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    Clinical Trial Results:
    An Open-Label, Multicenter Phase Ib/2 Study of E7080 Alone, And in Combination With Everolimus in Subjects With Unresectable Advanced or Metastatic Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment.

    Summary
    EudraCT number
    		 2010-019484-10
    Trial protocol
    		 GB   CZ   PL   ES  
    Global end of trial date
    08 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Feb 2019
    First version publication date
    23 Feb 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    E7080-G000-205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01136733
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Ltd
    Sponsor organisation address
    Mosquito Way, Hatfield, Hertfordshire, United Kingdom, AL10 9SN
    Public contact
    Medical Information, Eisai Ltd, +1 888-274-2378, esi_medinfo@eisai.com
    Scientific contact
    Medical Information, Eisai Ltd, +1 888-274-2378, esi_medinfo@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
    08 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase Ib: To determine the dose-limiting toxicities (DLTs) and maximally tolerated dose (MTD) and establish the recommended phase 2 (RP2) dose for E7080 in combination with everolimus in subjects with unresectable advanced or metastatic renal cell carcinoma (RCC). Phase 2: To compare the progression-free survival (PFS) of 1) E7080 in combination with everolimus at the RP2 dose once daily (Arm A) and 2) single agent E7080 24 milligram (mg) once daily (Arm B) to single agent everolimus 10 mg once daily (Arm C) in subjects with unresectable advanced or metastatic RCC and disease progression following one prior vascular endothelial growth factor (VEGF) targeted treatment.
    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 for 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 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 (SUSARs) 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
    05 Aug 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 3 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 26
    Country: Number of subjects enrolled
    Spain: 18
    Country: Number of subjects enrolled
    United Kingdom: 51
    Country: Number of subjects enrolled
    Czech Republic: 23
    Country: Number of subjects enrolled
    United States: 55
    Worldwide total number of subjects
    173
    EEA total number of subjects
    118
    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)
    114
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 41 sites across geographic regions (12 sites in the United Kingdom, 16 sites in the United states, 5 sites in the Czech Republic, 4 sites in Poland, and 4 sites in Spain) from 05 Aug 2010 to 08 Feb 2018.

    Pre-assignment
    Screening details
    		 A total of 173 subjects were enrolled into the study and treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus
    Arm description
    		 Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 2. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 1. If 1 or none of the 6 subjects had a DLT, then enrollment proceeded to Cohort 2. If 2 or more subjects had a DLT during Cycle 1, the dose escalation committee (DEC) decided whether they were lenvatinib-related and whether enrollment could proceed; lenvatinib was reduced to 6 mg daily (the everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment was stopped.
    Arm type
    		 Experimental

    Investigational medicinal product name
    lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima, Kisplyx
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 12 mg (one 10 mg capsule and two 1 mg capsules) was taken along with one 5 mg tablet of everolimus once daily in continuous 28-day (4-week) cycles.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg (one tablet) was taken once daily along with 12 mg lenvatinib (one 10 mg capsule and two 1 mg capsules) in continuous 28-day (4-week) cycles.

    Arm title
    		 Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus
    Arm description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 2. If 1 or none of the 6 subjects exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima, Kisplyx
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 18 mg (one 10 mg capsule and two 4 mg capsules) was taken along with one 5 mg tablet of everolimus once daily in continuous 28-day (4-week) cycles.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg (one tablet) was taken along with 18 mg lenvatinib (one 10 mg capsule and two 4 mg capsules) once daily in continuous 28-day (4-week) cycles.

    Arm title
    		 Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
    Arm description
    		 Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 subject had a DLT, 3 more subjects were enrolled Cohort 3. If 1 or none of the 6 subjects exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.
    Arm type
    		 Experimental

    Investigational medicinal product name
    lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima, Kisplyx
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 24 mg (two 10 mg capsule and one 4 mg capsules) was taken along with one 5 mg tablet of everolimus once daily in continuous 28-day (4-week) cycles.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg (one tablet) was taken along with 24 mg lenvatinib (two 10 mg capsule and one 4 mg capsules) once daily in continuous 28-day (4-week) cycles.

    Arm title
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus
    Arm description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic sampling days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima, Kisplyx
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral lenvatinib 18 mg (one 10 mg capsule and two 4 mg capsule) was taken along with one 5 mg tablet of everolimus once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg was taken along with lenvatinib 18 mg (one 10 mg capsule and two 4 mg capsule) once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Arm title
    		 Phase 2 (Arm B): 24 mg Lenvatinib
    Arm description
    		 Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Lenvima, Kisplyx
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Oral lenvatinib 24 mg was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Arm title
    		 Phase 2 (Arm C): 10 mg Everolimus
    Arm description
    		 Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral everolimus 10 mg (two 5 mg tablets) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.

    Number of subjects in period 1
    		Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Started
    7
    11
    2
    51
    52
    50
    Completed
    6
    6
    0
    0
    0
    0
    Not completed
    1
    5
    2
    51
    52
    50
         adverse event
    -
    3
    1
    11
    13
    5
         administrative-withdrew consent
    -
    1
    -
    -
    -
    -
         participant choice
    -
    -
    1
    3
    -
    1
         disease progression
    -
    -
    -
    30
    32
    38
         clinical progression
    1
    1
    -
    -
    -
    -
         unspecified
    -
    -
    -
    6
    7
    6
         administrative withdrew consent
    -
    -
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 2. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 1. If 1 or none of the 6 subjects had a DLT, then enrollment proceeded to Cohort 2. If 2 or more subjects had a DLT during Cycle 1, the dose escalation committee (DEC) decided whether they were lenvatinib-related and whether enrollment could proceed; lenvatinib was reduced to 6 mg daily (the everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment was stopped.

    Reporting group title
    Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 2. If 1 or none of the 6 subjects exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 subject had a DLT, 3 more subjects were enrolled Cohort 3. If 1 or none of the 6 subjects exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic sampling days.

    Reporting group title
    Phase 2 (Arm B): 24 mg Lenvatinib
    Reporting group description
    		 Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Reporting group title
    Phase 2 (Arm C): 10 mg Everolimus
    Reporting group description
    		 Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.

    Reporting group values
    		 Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus Total
    Number of subjects
    		 7 11 2 51 52 50 173
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 58.0 ( 3.92 ) 58.1 ( 7.97 ) 61.0 ( 2.83 ) 61.7 ( 8.2 ) 63.3 ( 8.6 ) 58.9 ( 9.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 2 1 16 13 12 47
        Male
    		 4 9 1 35 39 38 126

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 2. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 1. If 1 or none of the 6 subjects had a DLT, then enrollment proceeded to Cohort 2. If 2 or more subjects had a DLT during Cycle 1, the dose escalation committee (DEC) decided whether they were lenvatinib-related and whether enrollment could proceed; lenvatinib was reduced to 6 mg daily (the everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment was stopped.

    Reporting group title
    Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. In the Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. In Cycles 2, 3, etc. and the Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 2. If 1 or none of the 6 subjects exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 subject had a DLT, 3 more subjects were enrolled Cohort 3. If 1 or none of the 6 subjects exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) was once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic sampling days.

    Reporting group title
    Phase 2 (Arm B): 24 mg Lenvatinib
    Reporting group description
    		 Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Reporting group title
    Phase 2 (Arm C): 10 mg Everolimus
    Reporting group description
    		 Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4-week) cycles.

    Subject analysis set title
    Cycle 1, Day 1 (0 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration

    Subject analysis set title
    Phase 1b: Dose Escalation and MTD Expansion Cohorts
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Oral everolimus (18 mg) and lenvatinib (5 mg) were taken once daily in the morning (consistently with or without food) with water. Any dietary habits around the time of study medication intake had to be kept as consistent as possible throughout the study.

    Subject analysis set title
    Cycle 1, Day 1 (2-8 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.

    Subject analysis set title
    Cycle 2, Day 1 (0 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.

    Subject analysis set title
    Cycle 2, Day 1 (2-8 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.

    Subject analysis set title
    Cycle 3, Day 1 (0 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected immediately prior to study drug administration.

    Subject analysis set title
    Cycle 3, Day 1 (2-8 Hours)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Lenvatinib (18 mg) and everolimus (5 mg) were administered as described previously. Blood samples were collected 2 to 8 hours after study drug administration.

    Primary: Phase 1b: Number of Subjects With Dose-limiting Toxicity (DLT)

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    End point title
    		 Phase 1b: Number of Subjects With Dose-limiting Toxicity (DLT) [1] [2]
    End point description
    A DLT was defined as either a treatment-related failure to administer greater than or equal to (>=) 75% of the planned dosage of lenvatinib/everolimus or a specific National Cancer Institute Common Toxicity Criteria (NCI CTC) >= Grade 3 (severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care daily living activities) hematologic or nonhematologic toxicities considered to be possibly related to lenvatinib and/or everolimus therapy assessed during the first treatment cycle of each dose level. Higher grade indicates more severe toxicity. Safety analysis set included all subjects who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    First dose of study drug (Cycle 1 Day 1) to end of first 4 weeks of therapy (Cycle 1)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data were planned to be reported for this end point.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
    Number of subjects analysed
    7
    11
    2
    Units: subjects
        Grade 3 abdominal pain
    1
    0
    0
        Grade 2 fatigue with Grade 1 GI reflux & anorexia
    0
    1
    0
        Grade 3 nausea
    0
    0
    1
        Grade 2 stomatitis
    0
    0
    1
    No statistical analyses for this end point

    Primary: Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose

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    End point title
    		 Phase 1b: Maximum Tolerated Dose (MTD) and Recommended Phase 2 (RP2) Dose [3]
    End point description
    The highest dose level resulting in 0 or 1 DLT in 6 subjects was to be considered the MTD of Phase 1b. Once the MTD was established, the subjects cohort was expanded to a minimum of 10 subjects. The MTD was confirmed by assessing DLTs during Cycle 1 and intolerable toxicities (i.e., not manageable with dose interruption and/or reduction) during Cycle 2 of therapy. Once the dose of lenvatinib/everolimus combination to be used in the succeeding Phase 2 part of the study was established, enrollment into Phase 2 was started. The RP2 dose was the same as the confirmed MTD and was used for the Phase 2 Treatment Arm A of this study. Safety analysis set included all subjects who received at least one dose of study treatment.
    End point type
    Primary
    End point timeframe
    First dose of study drug (Cycle 1 Day 1) to end of Cycle 2 (1 cycle = 28 days/4 weeks)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data were planned to be reported for this end point.
    End point values
    		 Phase 1b: Dose Escalation and MTD Expansion Cohorts
    Number of subjects analysed
    11
    Units: mg/day
        number (not applicable)
    18.0
    No statistical analyses for this end point

    Primary: Phase 2: Progression-Free Survival (PFS)

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    End point title
    		 Phase 2: Progression-Free Survival (PFS) [4]
    End point description
    PFS is the time (in months) from the date of first dose of study drug to the first documentation of disease progression or death, whichever occurred first. Kaplan-Meier (K-M) estimates median PFS, presented with 2-sided 95% confidence intervals (CIs). Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease using computed tomography (CT) or magnetic resonance imaging (MRI) and scan acquisition techniques (including use or nonuse of intravenous (IV) contrast). Tumor response determined at the site by the investigator and radiologist using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 in the evaluation of the tumor assessment scans. The date of objective disease progression is the earliest date of radiological disease progression. Participants removed from therapy due to clinical progression with no radiologic confirmation censored at their last radiologic assessment date. Full analysis set included all randomized subjects.
    End point type
    Primary
    End point timeframe
    Date of randomization into Phase 2 (Cycle 1 Day 1) to the date of first documentation of disease progression or death (whichever occurred first), assessed up to the data cutoff date (13 Jun 2014), up to approximately 2 years and 3 months.
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: months
    median (confidence interval 95%)
        Progression free survival
    14.6 (5.9 to 20.1)
    7.4 (5.6 to 10.2)
    5.5 (3.5 to 7.1)
    Statistical analysis title
    		 Phase 2 (Arm A) versus (vs) Phase 2 (Arm C)
    Statistical analysis description
    Null hypothesis of no difference in PFS was analyzed using the stratified log-rank test with hemoglobin (less than or equal to 13 g/dL vs greater than 13 g/dL for males; and less than or equal to 11.5 g/dL vs greater than 11.5 g/dL for females) and corrected serum calcium (greater than or equal to 10 mg/dL vs less than 10 mg/dL) as stratification factors. Each null hypothesis was tested at a nominal alpha=0.05.
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0005
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.24
         upper limit
    		 0.68
    Statistical analysis title
    		 Phase 2 (Arm B) vs Phase 2 (Arm C)
    Comparison groups
    Phase 2 (Arm B): 24 mg Lenvatinib v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0479
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 0.98
    Statistical analysis title
    		 Phase 2 (Arm A) vs Phase 2 (Arm B)
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1209
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 1.1

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [5]
    End point description
    OS was defined as the time (in months) from the date of randomization until date of death from any cause. Median survival time was calculated using K-M estimate for each treatment arm and presented with 2-sided 95% CIs. Subjects who were lost to follow-up or alive at the data cutoff date (10 Dec 2014) were censored at the date the subjects were last known to be alive. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Randomization (Cycle 1 Day 1) until date of death from any cause, assessed up to the data cutoff date (10 Dec 2014), up to approximately 2 years and 9 months.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: months
    median (confidence interval 95%)
        overall survival
    25.5 (16.4 to 99999)
    19.1 (13.6 to 26.2)
    15.4 (11.8 to 19.6)
    Statistical analysis title
    		 Phase 2 (Arm A) vs Phase 2 (Arm C)
    Statistical analysis description
    Planned analyses were performed to test null hypothesis of treatment difference in OS at a nominal significance level of 0.05 (2-sided) using the stratified log-rank test using stratification factors.
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0242
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.514
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.299
         upper limit
    		 0.884
    Statistical analysis title
    		 Phase 2 (Arm B) vs Phase 2 (Arm C)
    Comparison groups
    Phase 2 (Arm B): 24 mg Lenvatinib v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1181
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.411
         upper limit
    		 1.138
    Statistical analysis title
    		 Phase 2 (Arm A) vs Phase 2 (Arm B)
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3157
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.751
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.433
         upper limit
    		 1.301

    Secondary: Phase 2: Objective Response Rate (ORR)

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    End point title
    		 Phase 2: Objective Response Rate (ORR) [6]
    End point description
    The ORR was defined as the percentage of subjects who had the best overall response (BOR) of complete response (CR) or partial response (PR) as determined by the investigator, using RECIST 1.1 in the evaluation of MRI or CT scans of targeted lesions. Tumor assessments were performed every 8 weeks (or sooner if there was evidence of progressive disease). The BOR was defined as the best response recorded from the start of the study treatment until discontinuation from the study. 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 was calculated with exact 95% CIs using the method of Clopper and Pearson. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Randomization (Cycle 1 Day 1) until first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: percentage of subjects
    number (confidence interval 95%)
        objective response rate
    43.1 (29.3 to 57.8)
    26.9 (15.6 to 41.0)
    6.0 (1.3 to 16.5)
    Statistical analysis title
    		 Phase 2 (Arm A) vs Phase 2 (Arm C)
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001 [7]
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.3
         upper limit
    		 22.5
    Notes
    [7] - Analysis performed after database lock. P-value was based on the 2-sided Fisher’s exact P-value.
    Statistical analysis title
    		 Phase 2 (Arm B) vs Phase 2 (Arm C)
    Comparison groups
    Phase 2 (Arm B): 24 mg Lenvatinib v Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects included in analysis
    102
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0067 [8]
    Method
    		 Fisher exact
    Parameter type
    		 Rate ratio
    Point estimate
    4.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.4
         upper limit
    		 14.7
    Notes
    [8] - Analysis performed after database lock. P-value was based on the 2-sided Fisher’s exact P-value.
    Statistical analysis title
    		 Phase 2 (Arm A) vs Phase 2 (Arm B)
    Comparison groups
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus v Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects included in analysis
    103
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1007 [9]
    Method
    		 Fisher exact
    Parameter type
    		 Rate ratio
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.9
         upper limit
    		 2.8
    Notes
    [9] - Analysis performed after database lock. P-value was based on the 2-sided Fisher’s exact P-value.

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR) [10]
    End point description
    The DCR was defined as the percentage of subjects who had a BOR of CR or PR or SD (minimum duration from randomization to SD greater than or equal to 7 weeks). Assessments were performed every 8 weeks and were based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. DCR = CR + PR + SD greater than or equal to 7 weeks. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months.
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: percentage of subjects
    number (confidence interval 95%)
        Disease control rate
    84.3 (71.4 to 93.0)
    78.8 (65.3 to 88.9)
    68.0 (53.3 to 80.5)
    No statistical analyses for this end point

    Secondary: Durable Stable Disease (SD) Rate

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    End point title
    		 Durable Stable Disease (SD) Rate [11]
    End point description
    The durable SD rate was defined as the percentage of subjects whose BOR was SD and the duration of SD was greater than or equal to 23 weeks. The durable SD was based on investigator review data using RECIST 1.1. The 95% CI was constructed using the method of Clopper and Pearson. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: percentage of subjects
    number (confidence interval 95%)
        Durable Stable Disease (SD) Rate
    25.5 (14.3 to 39.6)
    38.5 (25.3 to 53.0)
    36.0 (22.9 to 50.8)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR) [12]
    End point description
    The CBR was defined as the percentage of subjects who had BOR of CR, PR, or durable SD (duration of SD was greater than or equal to 23 weeks) and was based on investigator review data using RECIST 1.1. The BOR was defined as the best response recorded from the start of study treatment until discontinuation from the study. There was no requirement for confirmatory measurement of PR or CR to deem either one the BOR. The 95% CI was constructed using the method of Clopper and Pearson. CBR = CR + PR + SD greater than or equal to 23 weeks. Full analysis set included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization) to first evidence of disease progression, assessed up to the data cutoff date (13 Jun 2014), or up to approximately 2 years and 3 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    51
    52
    50
    Units: percentage of subjects
    number (confidence interval 95%)
        Clinical Benefit Rate (CBR)
    68.6 (54.1 to 80.9)
    65.4 (50.9 to 78.0)
    42.0 (28.2 to 56.8)
    No statistical analyses for this end point

    Secondary: Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2

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    End point title
    		 Summary of Plasma Concentrations of Lenvatinib for Sparse Pharmacokinetic (PK) Sampling for Phase 1b and Phase 2
    End point description
    Blood samples were collected during the Randomization Phase. Most subjects had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Plasma concentrations of lenvatinib were measured and concentration data were summarized. The summary statistics at time points with one or more below the limit of quantitation (BLQ) values were calculated by assigning zero for each BLQ value.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
    End point values
    		 Cycle 1, Day 1 (0 Hours) Cycle 1, Day 1 (2-8 Hours) Cycle 2, Day 1 (0 Hours) Cycle 2, Day 1 (2-8 Hours) Cycle 3, Day 1 (0 Hours) Cycle 3, Day 1 (2-8 Hours)
    Number of subjects analysed
    57
    55
    45
    41
    40
    40
    Units: ng/mL
    geometric mean (standard deviation)
        Summary of Plasma Concentrations of Lenvatinib for
    5.6 ( 29.8 )
    197 ( 140 )
    66.9 ( 52.7 )
    237 ( 154 )
    37.0 ( 35.5 )
    180 ( 118 )
    No statistical analyses for this end point

    Secondary: Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2

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    End point title
    		 Summary of Blood Concentrations of Everolimus for Sparse PK Sampling for Phase 1b and Phase 2
    End point description
    Blood samples were collected during the Randomization Phase. Most subjects had 6 samples taken over 3 cycles of treatment (sparse sampling - 2 samples taken per cycle, one at predose and one at 2 to 8 hours postdose). Whole blood concentrations of everolimus were measured and concentration data were summarized. The summary statistics at time points with one or more BLQ values were calculated by assigning zero for each BLQ value. Pharmacokinetic analysis set included all participants who received at least one dose of study drug (lenvatinib or everolimus) and had evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 1), Cycle 2 (Day 1), Cycle 3 (Day 1)
    End point values
    		 Cycle 1, Day 1 (0 Hours) Cycle 1, Day 1 (2-8 Hours) Cycle 2, Day 1 (0 Hours) Cycle 2, Day 1 (2-8 Hours) Cycle 3, Day 1 (0 Hours) Cycle 3, Day 1 (2-8 Hours)
    Number of subjects analysed
    37
    35
    29
    28
    27
    25
    Units: ng/mL
    geometric mean (standard deviation)
        Summary of Blood Concentrations of Everolimus for
    0.0 ( 0.0 )
    19.4 ( 9.16 )
    10.0 ( 7.28 )
    24.3 ( 14.2 )
    6.8 ( 6.06 )
    26.4 ( 14.8 )
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus

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    End point title
    		 Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC(0-24)) for Lenvatinib When Administered Alone or in Combination With Everolimus [13]
    End point description
    Between 9 and 12 subjects in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for lenvatinib were derived from lenvatinib concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy. Pharmacokinetic sub analysis set consisted of all subjects who agreed to participate in the intensive PK sampling portion of Phase 2 of the study, had received at least 1 dose of study drug (lenvatinib or everolimus), and had evaluable concentration data.
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects analysed
    8
    9
    Units: ng.hr/mL
    arithmetic mean (standard deviation)
        Area Under the Plasma Concentration-Time Curve Fro
    3185 ( 1030 )
    5252 ( 2717 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus

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    End point title
    		 Maximum Concentration (Cmax) of Lenvatinib in Plasma When Administered Alone or in Combination With Everolimus [14]
    End point description
    Cmax for lenvatinib was defined as the maximum observed concentration of lenvatinib in plasma following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured plasma concentration-time curves. PK sub analysis set.
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects analysed
    8
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        Maximum Concentration (Cmax) of Lenvatinib in Plas
    327 ( 179 )
    403 ( 165 )
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus

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    End point title
    		 Time to Cmax (Tmax) for Lenvatinib When Administered Alone or in Combination With Everolimus [15]
    End point description
    Tmax for lenvatinib was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach maximum concentration (Cmax) of lenvatinib in plasma. PK sub analysis set.
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects analysed
    8
    9
    Units: hours
    median (full range (min-max))
        Time to Cmax (Tmax) for Lenvatinib When Administer
    2.0 (2.0 to 8.2)
    4.0 (0.5 to 8.0)
    No statistical analyses for this end point

    Secondary: Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib

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    End point title
    		 Area Under the Blood Concentration-Time Curve From 0 to 24 Hours for Everolimus When Administered Alone or in Combination With Lenvatinib [16]
    End point description
    Between 9 and 12 subjects in each of the 3 treatment arms participated in an optional substudy where instead of the sparse sampling, 9 samples were to be taken over 1 single 24-hour period (i.e., intensive sampling) for full PK profiling. Blood samples were analyzed for study drug using standardized methods. PK parameters for everolimus were derived from everolimus concentration data using non-compartmental methods. Data were compared via descriptive statistics between single agent and combination therapy. PK sub analysis set. n=8 for AUC(0-24).
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15 immediately predose, and 30 minutes, 1, 2, 3, 4, 8, 12 (optional), and 24 hours postdose (predose on Day 16)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects analysed
    4
    8
    Units: ng.hr/mL
    arithmetic mean (standard deviation)
        Area Under the Blood Concentration-Time Curve From
    378 ( 88.1 )
    463 ( 263 )
    No statistical analyses for this end point

    Secondary: Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib

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    End point title
    		 Maximum Concentration of Everolimus (Cmax) in Blood When Administered Alone or in Combination With Lenvatinib [17]
    End point description
    Cmax for everolimus was defined as the maximum observed concentration of everolimus in blood following administration of study treatment on Cycle 1 Day 15 and was obtained directly from the measured blood concentration-time curves. PK sub analysis set.
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib
    Number of subjects analysed
    4
    11
    Units: ng/mL
    arithmetic mean (standard deviation)
        Maximum Concentration of Everolimus (Cmax) in Bloo
    38 ( 14.5 )
    54 ( 24.9 )
    No statistical analyses for this end point

    Secondary: Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib

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    End point title
    		 Time to Cmax (Tmax) for Everolimus When Administered Alone or in Combination With Lenvatinib [18]
    End point description
    Tmax for everolimus was the amount of time taken after administration of study treatment on Cycle 1 Day 15 to reach the maximum concentration (Cmax) of everolimus in blood. PK sub analysis set.
    End point type
    Secondary
    End point timeframe
    Phase 2: Cycle 1 Day 15
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for only arms Phase 2 (Arm A): 18 mg Lenvatinib + 5 mg Everolimus, Phase 2 (Arm B): 24 mg Lenvatinib, and Phase 2 (Arm C): 10 mg Everolimus were planned to be reported for this end point.
    End point values
    		 Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm C): 10 mg Everolimus
    Number of subjects analysed
    4
    11
    Units: Hours
    median (full range (min-max))
        Time to Cmax (Tmax) for Everolimus When Administer
    1.0 (0.5 to 8.0)
    1.0 (0.5 to 25.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (AEs) were collected and defined as those AEs that occurred after the first dose of study medication and up to 30 days after the last dose of study medication. AEs were collected for approximately 4 years.
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least one dose of study drug/s and had at least one postbaseline safety evaluation. AE severity was assessed using Common Terminology for Adverse Events (CTCAE). Serious AEs were followed until the event resolved or the event or sequelae stabilized.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (12 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in a fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no dose-limiting toxicity (DLT) occurred, then enrollment proceeded to Cohort 2. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 1. If 1 or none of the 6 subjects had a DLT, then enrollment proceeded to Cohort 2. If 2 or more subjects had a DLT during Cycle 1, the dose escalation committee (DEC) decided if they were lenvatinib-related and if enrollment could proceed, lenvatinib was reduced to 6 mg daily (everolimus dose was not reduced). If it could not be determined that the DLTs were lenvatinib-related, enrollment stopped.

    Reporting group title
    Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment would proceed to Cohort 3. If 1 subject had a DLT, 3 more subjects were enrolled in Cohort 2. If 1 or none of the 6 subjects exhibited a DLT, enrollment proceeded to Cohort 3. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (24 mg) and everolimus (5 mg) were taken once daily in continuous 28-day cycles. Dose Escalation Cohort-Cycle 1: both study drugs were taken at the same time of day in the fasting state with water. Cycles 2, 3, etc. and Expansion Cohort: both study drugs were taken at the same time of day with water, either after a meal or in a fasting state. Dose escalation began with 3 subjects in Cohort 1. If no DLT occurred, then enrollment proceeded to Cohort 4. If 1 subject had a DLT, 3 more subjects were enrolled Cohort 3. If 1 or none of the 6 subjects exhibited a DLT, then enrollment proceeded to Cohort 4. If 2 or more subjects had a DLT during Cycle 1, dose escalation ceased and additional subjects were enrolled to the next lower dose to achieve a total of 6 subjects in that cohort.

    Reporting group title
    Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus
    Reporting group description
    		 Oral lenvatinib (18 mg) and everolimus (5 mg) were taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles. Treatment cycles began with the first dose of study drug in Cycle 1 and continued in 28-day (4-week) consecutive cycles until completion of the off-treatment assessments (within 30 days after the last study treatment administration). Study drugs were administered at the clinic for the first dose and on the pharmacokinetic (PK) sampling days.

    Reporting group title
    Phase 2 (Arm B): 24 mg Lenvatinib
    Reporting group description
    		 Oral lenvatinib (24 mg) was taken once daily in the morning (consistently with or without food) with water, in continuous 28-day (4-week) cycles.

    Reporting group title
    Phase 2 (Arm C): 10 mg Everolimus
    Reporting group description
    		 Oral everolimus (10 mg) was taken once daily in the morning (consistently either with or without food) with water, in continuous 28-day (4 week) cycles.

    Serious adverse events
    		 Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 7 (85.71%)
    8 / 11 (72.73%)
    0 / 2 (0.00%)
    30 / 51 (58.82%)
    28 / 52 (53.85%)
    21 / 50 (42.00%)
         number of deaths (all causes)
    6
    9
    0
    43
    40
    45
         number of deaths resulting from adverse events
    0
    0
    0
    2
    3
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hot Flush
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian Vein Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Venous Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest Discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 2
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    3 / 50 (6.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional State
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Phosphokinase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Body Temperature Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ejection Fraction Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram Repolarisation Abnormality
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fibrin D Dimer Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Joint Dislocation
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid Artery Occlusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage Intracranial
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Posterior Reversible Encephalopathy Syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Trigeminal Neuralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    1 / 52 (1.92%)
    4 / 50 (8.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 4
    0 / 1
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sideroblastic Anaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo Positional
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    4 / 52 (7.69%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    2 / 3
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Back Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psoriatic Arthropathy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis Perforated
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic Foot Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal Abscess
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    3 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to Thrive
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glucose Tolerance Impaired
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1b (Cohort 1): 12 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 2): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 1b (Cohort 3): 24 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm A): 18 mg Lenvatinib Plus 5 mg Everolimus Phase 2 (Arm B): 24 mg Lenvatinib Phase 2 (Arm C): 10 mg Everolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 7 (100.00%)
    11 / 11 (100.00%)
    2 / 2 (100.00%)
    51 / 51 (100.00%)
    51 / 52 (98.08%)
    50 / 50 (100.00%)
    Vascular disorders
    Aortic Dilatation
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Hot Flush
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    3 / 52 (5.77%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    2
    3
    0
    Hypertension
         subjects affected / exposed
    5 / 7 (71.43%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
    21 / 51 (41.18%)
    26 / 52 (50.00%)
    5 / 50 (10.00%)
         occurrences all number
    7
    5
    0
    28
    44
    6
    Hypotension
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    4
    0
    3
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    13 / 51 (25.49%)
    8 / 52 (15.38%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    0
    26
    34
    5
    Chills
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    6
    5
    4
    Fatigue
         subjects affected / exposed
    4 / 7 (57.14%)
    11 / 11 (100.00%)
    2 / 2 (100.00%)
    26 / 51 (50.98%)
    21 / 52 (40.38%)
    16 / 50 (32.00%)
         occurrences all number
    12
    26
    2
    53
    46
    18
    Gait Disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    1
    3
    2
    Influenza Like Illness
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    6
    4
    0
    Localised Oedema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Malaise
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    1
    10
    1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    0
    0
    2
    1
    Oedema Peripheral
         subjects affected / exposed
    1 / 7 (14.29%)
    6 / 11 (54.55%)
    0 / 2 (0.00%)
    15 / 51 (29.41%)
    9 / 52 (17.31%)
    9 / 50 (18.00%)
         occurrences all number
    7
    16
    0
    22
    15
    13
    Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    4
    2
    1
    Peripheral Swelling
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    0
    5
    1
    3
    Pyrexia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    9 / 51 (17.65%)
    5 / 52 (9.62%)
    5 / 50 (10.00%)
         occurrences all number
    0
    2
    0
    13
    8
    9
    Reproductive system and breast disorders
    Vaginal Haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    1 / 2 (50.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    6 / 7 (85.71%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    20 / 51 (39.22%)
    9 / 52 (17.31%)
    16 / 50 (32.00%)
         occurrences all number
    6
    4
    0
    34
    18
    24
    Dysphonia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    10 / 51 (19.61%)
    19 / 52 (36.54%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    13
    26
    2
    Dyspnoea
         subjects affected / exposed
    1 / 7 (14.29%)
    7 / 11 (63.64%)
    1 / 2 (50.00%)
    11 / 51 (21.57%)
    11 / 52 (21.15%)
    11 / 50 (22.00%)
         occurrences all number
    1
    10
    2
    15
    12
    16
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    1 / 52 (1.92%)
    5 / 50 (10.00%)
         occurrences all number
    1
    0
    0
    4
    1
    6
    Epistaxis
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 11 (45.45%)
    1 / 2 (50.00%)
    9 / 51 (17.65%)
    4 / 52 (7.69%)
    12 / 50 (24.00%)
         occurrences all number
    6
    7
    1
    11
    5
    14
    Haemoptysis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    0
    4
    5
    Lung Infiltration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    1 / 2 (50.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    0
    0
    3
    Nasal Congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    2
    1
    1
    Oropharyngeal Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    1
    4
    0
    7
    2
    2
    Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    0
    0
    0
    3
    Pneumonitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    1
    0
    0
    2
    0
    10
    Productive Cough
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    0
    1
    3
    4
    Rhinorrhoea
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    4
    2
    Sinus Congestion
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    Sputum Discoloured
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper-Airway Cough Syndrome
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    0
    0
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    0
    1
    3
    2
    Paranasal sinus discomfort
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    2
    3
    2
    Confusional State
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 11 (0.00%)
    1 / 2 (50.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    1
    2
    1
    0
    Depression
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    4
    1
    3
    Insomnia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    10 / 51 (19.61%)
    8 / 52 (15.38%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    0
    20
    9
    1
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    3 / 52 (5.77%)
    3 / 50 (6.00%)
         occurrences all number
    0
    4
    0
    6
    4
    8
    Amylase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    1
    3
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    2 / 52 (3.85%)
    3 / 50 (6.00%)
         occurrences all number
    0
    5
    0
    4
    2
    9
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences all number
    2
    3
    0
    2
    1
    3
    Blood Bilirubin Increased
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    1
    1
    0
    Blood Cholesterol Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    2 / 52 (3.85%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    0
    21
    4
    11
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    4
    0
    18
    0
    7
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    2 / 52 (3.85%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    0
    4
    3
    5
    Blood Glucose Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    3
    0
    3
    Blood Phosphorus Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    3
    0
    Blood Potassium Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Blood Thyroid Stimulating Hormone Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    7 / 51 (13.73%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    8
    2
    1
    Blood Triglycerides Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    6
    0
    0
    2
    1
    Cardiac Murmur
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Computerised Tomogram Thorax Abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Ejection Fraction Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    4 / 52 (7.69%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    7
    0
    Electrocardiogram QT Prolonged
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    2
    2
    0
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    5 / 50 (10.00%)
         occurrences all number
    0
    3
    0
    1
    2
    10
    Lipase Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    5 / 52 (9.62%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    0
    10
    7
    11
    Liver Function Test Abnormal
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Murphy’s Sign Positive
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Platelet Count Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Protein Urine Present
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Transaminases Increased
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    3
    0
    Weight Decreased
         subjects affected / exposed
    2 / 7 (28.57%)
    5 / 11 (45.45%)
    0 / 2 (0.00%)
    16 / 51 (31.37%)
    26 / 52 (50.00%)
    4 / 50 (8.00%)
         occurrences all number
    3
    14
    0
    22
    38
    4
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    White Blood Cell Count Increased
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Arthropod Bite
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Contusion
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    1
    2
    0
    Fall
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    1
    1
    Periorbital Contusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Toxicity to Various Agents
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Aortic Valve Incompetence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Coronary Artery Disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Coronary Artery Occlusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    0
    11
    Mitral Valve Incompetence
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Palpitations
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    0
    0
    0
    2
    Tachycardia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Ventricular Hypokinesia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nervous system disorders
    Disturbance In Attention
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    1 / 7 (14.29%)
    5 / 11 (45.45%)
    1 / 2 (50.00%)
    2 / 51 (3.92%)
    4 / 52 (7.69%)
    2 / 50 (4.00%)
         occurrences all number
    1
    8
    1
    2
    7
    2
    Dysgeusia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    4 / 52 (7.69%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    4
    5
    2
    Headache
         subjects affected / exposed
    4 / 7 (57.14%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    10 / 51 (19.61%)
    13 / 52 (25.00%)
    4 / 50 (8.00%)
         occurrences all number
    4
    3
    0
    14
    21
    6
    Hyperaesthesia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    1 / 2 (50.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    0
    2
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    7 / 52 (13.46%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    7
    10
    2
    Paraesthesia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    1 / 2 (50.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    1
    3
    1
    1
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    4 / 52 (7.69%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    0
    6
    0
    Sensory Disturbance
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Sinus Headache
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Tremor
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    1 / 2 (50.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    1
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    7 / 51 (13.73%)
    3 / 52 (5.77%)
    11 / 50 (22.00%)
         occurrences all number
    4
    2
    0
    10
    3
    13
    Haemorrhagic Disorder
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    1 / 52 (1.92%)
    4 / 50 (8.00%)
         occurrences all number
    0
    4
    0
    18
    4
    5
    Ear and labyrinth disorders
    Ear Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    3 / 52 (5.77%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    Eye Swelling
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    Ocular Hyperaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    Vision Blurred
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Gastrointestinal disorders
    Abdominal Discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Abdominal Distension
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    1 / 2 (50.00%)
    4 / 51 (7.84%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    1
    12
    4
    0
    Abdominal Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    12 / 51 (23.53%)
    11 / 52 (21.15%)
    1 / 50 (2.00%)
         occurrences all number
    2
    5
    0
    16
    23
    1
    Abdominal Pain Lower
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    8 / 51 (15.69%)
    7 / 52 (13.46%)
    3 / 50 (6.00%)
         occurrences all number
    4
    1
    0
    16
    10
    4
    Anal Fissure
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    Anal Pruritus
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Anorectal Discomfort
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Aphthous Stomatitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    3
    1
    0
    Cheilitis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    3
    2
    1
    Constipation
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 11 (36.36%)
    1 / 2 (50.00%)
    6 / 51 (11.76%)
    19 / 52 (36.54%)
    9 / 50 (18.00%)
         occurrences all number
    4
    7
    1
    6
    30
    10
    Diarrhoea
         subjects affected / exposed
    3 / 7 (42.86%)
    7 / 11 (63.64%)
    1 / 2 (50.00%)
    43 / 51 (84.31%)
    37 / 52 (71.15%)
    17 / 50 (34.00%)
         occurrences all number
    10
    19
    1
    199
    134
    22
    Dry Mouth
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    1 / 2 (50.00%)
    2 / 51 (3.92%)
    6 / 52 (11.54%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    1
    2
    6
    3
    Dyspepsia
         subjects affected / exposed
    0 / 7 (0.00%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
    6 / 51 (11.76%)
    6 / 52 (11.54%)
    6 / 50 (12.00%)
         occurrences all number
    0
    4
    0
    9
    7
    7
    Flatulence
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    3 / 52 (5.77%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    10
    3
    0
    Gastric Haemorrhage
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Gastritis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    3
    0
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    2
    3
    0
    Gingival Bleeding
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    4
    0
    Glossitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    0
    Glossodynia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    2
    0
    Haemorrhoidal Haemorrhage
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    2
    1
    0
    Lip Discolouration
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Mouth Ulceration
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    0 / 52 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    0
    0
    7
    0
    9
    Nausea
         subjects affected / exposed
    6 / 7 (85.71%)
    6 / 11 (54.55%)
    1 / 2 (50.00%)
    22 / 51 (43.14%)
    32 / 52 (61.54%)
    8 / 50 (16.00%)
         occurrences all number
    10
    16
    2
    50
    59
    12
    Oral Mucosal Blistering
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Oral Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    6 / 51 (11.76%)
    5 / 52 (9.62%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    0
    6
    6
    1
    Paraesthesia Oral
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    4 / 7 (57.14%)
    7 / 11 (63.64%)
    2 / 2 (100.00%)
    15 / 51 (29.41%)
    13 / 52 (25.00%)
    21 / 50 (42.00%)
         occurrences all number
    5
    18
    3
    29
    27
    28
    Toothache
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    6
    3
    1
    Vomiting
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 11 (45.45%)
    1 / 2 (50.00%)
    24 / 51 (47.06%)
    20 / 52 (38.46%)
    6 / 50 (12.00%)
         occurrences all number
    10
    8
    2
    50
    50
    6
    Hepatobiliary disorders
    Dilatation Intrahepatic Duct Acquired
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    3
    1
    3
    Dermatitis Acneiform
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    0
    2
    Dry Skin
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    5 / 51 (9.80%)
    3 / 52 (5.77%)
    3 / 50 (6.00%)
         occurrences all number
    3
    4
    0
    7
    4
    4
    Ecchymosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Erythema
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Erythema Multiforme
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    2
    0
    1
    Hyperkeratosis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    2
    0
    1
    Night Sweats
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    0
    0
    2
    3
    Onychoclasis
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    0
    3
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    8 / 52 (15.38%)
    2 / 50 (4.00%)
         occurrences all number
    0
    4
    0
    10
    19
    3
    Petechiae
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    7 / 51 (13.73%)
    3 / 52 (5.77%)
    7 / 50 (14.00%)
         occurrences all number
    2
    1
    0
    9
    5
    7
    Rash
         subjects affected / exposed
    3 / 7 (42.86%)
    5 / 11 (45.45%)
    1 / 2 (50.00%)
    9 / 51 (17.65%)
    8 / 52 (15.38%)
    11 / 50 (22.00%)
         occurrences all number
    3
    10
    1
    11
    17
    19
    Rash Erythematous
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    3 / 52 (5.77%)
    4 / 50 (8.00%)
         occurrences all number
    0
    2
    0
    2
    3
    5
    Rash Macular
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    5 / 50 (10.00%)
         occurrences all number
    1
    1
    0
    1
    3
    5
    Skin Mass
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    1
    0
    Skin Ulcer
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    2 / 52 (3.85%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    1
    4
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    1 / 2 (50.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    1
    2
    1
    0
    Nocturia
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    0
    0
    2
    3
    Pollakiuria
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    2 / 52 (3.85%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    0
    0
    2
    4
    Proteinuria
         subjects affected / exposed
    5 / 7 (71.43%)
    6 / 11 (54.55%)
    0 / 2 (0.00%)
    13 / 51 (25.49%)
    16 / 52 (30.77%)
    7 / 50 (14.00%)
         occurrences all number
    7
    28
    0
    39
    82
    8
    Renal Failure Acute
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    0
    1
    0
    Renal Failure Chronic
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Renal Mass
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    12 / 51 (23.53%)
    19 / 52 (36.54%)
    1 / 50 (2.00%)
         occurrences all number
    2
    3
    0
    16
    21
    1
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 7 (57.14%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    14 / 51 (27.45%)
    13 / 52 (25.00%)
    7 / 50 (14.00%)
         occurrences all number
    4
    3
    0
    20
    27
    7
    Back Pain
         subjects affected / exposed
    3 / 7 (42.86%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
    11 / 51 (21.57%)
    11 / 52 (21.15%)
    7 / 50 (14.00%)
         occurrences all number
    3
    4
    0
    22
    13
    11
    Bone Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    4 / 52 (7.69%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    0
    3
    5
    2
    Flank Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    2 / 52 (3.85%)
    2 / 50 (4.00%)
         occurrences all number
    0
    3
    0
    2
    2
    4
    Groin Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    5
    1
    0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    0
    0
    0
    Muscle Spasms
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    1
    2
    2
    Muscular Weakness
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    3 / 52 (5.77%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    2
    4
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    8 / 51 (15.69%)
    7 / 52 (13.46%)
    2 / 50 (4.00%)
         occurrences all number
    1
    2
    0
    14
    9
    4
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 7 (42.86%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    8 / 52 (15.38%)
    1 / 50 (2.00%)
         occurrences all number
    5
    4
    0
    8
    16
    2
    Myalgia
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    7 / 52 (13.46%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    5
    14
    1
    Neck Pain
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    0
    2
    0
    1
    Pain In Jaw
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    3
    1
    0
    Pain in Extremity
         subjects affected / exposed
    2 / 7 (28.57%)
    4 / 11 (36.36%)
    0 / 2 (0.00%)
    6 / 51 (11.76%)
    6 / 52 (11.54%)
    3 / 50 (6.00%)
         occurrences all number
    5
    6
    0
    7
    15
    9
    Spinal Osteoarthritis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    4 / 52 (7.69%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    0
    3
    5
    1
    Cellulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    Gingivitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    3 / 51 (5.88%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    3
    0
    0
    Infectious Pleural Effusion
         subjects affected / exposed
    0 / 7 (0.00%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    2
    1
    0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    4 / 52 (7.69%)
    4 / 50 (8.00%)
         occurrences all number
    0
    0
    0
    4
    4
    4
    Lymph Gland Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    7 / 51 (13.73%)
    4 / 52 (7.69%)
    7 / 50 (14.00%)
         occurrences all number
    1
    1
    0
    9
    5
    8
    Oral Herpes
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    1 / 52 (1.92%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    0
    1
    1
    3
    Osteomyelitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Paronychia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    2
    1
    1
    Respiratory Tract Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    4 / 52 (7.69%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    4
    4
    1
    Sinusitis
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    0
    Skin Infection
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 7 (28.57%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    7 / 52 (13.46%)
    7 / 50 (14.00%)
         occurrences all number
    3
    0
    0
    4
    9
    12
    Urinary Tract Infection
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    4 / 52 (7.69%)
    3 / 50 (6.00%)
         occurrences all number
    1
    1
    0
    0
    4
    4
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    3 / 7 (42.86%)
    6 / 11 (54.55%)
    1 / 2 (50.00%)
    27 / 51 (52.94%)
    30 / 52 (57.69%)
    10 / 50 (20.00%)
         occurrences all number
    5
    10
    2
    41
    53
    12
    Dehydration
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    2 / 51 (3.92%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    0
    2
    1
    1
    Failure to Thrive
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    4
    1
    0
    0
    0
    2
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    18 / 51 (35.29%)
    6 / 52 (11.54%)
    8 / 50 (16.00%)
         occurrences all number
    0
    2
    0
    42
    9
    8
    Hyperglycaemia
         subjects affected / exposed
    2 / 7 (28.57%)
    3 / 11 (27.27%)
    0 / 2 (0.00%)
    8 / 51 (15.69%)
    3 / 52 (5.77%)
    12 / 50 (24.00%)
         occurrences all number
    3
    3
    0
    11
    4
    44
    Hyperkalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    3 / 52 (5.77%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    0
    1
    3
    1
    Hyperlipidaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    0
    7
    Hypernatraemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    7 / 11 (63.64%)
    0 / 2 (0.00%)
    18 / 51 (35.29%)
    7 / 52 (13.46%)
    12 / 50 (24.00%)
         occurrences all number
    2
    20
    0
    79
    18
    14
    Hypocalcaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    4 / 51 (7.84%)
    3 / 52 (5.77%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    0
    8
    4
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    7 / 51 (13.73%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    0
    12
    0
    2
    Hypomagnesaemia
         subjects affected / exposed
    0 / 7 (0.00%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    1 / 51 (1.96%)
    4 / 52 (7.69%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    4
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 7 (14.29%)
    2 / 11 (18.18%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    0 / 50 (0.00%)
         occurrences all number
    1
    5
    0
    0
    1
    0
    Hypophagia
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    3 / 7 (42.86%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    1 / 52 (1.92%)
    1 / 50 (2.00%)
         occurrences all number
    4
    0
    0
    0
    1
    1
    Hypovolaemia
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    Malnutrition
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 11 (0.00%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    Metabolic Acidosis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 11 (9.09%)
    0 / 2 (0.00%)
    0 / 51 (0.00%)
    0 / 52 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2011
    Phase 1b Amendment 01: Change in inclusion criteria with regard to subjects who were treated with Afinitor (everolimus) and change with regard to contraceptive use in subjects. Change in dose reduction and interruption instructions for subjects who experienced lenvatinib-everolimus combination therapy related toxicity and single agent lenvatinib-related toxicity for subjects with tolerable Grade 2 toxicities.
    09 Jul 2012
    Phase 1b Amendment 02: Change in dose reduction and interruption instructions for subjects who experienced lenvatinib-everolimus combination therapy-related toxicity and single agent lenvatinib-related toxicity.
    28 Feb 2013
    Phase 1b Amendment 03: Window of consent was extended so that informed consent could be signed up to 8 weeks before the first dose of study drug was administered. Phase 2 eligibility criteria were revised to include subjects with evidence of disease progression on or within 9 months of stopping prior therapy instead of 6 months. Phase 2 eligibility criteria were revised from 1 prior VEGF-targeted treatment for unresectable advanced or metastatic RCC to 1 prior disease progression episode on or after VEGF-targeted treatment to allow subjects to have had, for example, 2 prior VEGF-targeted treatments if 1 of these was given in the adjuvant setting. Additional information on dose adjustment for special populations who received everolimus was added to reflect changes in everolimus prescribing information (January 2013). Modification allowed concomitant therapies to allow bisphosphonates to be administered as prescribed by the treating physician. The 12 hour PK sampling time point was made optional, and the intensive PK sampling was to be made mandatory if an insufficient number of subjects entered voluntarily. Vital sign measurements were changed from supine to resting. Definition of end of study was added.

    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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