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    Clinical Trial Results:
    A Multicenter, Randomized, Double- Blind, Placebo-Controlled, Phase 3 Trial of Lenvatinib (E7080) in 131I- Refractory Differentiated Thyroid Cancer

    Summary
    EudraCT number
    		 2010-023783-41
    Trial protocol
    		 BE   CZ   PT   GB   DE   ES   PL   DK   AT   IT   SE  
    Global end of trial date
    19 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Apr 2020
    First version publication date
    03 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-G000-303
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01321554
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd.
    Sponsor organisation address
    European Knowledge Centre Mosquito Way, Hatfield, Hertfordshire , United Kingdom, AL10 9SN
    Public contact
    Medical Information, Eisai Ltd., +1 1-888-274-2378, esi_oncmedinfo@eisai.com
    Scientific contact
    Medical Information, Eisai Ltd., +1 1-888-274-2378, esi_oncmedinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the progression-free survival of subjects with 131I-refractory differentiated thyroid cancer with radiographic evidence of disease progression within the prior 12 months treated with E7080 versus placebo.
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use -Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. -Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Mar 2011
    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
    Sweden: 6
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 48
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Italy: 48
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Portugal: 2
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Australia: 19
    Country: Number of subjects enrolled
    Brazil: 9
    Country: Number of subjects enrolled
    Canada: 10
    Country: Number of subjects enrolled
    Chile: 2
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    Romania: 5
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    United States: 87
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    Poland: 14
    Worldwide total number of subjects
    392
    EEA total number of subjects
    195
    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)
    220
    From 65 to 84 years
    170
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 117 investigative sites in Europe, North America, Asia Pacific, Japan, and Latin America from 17 March 2011 to 19 March 2019.

    Pre-assignment
    Screening details
    		 A total of 612 subjects were screened for entry into the study. Of these 612 subjects, 220 subjects were screening failures and 392 subjects were randomly assigned to receive either lenvatinib or placebo in a 2:1 ratio.

    Period 1
    Period 1 title
    Randomization Phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Randomization Phase: Lenvatinib 24 mg
    Arm description
    		 Subjects received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research [IIR]), development of unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Arm title
    		 Randomization Phase: Placebo
    Arm description
    		 Subjects received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Number of subjects in period 1
    		Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Started
    261
    131
    Completed
    261
    131
    Period 2
    Period 2 title
    OOL Lenvatinib Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 OOL, Treatment Period: Lenvatinib 24 mg
    Arm description
    		 Subjects received lenvatinib, hard capsule, 24 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. OOL refers to Optional Open-Label.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenvatinib, hard capsule, 24 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.

    Arm title
    		 OOL, Treatment Period: Lenvatinib 20 mg
    Arm description
    		 Subjects received lenvatinib, hard capsule, 20 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received lenvatinib, hard capsule, 20 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.

    Number of subjects in period 2 [1]
    		OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Started
    85
    30
    Completed
    85
    30
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Subjects from Randomization phase were re-randomised to OOL Lenvatinib treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Randomization Phase: Lenvatinib 24 mg
    Reporting group description
    		 Subjects received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research [IIR]), development of unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Randomization Phase: Placebo
    Reporting group description
    		 Subjects received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Reporting group values
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo Total
    Number of subjects
    		 261 131 392
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 62.1 ( 10.57 ) 61.5 ( 10.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 136 56 192
        Male
    		 125 75 200

    End points

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    End points reporting groups
    Reporting group title
    Randomization Phase: Lenvatinib 24 mg
    Reporting group description
    		 Subjects received lenvatinib 24 milligram (mg), hard capsule, orally, once daily, until documentation of disease progression (confirmed by Investigator-Initiated Research [IIR]), development of unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Randomization Phase: Placebo
    Reporting group description
    		 Subjects received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.
    Reporting group title
    OOL, Treatment Period: Lenvatinib 24 mg
    Reporting group description
    		 Subjects received lenvatinib, hard capsule, 24 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib. OOL refers to Optional Open-Label.

    Reporting group title
    OOL, Treatment Period: Lenvatinib 20 mg
    Reporting group description
    		 Subjects received lenvatinib, hard capsule, 20 mg, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.

    Subject analysis set title
    Lenvatinib 24 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Subjects received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Primary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of first documentation of disease progression or death (whichever occurred first), as determined by blinded IIR using Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for the double-blind treatment period (Randomization Phase). Disease progression per RECIST v1.1 was defined as at least a 20 percent (%) relative increase and 5 millimeter (mm) absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions. The full analysis set (Intent-to-Treat Analysis Set) included all randomized subjects. Here “99999” refers to data not available and therefore we have added 99999 as space-fillers. 
    End point type
    Primary
    End point timeframe
    Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
    End point values
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Number of subjects analysed
    261
    131
    Units: months
        median (confidence interval 95%)
    18.3 (15.1 to 99999)
    3.6 (2.2 to 3.7)
    Statistical analysis title
    		 Statistical analysis 1
    Comparison groups
    Randomization Phase: Lenvatinib 24 mg v Randomization Phase: Placebo
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.21
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 0.14
         upper limit
    		 0.31

    Secondary: Overall Response Rate (ORR)

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    End point title
    		 Overall Response Rate (ORR)
    End point description
    ORR, defined as the percentage of subjects who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by blinded IIR using RECIST 1.1 for target lesions and assessed by magnetic resonance therapy/computed tomography (MRI/CT) scans (for double blind treatment period i.e. Randomization Phase). CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR. The full analysis set (Intent-to-Treat Analysis Set) included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Date of randomization to the date of disease progression or death (whichever occurred first), assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
    End point values
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Number of subjects analysed
    261
    131
    Units: percentage of subjects
        number (confidence interval 95%)
    64.8 (59.0 to 70.5)
    1.5 (0.0 to 3.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall survival measured from the date of randomization until date of death from any cause. Overall survival is adjusted with rank preserving structural failure time. The full analysis set (Intent-to-Treat Analysis Set) included all randomized subjects. Here “99999” refers to data not available and therefore we have added 99999 as space-fillers. 
    End point type
    Secondary
    End point timeframe
    Date of randomization until date of death from any cause, assessed up to data cutoff date (15 Nov 2013) or up to approximately 2.5 years
    End point values
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo
    Number of subjects analysed
    261
    131
    Units: months
        median (confidence interval 95%)
    99999 (22.0 to 99999)
    99999 (14.3 to 99999)
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve

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    End point title
    		 Pharmacokinetic (PK) Profile of Lenvatinib: Area Under the Plasma Concentration Curve
    End point description
    The PK analysis set included all the subjects who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Days 1 and 15: 0-10 hours postdose; Cycle 2 Day 1: 0-12 hour postdose (Cycle length = )
    End point values
    		 Lenvatinib 24 mg
    Number of subjects analysed
    261
    Units: nanogram*hour per milliliter (ng*h/mL)
        median (full range (min-max))
    3490 (1410 to 10700)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For each subject, from the first dose till 30 days up to approximately 8 years
    Adverse event reporting additional description
    Safety was assessed by the monitoring and recording of all adverse events (AEs) and serious adverse events (SAEs); regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, electrocardiograms (ECG), and echocardiograms.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Randomization Phase: Lenvatinib 24 mg
    Reporting group description
    		 Subjects received lenvatinib 24 mg, hard capsule, orally, once daily, until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Randomization Phase: Placebo
    Reporting group description
    		 Subjects received matching-placebo, hard capsule, orally, once daily until documentation of disease progression (confirmed by IIR), development of unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    OOL, Treatment Period: Lenvatinib 24 mg
    Reporting group description
    		 Subjects received lenvatinib 24 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.

    Reporting group title
    OOL, Treatment Period: Lenvatinib 20 mg
    Reporting group description
    		 Subjects received lenvatinib 20 mg, hard capsule, orally, once daily in Treatment Period. Placebo treated subjects in the Randomization Phase who had progressive disease confirmed by IIR, and who requested treatment with lenvatinib.

    Serious adverse events
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    171 / 261 (65.52%)
    31 / 131 (23.66%)
    62 / 85 (72.94%)
    16 / 30 (53.33%)
         number of deaths (all causes)
    161
    13
    62
    15
         number of deaths resulting from adverse events
    29
    6
    11
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial tumour haemorrhage
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lymphocytic leukaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant pleural effusion
         subjects affected / exposed
    5 / 261 (1.92%)
    1 / 131 (0.76%)
    3 / 85 (3.53%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    3 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    Metastases to bone
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic pulmonary embolism
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasmacytoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spindle cell sarcoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aneurysm ruptured
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    10 / 261 (3.83%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    11 / 11
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 261 (1.92%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    3 / 85 (3.53%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 3
    Device breakage
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 261 (2.68%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contrast media allergy
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Cystocele
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital prolapse
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectocele
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine prolapse
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atelectasis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial secretion retention
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 261 (2.30%)
    5 / 131 (3.82%)
    3 / 85 (3.53%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 7
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    1 / 1
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 261 (0.00%)
    3 / 131 (2.29%)
    2 / 85 (2.35%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal obstruction
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal necrosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    6 / 261 (2.30%)
    2 / 131 (1.53%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    5 / 8
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory depression
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 261 (0.77%)
    2 / 131 (1.53%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood calcium increased
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Eschar
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Traumatic fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute left ventricular failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    5 / 261 (1.92%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular hypertrophy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus tachycardia
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular hypokinesia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cauda equina syndrome
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coma
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic encephalopathy
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parkinson’s disease
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osmotic demyelination syndrome
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postictal paralysis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    4 / 261 (1.53%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord ischaemia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic haemorrhage
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal vein thrombosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    4 / 85 (4.71%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental cyst
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    3 / 261 (1.15%)
    3 / 131 (2.29%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Functional gastrointestinal disorder
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mesenteric artery thrombosis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 261 (0.00%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumatosis intestinalis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    5 / 261 (1.92%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder mucocoele
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis contact
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erythema
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    6 / 261 (2.30%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute prerenal failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic syndrome
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 261 (1.15%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mobility decreased
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot deformity
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    2 / 85 (2.35%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue necrosis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess intestinal
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bartholin’s abscess
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary tract infection
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colonic abscess
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal skin infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    4 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Osteomyelitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis infective
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    12 / 261 (4.60%)
    3 / 131 (2.29%)
    5 / 85 (5.88%)
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    7 / 14
    0 / 3
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumonia necrotising
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    6 / 261 (2.30%)
    2 / 131 (1.53%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Testicular abscess
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 261 (0.77%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 261 (0.38%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    9 / 261 (3.45%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    4 / 9
    0 / 0
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    4 / 261 (1.53%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    2 / 8
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 261 (0.38%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 261 (1.15%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypovolaemia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 261 (0.77%)
    1 / 131 (0.76%)
    1 / 85 (1.18%)
    0 / 30 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomization Phase: Lenvatinib 24 mg Randomization Phase: Placebo OOL, Treatment Period: Lenvatinib 24 mg OOL, Treatment Period: Lenvatinib 20 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    259 / 261 (99.23%)
    118 / 131 (90.08%)
    84 / 85 (98.82%)
    29 / 30 (96.67%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    181 / 261 (69.35%)
    19 / 131 (14.50%)
    52 / 85 (61.18%)
    21 / 30 (70.00%)
         occurrences all number
    720
    36
    124
    69
    Hypotension
         subjects affected / exposed
    27 / 261 (10.34%)
    3 / 131 (2.29%)
    8 / 85 (9.41%)
    4 / 30 (13.33%)
         occurrences all number
    37
    3
    12
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    116 / 261 (44.44%)
    33 / 131 (25.19%)
    35 / 85 (41.18%)
    13 / 30 (43.33%)
         occurrences all number
    298
    45
    64
    28
    Asthenia
         subjects affected / exposed
    69 / 261 (26.44%)
    18 / 131 (13.74%)
    21 / 85 (24.71%)
    10 / 30 (33.33%)
         occurrences all number
    209
    29
    43
    26
    Influenza like illness
         subjects affected / exposed
    20 / 261 (7.66%)
    4 / 131 (3.05%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    25
    4
    0
    0
    Malaise
         subjects affected / exposed
    17 / 261 (6.51%)
    0 / 131 (0.00%)
    5 / 85 (5.88%)
    1 / 30 (3.33%)
         occurrences all number
    29
    0
    8
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    6 / 85 (7.06%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    7
    1
    Non-cardiac chest pain
         subjects affected / exposed
    14 / 261 (5.36%)
    4 / 131 (3.05%)
    3 / 85 (3.53%)
    2 / 30 (6.67%)
         occurrences all number
    16
    5
    3
    2
    Pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    65 / 261 (24.90%)
    10 / 131 (7.63%)
    18 / 85 (21.18%)
    3 / 30 (10.00%)
         occurrences all number
    124
    12
    20
    8
    Pyrexia
         subjects affected / exposed
    41 / 261 (15.71%)
    15 / 131 (11.45%)
    10 / 85 (11.76%)
    5 / 30 (16.67%)
         occurrences all number
    58
    17
    20
    8
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    0
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    77 / 261 (29.50%)
    24 / 131 (18.32%)
    23 / 85 (27.06%)
    8 / 30 (26.67%)
         occurrences all number
    114
    36
    30
    13
    Dysphonia
         subjects affected / exposed
    87 / 261 (33.33%)
    7 / 131 (5.34%)
    33 / 85 (38.82%)
    10 / 30 (33.33%)
         occurrences all number
    135
    8
    55
    13
    Dyspnoea
         subjects affected / exposed
    47 / 261 (18.01%)
    21 / 131 (16.03%)
    16 / 85 (18.82%)
    5 / 30 (16.67%)
         occurrences all number
    65
    29
    26
    5
    Dyspnoea exertional
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    5
    Haemoptysis
         subjects affected / exposed
    12 / 261 (4.60%)
    12 / 131 (9.16%)
    9 / 85 (10.59%)
    3 / 30 (10.00%)
         occurrences all number
    17
    14
    10
    4
    Epistaxis
         subjects affected / exposed
    36 / 261 (13.79%)
    1 / 131 (0.76%)
    14 / 85 (16.47%)
    5 / 30 (16.67%)
         occurrences all number
    58
    1
    20
    6
    Oropharyngeal pain
         subjects affected / exposed
    43 / 261 (16.48%)
    2 / 131 (1.53%)
    9 / 85 (10.59%)
    4 / 30 (13.33%)
         occurrences all number
    86
    2
    13
    4
    Productive cough
         subjects affected / exposed
    13 / 261 (4.98%)
    8 / 131 (6.11%)
    3 / 85 (3.53%)
    2 / 30 (6.67%)
         occurrences all number
    23
    8
    3
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 261 (5.75%)
    5 / 131 (3.82%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    16
    6
    5
    0
    Insomnia
         subjects affected / exposed
    38 / 261 (14.56%)
    4 / 131 (3.05%)
    11 / 85 (12.94%)
    3 / 30 (10.00%)
         occurrences all number
    39
    5
    13
    3
    Depression
         subjects affected / exposed
    22 / 261 (8.43%)
    3 / 131 (2.29%)
    5 / 85 (5.88%)
    3 / 30 (10.00%)
         occurrences all number
    31
    3
    7
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 261 (8.05%)
    0 / 131 (0.00%)
    8 / 85 (9.41%)
    2 / 30 (6.67%)
         occurrences all number
    33
    0
    9
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    17 / 261 (6.51%)
    2 / 131 (1.53%)
    6 / 85 (7.06%)
    0 / 30 (0.00%)
         occurrences all number
    30
    2
    7
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    18 / 261 (6.90%)
    3 / 131 (2.29%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    29
    3
    5
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    25 / 261 (9.58%)
    2 / 131 (1.53%)
    6 / 85 (7.06%)
    1 / 30 (3.33%)
         occurrences all number
    54
    2
    8
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    18 / 261 (6.90%)
    0 / 131 (0.00%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    20
    0
    5
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    27 / 261 (10.34%)
    2 / 131 (1.53%)
    9 / 85 (10.59%)
    1 / 30 (3.33%)
         occurrences all number
    53
    3
    26
    5
    Lipase increased
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    4 / 85 (4.71%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    7
    5
    Ejection fraction decreased
         subjects affected / exposed
    18 / 261 (6.90%)
    1 / 131 (0.76%)
    7 / 85 (8.24%)
    2 / 30 (6.67%)
         occurrences all number
    31
    1
    9
    2
    Platelet count decreased
         subjects affected / exposed
    17 / 261 (6.51%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    5 / 30 (16.67%)
         occurrences all number
    108
    0
    2
    7
    Weight decreased
         subjects affected / exposed
    142 / 261 (54.41%)
    20 / 131 (15.27%)
    44 / 85 (51.76%)
    18 / 30 (60.00%)
         occurrences all number
    450
    22
    101
    49
    White blood cell count decreased
         subjects affected / exposed
    14 / 261 (5.36%)
    4 / 131 (3.05%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    47
    4
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    48 / 261 (18.39%)
    4 / 131 (3.05%)
    10 / 85 (11.76%)
    6 / 30 (20.00%)
         occurrences all number
    70
    4
    13
    9
    Dizziness
         subjects affected / exposed
    45 / 261 (17.24%)
    13 / 131 (9.92%)
    15 / 85 (17.65%)
    8 / 30 (26.67%)
         occurrences all number
    77
    14
    19
    12
    Hyperaesthesia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Headache
         subjects affected / exposed
    105 / 261 (40.23%)
    15 / 131 (11.45%)
    19 / 85 (22.35%)
    10 / 30 (33.33%)
         occurrences all number
    223
    21
    28
    35
    Paraesthesia
         subjects affected / exposed
    14 / 261 (5.36%)
    4 / 131 (3.05%)
    2 / 85 (2.35%)
    3 / 30 (10.00%)
         occurrences all number
    18
    8
    2
    4
    Sciatica
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 261 (11.88%)
    6 / 131 (4.58%)
    7 / 85 (8.24%)
    3 / 30 (10.00%)
         occurrences all number
    60
    13
    11
    11
    Leukopenia
         subjects affected / exposed
    15 / 261 (5.75%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    47
    1
    0
    0
    Lymphopenia
         subjects affected / exposed
    20 / 261 (7.66%)
    2 / 131 (1.53%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    60
    2
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    25 / 261 (9.58%)
    3 / 131 (2.29%)
    7 / 85 (8.24%)
    1 / 30 (3.33%)
         occurrences all number
    83
    4
    84
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    50 / 261 (19.16%)
    5 / 131 (3.82%)
    20 / 85 (23.53%)
    8 / 30 (26.67%)
         occurrences all number
    109
    10
    34
    15
    Abdominal distension
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    46 / 261 (17.62%)
    11 / 131 (8.40%)
    11 / 85 (12.94%)
    9 / 30 (30.00%)
         occurrences all number
    85
    11
    13
    11
    Cheilitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Constipation
         subjects affected / exposed
    83 / 261 (31.80%)
    20 / 131 (15.27%)
    25 / 85 (29.41%)
    5 / 30 (16.67%)
         occurrences all number
    113
    26
    32
    8
    Diarrhoea
         subjects affected / exposed
    182 / 261 (69.73%)
    22 / 131 (16.79%)
    55 / 85 (64.71%)
    21 / 30 (70.00%)
         occurrences all number
    740
    27
    263
    66
    Dyspepsia
         subjects affected / exposed
    38 / 261 (14.56%)
    6 / 131 (4.58%)
    11 / 85 (12.94%)
    3 / 30 (10.00%)
         occurrences all number
    66
    6
    14
    10
    Dry mouth
         subjects affected / exposed
    46 / 261 (17.62%)
    11 / 131 (8.40%)
    11 / 85 (12.94%)
    1 / 30 (3.33%)
         occurrences all number
    58
    13
    12
    1
    Flatulence
         subjects affected / exposed
    15 / 261 (5.75%)
    1 / 131 (0.76%)
    3 / 85 (3.53%)
    2 / 30 (6.67%)
         occurrences all number
    18
    1
    4
    6
    Dysphagia
         subjects affected / exposed
    34 / 261 (13.03%)
    9 / 131 (6.87%)
    15 / 85 (17.65%)
    3 / 30 (10.00%)
         occurrences all number
    47
    10
    15
    5
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Gingival pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    3
    2
    Glossodynia
         subjects affected / exposed
    18 / 261 (6.90%)
    0 / 131 (0.00%)
    9 / 85 (10.59%)
    0 / 30 (0.00%)
         occurrences all number
    32
    0
    12
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    6 / 85 (7.06%)
    1 / 30 (3.33%)
         occurrences all number
    0
    0
    6
    1
    Nausea
         subjects affected / exposed
    127 / 261 (48.66%)
    34 / 131 (25.95%)
    34 / 85 (40.00%)
    12 / 30 (40.00%)
         occurrences all number
    295
    48
    67
    31
    Oral pain
         subjects affected / exposed
    26 / 261 (9.96%)
    1 / 131 (0.76%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    44
    3
    9
    0
    Stomatitis
         subjects affected / exposed
    100 / 261 (38.31%)
    9 / 131 (6.87%)
    28 / 85 (32.94%)
    13 / 30 (43.33%)
         occurrences all number
    246
    10
    50
    22
    Toothache
         subjects affected / exposed
    18 / 261 (6.90%)
    5 / 131 (3.82%)
    7 / 85 (8.24%)
    2 / 30 (6.67%)
         occurrences all number
    22
    5
    8
    3
    Vomiting
         subjects affected / exposed
    100 / 261 (38.31%)
    19 / 131 (14.50%)
    36 / 85 (42.35%)
    9 / 30 (30.00%)
         occurrences all number
    217
    24
    67
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    34 / 261 (13.03%)
    7 / 131 (5.34%)
    9 / 85 (10.59%)
    6 / 30 (20.00%)
         occurrences all number
    39
    7
    14
    8
    Dermatitis acneiform
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    4 / 85 (4.71%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    5
    4
    Decubitus ulcer
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Dry skin
         subjects affected / exposed
    32 / 261 (12.26%)
    8 / 131 (6.11%)
    10 / 85 (11.76%)
    2 / 30 (6.67%)
         occurrences all number
    35
    8
    11
    3
    Hyperkeratosis
         subjects affected / exposed
    19 / 261 (7.28%)
    2 / 131 (1.53%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    36
    3
    0
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    86 / 261 (32.95%)
    1 / 131 (0.76%)
    24 / 85 (28.24%)
    9 / 30 (30.00%)
         occurrences all number
    268
    1
    85
    44
    Hyperhidrosis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Pruritus
         subjects affected / exposed
    19 / 261 (7.28%)
    6 / 131 (4.58%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    25
    6
    0
    0
    Skin fissures
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    1 / 85 (1.18%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    1
    2
    Rash
         subjects affected / exposed
    55 / 261 (21.07%)
    2 / 131 (1.53%)
    14 / 85 (16.47%)
    6 / 30 (20.00%)
         occurrences all number
    81
    4
    16
    8
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    15 / 261 (5.75%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    17
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    99 / 261 (37.93%)
    4 / 131 (3.05%)
    26 / 85 (30.59%)
    12 / 30 (40.00%)
         occurrences all number
    604
    5
    126
    24
    Haematuria
         subjects affected / exposed
    18 / 261 (6.90%)
    3 / 131 (2.29%)
    6 / 85 (7.06%)
    0 / 30 (0.00%)
         occurrences all number
    22
    4
    9
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    14 / 261 (5.36%)
    0 / 131 (0.00%)
    7 / 85 (8.24%)
    2 / 30 (6.67%)
         occurrences all number
    26
    0
    7
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    52 / 261 (19.92%)
    12 / 131 (9.16%)
    18 / 85 (21.18%)
    6 / 30 (20.00%)
         occurrences all number
    81
    14
    29
    7
    Arthralgia
         subjects affected / exposed
    85 / 261 (32.57%)
    9 / 131 (6.87%)
    19 / 85 (22.35%)
    12 / 30 (40.00%)
         occurrences all number
    148
    15
    39
    25
    Flank pain
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    3 / 85 (3.53%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    3
    3
    Muscle spasms
         subjects affected / exposed
    22 / 261 (8.43%)
    5 / 131 (3.82%)
    11 / 85 (12.94%)
    5 / 30 (16.67%)
         occurrences all number
    31
    5
    15
    13
    Joint swelling
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    2 / 85 (2.35%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    2
    2
    Muscular weakness
         subjects affected / exposed
    20 / 261 (7.66%)
    3 / 131 (2.29%)
    5 / 85 (5.88%)
    0 / 30 (0.00%)
         occurrences all number
    23
    3
    8
    0
    Musculoskeletal pain
         subjects affected / exposed
    46 / 261 (17.62%)
    11 / 131 (8.40%)
    14 / 85 (16.47%)
    4 / 30 (13.33%)
         occurrences all number
    60
    13
    27
    6
    Musculoskeletal chest pain
         subjects affected / exposed
    32 / 261 (12.26%)
    13 / 131 (9.92%)
    11 / 85 (12.94%)
    3 / 30 (10.00%)
         occurrences all number
    40
    14
    14
    5
    Myalgia
         subjects affected / exposed
    51 / 261 (19.54%)
    6 / 131 (4.58%)
    12 / 85 (14.12%)
    9 / 30 (30.00%)
         occurrences all number
    95
    9
    16
    16
    Pain in extremity
         subjects affected / exposed
    48 / 261 (18.39%)
    9 / 131 (6.87%)
    12 / 85 (14.12%)
    7 / 30 (23.33%)
         occurrences all number
    73
    13
    27
    9
    Neck pain
         subjects affected / exposed
    23 / 261 (8.81%)
    15 / 131 (11.45%)
    6 / 85 (7.06%)
    1 / 30 (3.33%)
         occurrences all number
    33
    19
    8
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    17 / 261 (6.51%)
    2 / 131 (1.53%)
    5 / 85 (5.88%)
    2 / 30 (6.67%)
         occurrences all number
    24
    2
    13
    3
    Influenza
         subjects affected / exposed
    16 / 261 (6.13%)
    1 / 131 (0.76%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    17
    1
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Pneumonia
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    6 / 85 (7.06%)
    0 / 30 (0.00%)
         occurrences all number
    0
    0
    11
    0
    Nasopharyngitis
         subjects affected / exposed
    28 / 261 (10.73%)
    8 / 131 (6.11%)
    6 / 85 (7.06%)
    6 / 30 (20.00%)
         occurrences all number
    54
    8
    7
    6
    Upper respiratory tract infection
         subjects affected / exposed
    26 / 261 (9.96%)
    7 / 131 (5.34%)
    5 / 85 (5.88%)
    3 / 30 (10.00%)
         occurrences all number
    40
    9
    10
    4
    Sinusitis
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    6 / 85 (7.06%)
    3 / 30 (10.00%)
         occurrences all number
    0
    0
    11
    5
    Urinary tract infection
         subjects affected / exposed
    30 / 261 (11.49%)
    7 / 131 (5.34%)
    6 / 85 (7.06%)
    3 / 30 (10.00%)
         occurrences all number
    54
    9
    8
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    148 / 261 (56.70%)
    24 / 131 (18.32%)
    43 / 85 (50.59%)
    11 / 30 (36.67%)
         occurrences all number
    352
    31
    86
    24
    Dehydration
         subjects affected / exposed
    24 / 261 (9.20%)
    3 / 131 (2.29%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    29
    3
    0
    0
    Hyperglycaemia
         subjects affected / exposed
    15 / 261 (5.75%)
    6 / 131 (4.58%)
    5 / 85 (5.88%)
    1 / 30 (3.33%)
         occurrences all number
    22
    7
    5
    3
    Hypoalbuminaemia
         subjects affected / exposed
    27 / 261 (10.34%)
    2 / 131 (1.53%)
    12 / 85 (14.12%)
    1 / 30 (3.33%)
         occurrences all number
    50
    2
    17
    3
    Hypokalaemia
         subjects affected / exposed
    41 / 261 (15.71%)
    5 / 131 (3.82%)
    0 / 85 (0.00%)
    0 / 30 (0.00%)
         occurrences all number
    78
    5
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    38 / 261 (14.56%)
    0 / 131 (0.00%)
    11 / 85 (12.94%)
    3 / 30 (10.00%)
         occurrences all number
    74
    0
    23
    6
    Hypomagnesaemia
         subjects affected / exposed
    20 / 261 (7.66%)
    2 / 131 (1.53%)
    6 / 85 (7.06%)
    2 / 30 (6.67%)
         occurrences all number
    28
    2
    13
    2
    Vitamin D deficiency
         subjects affected / exposed
    0 / 261 (0.00%)
    0 / 131 (0.00%)
    0 / 85 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    0
    0
    2
    Hyponatraemia
         subjects affected / exposed
    17 / 261 (6.51%)
    3 / 131 (2.29%)
    5 / 85 (5.88%)
    1 / 30 (3.33%)
         occurrences all number
    25
    6
    11
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jun 2011
    Amendment 1: The purpose of this amendment is to address a specific requirement from the EU-VHP assessment to add an inclusion criterion specifying that eligibility must exclude possible curative surgery.
    07 Jul 2011
    Amendment 02: the purpose of this amendment is to comply with local regulatory and health authority (PMDA and MHLW) requirements in Japan.
    10 Apr 2012
    Amendment 03: the purpose of this amendment is to update the protocol with the study name 'SELECT' and the approved generic name for E7080 (lenvatinib).
    20 Feb 2013
    Amendment 04: the purpose of this amendment is to comply with Data Monitoring Committee (DMC) recommendations.
    19 Feb 2014
    Amendment 05: the purpose of this amendment is to include guidance on management of hepatotoxicity and thromboembolic events under section headings, as per the agreement with Voluntary Harmonisation Procedure (VHP).
    06 Oct 2014
    Amendment 06: The purpose of this amendment is to 1. Clarified that when the study becomes a postmarketing study in Japan, study drug for individual subjects in Japan may be switched to postmarketing-labeled study drug until lenvatinib is commercially available for individual subjects, at which time the subjects in Japan may be switched to commercial lenvatinib. 2. Clarified that overall survival data collection and source verification will continue during the postmarketing study in Japan. 3. Increased the time window for performing some assessments (tumor assessments [CT/MRI], echocardiograms, etc) in the Open Label Lenvatinib Treatment Period. 4. Noted that, as of this amendment, clinical laboratory assessments will be performed by local laboratory only.
    29 Oct 2014
    Amendment 07: the purpose of this amendment is addition of a new section (Section 8.4.2.5) on the management of posterior reversible encephalopathy syndrome in agreement with the Voluntary Harmonisation Procedure (VHP).
    10 Aug 2015
    Amendment 08: the purpose of this amendment is 1. clarified that following approval of lenvatinib in Japan, all subjects treated in Japan will be discontinued from the study and transitioned to commercial lenvatinib, and will be followed under the postmarketing program in Japan. 2. Frequency of study visits and assessments in the OOL Lenvatinib Treatment Period of the Extension Phase of the study revised to once every 12 weeks. 3. Revised frequency of tumor assessments in the OOL Lenvatinib Treatment Period of the Extension Phase to no more frequently than once every 12 weeks and no less frequently than once every 24 weeks (±2 weeks) or sooner if clinically indicated, until documentation of disease progression. 4. Addition of a new section (Section 8.4.2.6) on the management of hypocalcemia in compliance with the Voluntary Harmonisation Procedure (VHP) assessment report.
    26 Jan 2016
    Amendment 09: the purpose of this amendment is to revised to change the frequency of echocardiograms from every 12 weeks to every 24 weeks in the Extension Phase of the study.
    22 Sep 2017
    Amendment 10: the purpose of this amendment is to update Synopsis, to clarify that subjects will continue to receive study treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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