
    3 / 7 (42.86%)
    3 / 9 (33.33%)
    1 / 15 (6.67%)
         occurrences all number
    0
    1
    7
    5
    4
    6
    Hyperkalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    2 / 7 (28.57%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    0
    4
    1
    0
    Hyperphosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    5
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    3 / 15 (20.00%)
         occurrences all number
    1
    0
    1
    1
    4
    3
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    3 / 9 (33.33%)
    4 / 15 (26.67%)
         occurrences all number
    0
    0
    4
    4
    4
    10
    Hypochloraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 9 (0.00%)
    1 / 15 (6.67%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 7 (42.86%)
    5 / 17 (29.41%)
    2 / 7 (28.57%)
    3 / 9 (33.33%)
    5 / 15 (33.33%)
         occurrences all number
    0
    3
    8
    4
    5
    7
    Hypomagnesaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    2 / 9 (22.22%)
    1 / 15 (6.67%)
         occurrences all number
    1
    2
    6
    0
    6
    1
    Hypophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    1 / 9 (11.11%)
    3 / 15 (20.00%)
         occurrences all number
    0
    0
    7
    2
    1
    5
    Hypophosphataemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    2 / 9 (22.22%)
    5 / 15 (33.33%)
         occurrences all number
    0
    1
    0
    2
    6
    20
    Hypoproteinaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 9 (0.00%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    Metabolic acidosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 9 (11.11%)
    0 / 15 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Apr 2008
    The primary reason for this protocol amendment was to adjust the prior distribution assumptions that underlie the Bayesian logistical model.In amendment 1 to the protocol, the probability of experiencing DLT when treated with 0.7 mg/m2, 1.0 mg/m2 and 1.3 mg/m2 of BTZ alone was revised to be 0.05, 0.1 and 0.15, respectively. In addition, a baseline chest X-ray assessment was introduced due to Health Authority recommendation. Amendment 1 to the protocol also improved the clarity and feasibility of certain protocol sections.
    19 Mar 2010
    Amendment 2 to the protocol was performed for following reasons: - To amend the dosing schedule by introducing a week of treatment holiday for PAN in the dose expansion phase. The purpose was to allow for accelerated platelet recovery and thus minimize dose interruptions and dose reductions due to thrombocytopenia. - To introduce Dex in all dose expansion phase patients, in contrast to dose escalation phase, where Dex was introduced only in patients with a suboptimal response to the combination. - To investigate the effect of Dex on the pharmacokinetics of both PAN and BTZ. PK evaluations of PAN and BTZ without and with Dex were planned in 12-15 patients to evaluate any potential enzyme induction effect. - In order to do this, and allow rationally a Dex-free period, Dex was introduced in all patients at Cycle 2 in this cohort. The PK profiles of PAN and BTZ without (in Cycle 1) and with (in Cycle 2) was to be compared. - To document with appropriate blood count sampling the kinetic profile of thrombocytopenia during the treatment cycle including recovery profile during the week of treatment holiday.

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

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