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    Clinical Trial Results:
    A Randomized, Open-Label (formerly Double-Blind), Phase 2 Trial to Assess Safety and Efficacy of Lenvatinib at Two Different Starting Doses (18 mg vs 14 mg QD) in Combination With Everolimus (5 mg QD) in Renal Cell Carcinoma Following One Prior VEGF-Targeted Treatment

    Summary
    EudraCT number
    		 2016-002778-11
    Trial protocol
    		 CZ   GB   NL   GR   FI   PL   ES   PT   IT   RO  
    Global end of trial date
    20 Jun 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2025
    First version publication date
    04 Apr 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-G000-218
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03173560
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai, Inc.
    Sponsor organisation address
    200 Metro Boulevard, Nutley, New Jersey, United States, 07110
    Public contact
    Eisai Medical Information, Eisai, Inc., +18 882742378, esi_oncmedinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai, Inc., +18 882742378, esi_oncmedinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Jun 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to assess whether a starting dose of lenvatinib 14 milligram (mg) in combination with everolimus 5 mg once daily (QD) will provide comparable efficacy (based on objective response rate [ORR]at 24 weeks [ORR24W]) with an improved safety profile compared to lenvatinib 18 mg in combination with everolimus 5 mg (based on treatment emergent intolerable Grade 2, or any greater than or equal to (>=) Grade 3 adverse events (AEs) in the first 24 weeks after randomization).
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures 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 (2013), 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 Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and 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 EU country.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Aug 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Portugal: 12
    Country: Number of subjects enrolled
    Spain: 47
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    Finland: 19
    Country: Number of subjects enrolled
    Greece: 22
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Korea, Republic of: 47
    Country: Number of subjects enrolled
    Taiwan: 9
    Country: Number of subjects enrolled
    Romania: 21
    Country: Number of subjects enrolled
    Russian Federation: 49
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    United States: 26
    Worldwide total number of subjects
    343
    EEA total number of subjects
    174
    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)
    215
    From 65 to 84 years
    127
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects took part in the study at 82 investigative sites in Australia, Korea, Taiwan, Czech, Poland, Romania, Russia, Finland, Greece, Italy, Netherlands, Portugal, Spain, United Kingdom, Canada and the United States from 17 August 2017 to 20 June 2024.

    Pre-assignment
    Screening details
    		 A total of 489 subjects were screened, of which 146 were screen failures and 343 were enrolled and randomized, out of which 341 subjects were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenvatinib 14 mg + Everolimus 5 mg
    Arm description
    		 Subjects received lenvatinib 14 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until progressive disease (PD), development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first. Subjects who had no intolerable Grade 2 or any greater than or equal to (>=) Grade 3 treatment-emergent adverse events (TEAEs) that required dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), had lenvatinib dose titrated to 18 mg once daily (along with everolimus 5 mg) beginning in Cycle 2 or later (cycle length equals to (=) 28 days) during randomization phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg, tablet, orally, once daily in each 28-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 14 mg, capsule, orally, once daily in each 28-day treatment cycle.

    Arm title
    		 Lenvatinib 18 mg + Everolimus 5 mg
    Arm description
    		 Subjects received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until PD, development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus 5 mg, tablet, orally, once daily in each 28-day treatment cycle.

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    Other name
    E7080
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Lenvatinib 18 mg capsule, orally, once daily in each 28-day treatment cycle.

    Number of subjects in period 1
    		Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Started
    172
    171
    Treated Subjects
    172
    169
    Completed
    91
    101
    Not completed
    81
    70
         Consent withdrawn by subject
    10
    5
         Death
    70
    60
         Unspecified
    -
    1
         Lost to follow-up
    1
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenvatinib 14 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 14 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until progressive disease (PD), development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first. Subjects who had no intolerable Grade 2 or any greater than or equal to (>=) Grade 3 treatment-emergent adverse events (TEAEs) that required dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), had lenvatinib dose titrated to 18 mg once daily (along with everolimus 5 mg) beginning in Cycle 2 or later (cycle length equals to (=) 28 days) during randomization phase.

    Reporting group title
    Lenvatinib 18 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until PD, development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first.

    Reporting group values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg Total
    Number of subjects
    		 172 171 343
    Age categorical
    Units: subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 114 101 215
        From 65-84 years
    		 58 69 127
        85 years and over
    		 0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.5 ( 9.59 ) 61.5 ( 9.90 ) -
    Sex: Female, Male
    Units: subjects
        Female
    		 39 42 81
        Male
    		 133 129 262
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 4 8 12
        Not Hispanic or Latino
    		 168 163 331
        Unknown or Not Reported
    		 0 0 0
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 33 27 60
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 137 140 277
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 2 4 6

    End points

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    End points reporting groups
    Reporting group title
    Lenvatinib 14 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 14 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until progressive disease (PD), development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first. Subjects who had no intolerable Grade 2 or any greater than or equal to (>=) Grade 3 treatment-emergent adverse events (TEAEs) that required dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), had lenvatinib dose titrated to 18 mg once daily (along with everolimus 5 mg) beginning in Cycle 2 or later (cycle length equals to (=) 28 days) during randomization phase.

    Reporting group title
    Lenvatinib 18 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until PD, development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first.

    Subject analysis set title
    Lenvatinib 18 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with RCC received lenvatinib 18 mg, capsule, orally, once daily until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up or until the end of the study, whichever occurred first in studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and in this current study E7080-G000-218 (NCT03173560).

    Subject analysis set title
    Everolimus 10 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with RCC received everolimus 10 mg, capsule, orally, once daily until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up or until the end of the study, whichever occurred first in studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or in this current study E7080-G000-218 (NCT03173560).

    Subject analysis set title
    Lenvatinib 18 mg + Everolimus 5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with RCC received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up or until the end of the study, whichever occurred first in studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and in this current study E7080-G000-218 (NCT03173560).

    Subject analysis set title
    Lenvatinib + Everolimus 5 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with RCC received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up or until the end of the study, whichever occurred first in studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or in this current study E7080-G000-218 (NCT03173560).

    Subject analysis set title
    Lenvatinib 14 mg + Everolimus 5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received lenvatinib 14 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first. Subjects who had no intolerable Grade 2 or any >=Grade 3 TEAEs that required dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), had lenvatinib dose titrated to 18 mg once daily (along with everolimus 5 mg) beginning in Cycle 2 or later (cycle length =28 days) during randomization phase.

    Subject analysis set title
    Lenvatinib 18 mg + Everolimus 5 mg
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Subjects received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose in a 28-day treatment cycle until PD, development of unacceptable toxicity, participant requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first.

    Primary: Objective Response Rate at Week 24 (ORR24W)

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    End point title
    		 Objective Response Rate at Week 24 (ORR24W)
    End point description
    ORR24W: percentage of subjects with best overall response(BOR) of complete response(CR) or partial response(PR) at Week 24(after randomization), during treatment or within 28 days after last dose date but on or prior to start of new anticancer therapy based on investigator assessment according to Response Evaluation Criteria In Solid Tumors(RECIST) version 1.1.CR: disappearance of all target and non-target lesions(non-lymph nodes). All pathological lymph nodes(whether target or non-target) must have reduction in their short axis to less than (<) 10 millimeters(mm).PR: at least a 30 percent(%) decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. To be considered BOR, all responses had to be confirmed no <4 weeks after initial assessment of response. Per-protocol analysis set 1(PPAS1) included all randomized subjects minus the 32 subjects who had received >=2 incorrect lenvatinib doses due to interactive voice and web response system(IxRS) issues.
    End point type
    Primary
    End point timeframe
    At Week 24
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    156
    155
    Units: percentage of subjects
        number (confidence interval 95%)
    32.1 (24.7 to 39.4)
    34.8 (27.3 to 42.3)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Lenvatinib 14 mg + Everolimus 5 mg v Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.2676
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.32
    Notes
    [1] - Odd ratio for ORR24W was analyzed along with 90% CI for each treatment arm using Cochran-Mantel-Haenszel (CMH) method, stratified by Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic group and prior programmed cell death protein 1/ programmed cell death protein ligand 1 (PD-1/PD-L1) treatment from IxRS data. Non-inferiority would be claimed if 1-sided P value is <=0.045 at the final analysis for the non-inferiority test with the non-inferiority margin of the odd ratio =0.76.

    Primary: Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks

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    End point title
    		 Percentage of Participants With Intolerable Grade 2 or Any Grade >=Grade 3 TEAEs Within 24 Weeks
    End point description
    TEAE was defined as an adverse event (AE) with an onset that had occurred after receiving study drug. A severity grade was defined by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.03. As per NCI-CTCAE, Grade 1 scales as Mild; Grade 2 scales as Moderate; Grade 3 scales as severe or medically significant but not immediately life threatening; Grade 4 scales as life-threatening consequences; and Grade 5 scales as death related to AE. Per-protocol safety analysis set included all randomized and treated participants minus 32 participants who had received >=2 incorrect lenvatinib doses due to IxRS issues according to actual treatment received.
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    157
    152
    Units: percentage of subjects
        number (confidence interval 95%)
    82.8 (76.9 to 88.7)
    79.6 (73.2 to 86.0)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Lenvatinib 14 mg + Everolimus 5 mg v Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects included in analysis
    309
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.4763
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference
    Point estimate
    3.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 11.9
    Notes
    [2] - Percentage of subjects with intolerable Grade 2 or any Grade >=Grade 3 TEAEs within 24 weeks was tested using CMH method at 2-sided α=0.05, stratified by MSKCC prognostic group and prior PD-1/PD-L1 treatment from IxRS data. The treatment difference and 95% CI were also calculated based on asymptotic normal approximation.

    Secondary: Progression-free Survival (PFS)

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    End point title
    		 Progression-free Survival (PFS)
    End point description
    PFS was defined as the time from the date of randomization to the date of the first documentation of PD by investigator assessment or date of death, whichever occurred first according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 millimeter [mm]) in the sum of diameter (SOD) of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% confidence interval (CI). PPAS1 included all randomized subjects minus the 32 participants who had received >=2 incorrect lenvatinib doses due to IxRS issues. As pre-specified in the protocol, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of the first documentation of PD or date of death, whichever occurred first or up to date of data cutoff for the primary analysis (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    156
    155
    Units: months
        median (confidence interval 95%)
    11.1 (9.0 to 12.9)
    14.7 (11.1 to 20.3)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Lenvatinib 14 mg + Everolimus 5 mg v Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.42
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 1.86
    Notes
    [3] - The hazard ratio and the corresponding 90% CIs were estimated using the Cox regression model with Efron’s method for ties, stratified by MSKCC prognostic group and prior PD-1/PD-L1 treatment.

    Secondary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    ORR was defined as the percentage of subjects with a BOR of CR or PR at the at the end of treatment based on investigator assessment according to RECIST v1.1. CR: defined as the disappearance of all target and non-target lesions (non-lymph nodes). All pathological lymph nodes (whether target or non-target) must have a reduction in their short axis to <10 mm. PR: defined as at least a 30 % decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. To be considered a BOR, all responses had to be confirmed no less than 4 weeks after the initial assessment of response. PPAS1 included all randomized subjects minus the 32 subjects who had received >=2 incorrect lenvatinib doses due to IxRS issues. As pre-specified in the protocol, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to first documentation of PD or date of death, whichever occurred first or up to the date of data cut off for the primary analysis (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    156
    155
    Units: percentage of subjects
        number (confidence interval 95%)
    34.6 (27.1 to 42.1)
    40.6 (32.9 to 48.4)
    Statistical analysis title
    		 Statistical analysis
    Comparison groups
    Lenvatinib 14 mg + Everolimus 5 mg v Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects included in analysis
    311
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.77
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 1.14
    Notes
    [4] - Odd ratio for ORR was analyzed along with 90% CI for each treatment arm using CMH method stratified by MSKCC prognostic group and PD-1/PD-L1 treatment from IxRS data.

    Secondary: Number of Subjects with TEAEs and Serious TEAEs

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    End point title
    		 Number of Subjects with TEAEs and Serious TEAEs
    End point description
    TEAEs were defined as those adverse events (AEs) that occurred (or worsened, if present at Baseline) after the first dose of study drug through 28 days after the last dose of study drug. An AE was defined as any untoward medical occurrence in a subjects or clinical investigation participant administered an investigational product. An AE does not necessarily have a causal relationship with medicinal product. A serious adverse event (SAE) was defined as any AE if it resulted in death or life-threatening AE or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions or was a congenital anomaly/birth defect. Safety analysis set (SAS) included all subjects who were randomized and received at least 1 dose of study drug according to the treatment starting dose actually received.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    173
    168
    Units: subjects
        Subjects With TEAEs
    173
    167
        Subjects With Serious TEAEs
    92
    87
    No statistical analyses for this end point

    Secondary: Time to Treatment Failure due to Toxicity

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    End point title
    		 Time to Treatment Failure due to Toxicity
    End point description
    Time to treatment failure due to toxicity was defined as the time from the date of randomization to the date that a subject discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to CTCAE v4.03. FAS included all randomized subjects. As planned, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to the date of discontinuation of study treatment due to TEAEs, or date of data cut off for the primary analysis (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    172
    171
    Units: months
        median (full range (min-max))
    3.15 (0.5 to 12.7)
    5.70 (0.8 to 24.6)
    No statistical analyses for this end point

    Secondary: Plasma Concentration of Lenvatinib

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    End point title
    		 Plasma Concentration of Lenvatinib
    End point description
    PK sparse sampling was performed. As planned, the post-dose plasma sample was collected anytime between 0.5 to 4 hours at Cycle 1 Days 1 and 15, between 6 to 10 hours at Cycle 1 Days 1 and 15, and between 2 to 12 hours at Cycle 2 Day 1. Only one sample was collected for each post-dose category between specified timepoints. Pharmacokinetic (PK) analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable lenvatinib plasma or everolimus whole blood concentration data. Here, "number of subjects analyzed” are the subjects who were evaluable for the endpoint and "n" were the subjects who were evaluable for this endpoint at given time points.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    168
    160
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 0.5-4 hours post-dose (n=168,160)
    57.9 ( 96.54 )
    82.3 ( 119.89 )
        Cycle 1 Day 1: 6-10 hours post-dose (n=166,154)
    136.3 ( 66.53 )
    193.7 ( 93.08 )
        Cycle 1 Day 15: Pre-dose (n=154,149)
    53.7 ( 62.31 )
    64.0 ( 59.71 )
        Cycle 1 Day 15: 0.5-4 hours post-dose (n=147,147)
    99.6 ( 102.54 )
    133.4 ( 125.65 )
        Cycle 1 Day 15: 6-10 hours post-dose (n=148,143)
    177.8 ( 89.42 )
    236.2 ( 135.21 )
        Cycle 2 Day 1: Pre-dose (n=160,151)
    42.8 ( 42.84 )
    50.6 ( 46.06 )
        Cycle 2 Day 1: 2-12 hours post-dose (154,143)
    172.8 ( 130.90 )
    190.3 ( 114.85 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects who Discontinued Treatment due to Toxicity

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    End point title
    		 Percentage of Subjects who Discontinued Treatment due to Toxicity
    End point description
    Percentage of subjects who discontinued treatment due to toxicity, defined as the percentage of subjects who discontinued study treatment due to TEAEs. Toxicity (except hypertension and non-infectious pneumonitis) was assessed according to NCI-CTCAE v4.03. FAS included all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    172
    171
    Units: percentage of subjects
        number (not applicable)
    17.4
    25.1
    No statistical analyses for this end point

    Secondary: Whole Blood Concentration of Everolimus

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    End point title
    		 Whole Blood Concentration of Everolimus
    End point description
    PK sparse sampling was performed. As planned, the post-dose whole blood sample was collected anytime between 0.5 to 4 hours at Cycle 1 Days 1 and 15, between 6 to 10 hours at Cycle 1 Days 1 and 15, and between 2 to 12 hours at Cycle 2 Day 1. Only one sample was collected for each post-dose category between specified timepoints. PK analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable lenvatinib plasma or everolimus whole blood concentration data. Here, "number of subjects analyzed" are the subjects who were evaluable for the endpoint and "n" were the subjects who were evaluable at given time points.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    120
    117
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cycle 1 Day 1: 0.5-4 hours post-dose (n=106,117)
    18.3 ( 15.89 )
    18.6 ( 16.39 )
        Cycle 1 Day 1: 6-10 hours post-dose (n=103,115)
    9.2 ( 6.60 )
    8.4 ( 5.64 )
        Cycle 1 Day 15: Pre-dose (n=110,111)
    8.4 ( 4.84 )
    7.4 ( 5.51 )
        Cycle 1 Day 15: 0.5-4 hours post-dose (n=106,111)
    23.7 ( 15.41 )
    23.4 ( 16.96 )
        Cycle 1 Day 15: 6-10 hours post-dose (n=107,106)
    14.3 ( 5.83 )
    14.3 ( 9.22 )
        Cycle 2 Day 1: Pre-dose (n=120,117)
    7.8 ( 5.44 )
    5.9 ( 4.02 )
        Cycle 2 Day 1: 2-12 hours post-dose (n=112,112)
    22.9 ( 12.67 )
    19.5 ( 9.74 )
    No statistical analyses for this end point

    Secondary: Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib Alone and When Coadministration With Everolimus in Renal Cell Carcinoma (RCC) Subjects to Assess Drug-Drug Interaction

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    End point title
    		 Model Predicted Apparent Total Clearance (CL/F) for Lenvatinib Alone and When Coadministration With Everolimus in Renal Cell Carcinoma (RCC) Subjects to Assess Drug-Drug Interaction
    End point description
    Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The lenvatinib concentration data was pooled from studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for lenvatinib was fitted to the pooled dataset. Individual lenvatinib CL/F value was derived from the final PK model. The endpoint was assessed for lenvatinib 18 mg dose only. PK analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable lenvatinib plasma concentration data. Population included subjects from E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and current study E7080-G000-218 (NCT03173560). Here, "number of subjects analyzed” are the subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Lenvatinib 18 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    48
    443
    Units: liter per hour (L/h)
        arithmetic mean (standard deviation)
    6.37 ( 2.01 )
    5.77 ( 2.01 )
    No statistical analyses for this end point

    Secondary: Model Predicted CL/F for Everolimus Alone and When Coadministration With Lenvatinib in RCC Subjects to Assess Drug-Drug Interaction

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    End point title
    		 Model Predicted CL/F for Everolimus Alone and When Coadministration With Lenvatinib in RCC Subjects to Assess Drug-Drug Interaction
    End point description
    Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The everolimus concentration data was pooled from studies E7080 -G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for everolimus was fitted to the pooled dataset. Individual everolimus CL/F value was derived from the final PK model. PK analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable everolimus whole blood concentration data. Population included subjects from E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or current study E7080-G000-218 (NCT03173560). Here, "number of subjects analyzed” are the subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Everolimus 10 mg Lenvatinib + Everolimus 5 mg
    Number of subjects analysed
    33
    345
    Units: liter per hour (L/h)
        arithmetic mean (standard deviation)
    22.3 ( 10.5 )
    19.4 ( 7.9 )
    No statistical analyses for this end point

    Secondary: Model Predicted Dose Normalized AUC for Everolimus Alone and When Coadministration With Lenvatinib in RCC Subjects to Assess Drug-Drug Interaction

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    End point title
    		 Model Predicted Dose Normalized AUC for Everolimus Alone and When Coadministration With Lenvatinib in RCC Subjects to Assess Drug-Drug Interaction
    End point description
    Sparse PK samples were collected and analyzed using a population PK approach to estimate PK parameters. The everolimus concentration data was pooled from studies E7080 -G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for everolimus was fitted to the pooled dataset. Individual everolimus AUC at steady state based on the starting dose was derived as a function of starting dose from the final PK model. PK analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable everolimus whole blood concentration data. Population included subjects from E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) or current study E7080-G000-218 (NCT03173560). "N” are the subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Everolimus 10 mg Lenvatinib + Everolimus 5 mg
    Number of subjects analysed
    33
    345
    Units: ng*hour/mL
        arithmetic mean (standard deviation)
    507.4 ( 176.6 )
    305.5 ( 174.0 )
    No statistical analyses for this end point

    Secondary: Model Predicted Dose Normalized Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib Alone and When Coadministration With Everolimus in RCC Subjects to Assess Drug-Drug Interaction

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    End point title
    		 Model Predicted Dose Normalized Area Under the Plasma Drug Concentration-time Curve (AUC) for Lenvatinib Alone and When Coadministration With Everolimus in RCC Subjects to Assess Drug-Drug Interaction
    End point description
    Sparse PK samples were collected and analyzed using population PK approach to estimate PK parameters. The lenvatinib concentration data was pooled from studies E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and from current study E7080-G000-218 (NCT03173560). A previously developed 3-compartment PK model for lenvatinib was fitted to the pooled dataset. Individual lenvatinib AUC at steady state based on the starting dose was derived as a function of starting dose from the final PK model. The endpoint was assessed for lenvatinib 18 mg dose only. PK analysis set included all subjects who received at least 1 dose of study drug with documented dosing history and had at least 1 evaluable lenvatinib plasma concentration data. Population included subjects from E7080-G000-205 (NCT01136733), E7080-M001-221 (NCT02915783), E7080-J081-112 (NCT02454478) and current study E7080-G000-218 (NCT03173560). "N” are the subjects who were evaluable for endpoint.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1: 0.5-4 hours and 6-10 hours post-dose; Cycle 1 Day 15: pre-dose, 0.5-4 hours and 6-10 hours post-dose; Cycle 2 Day 1: pre-dose and 2-12 hours post-dose (each cycle length =28 days)
    End point values
    		 Lenvatinib 18 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    48
    443
    Units: nanogram*hour per milliliter (ng*h/mL)
        arithmetic mean (standard deviation)
    3693 ( 1295 )
    4350 ( 2934 )
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores

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    End point title
    		 Health-Related Quality of Life (HRQoL) Assessed by Functional Assessment of Cancer Therapy Kidney Syndrome Index-Disease-Related Symptoms (FKSI-DRS) Scores
    End point description
    The FKSI-DRS consisted of 9 items that experts and subjects had indicated are important targets for the treatment of advanced kidney cancer, and that clinical experts had indicated are primarily disease-related, as opposed to treatment-related. Symptoms assessed on the FKSI-DRS included lack of energy, fatigue, weight loss, pain, bone pain, shortness of breath, cough, fever, or hematuria. Each item was scored on a 5-point Likert-type scale (0 = not at all; 4 = very much) where total score ranged from 0 (worst) to 36 (best), where higher scores correspond to better outcomes. Quality of Life (QoL) analysis set consisted of all subjects who had any QoL data. Here "number of subjects analyzed" are the subjects who were evaluable for the endpoint; "n" were the subjects who were evaluable at given time points and 99999 = no data was calculated due to less subjects. As pre-specified in the protocol, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    169
    162
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=169,162)
    29.69 ( 4.819 )
    29 ( 5.886 )
        Cycle 2 Day 1 (n=156,152)
    28.43 ( 5.269 )
    28.31 ( 5.162 )
        Cycle 3 Day 1 (n=146,140)
    28.26 ( 5.344 )
    28.80 ( 5.455 )
        Cycle 4 Day 1 (n=133,137)
    27.97 ( 5.524 )
    29.11 ( 5.183 )
        Cycle 5 Day 1 (n=125,127)
    28 ( 5.680 )
    29.14 ( 5.081 )
        Cycle 6 Day 1 (n=120,120)
    28.63 ( 5.185 )
    29.46 ( 5.107 )
        Cycle 7 Day 1 (n=105,103)
    28.31 ( 5.486 )
    29.58 ( 4.803 )
        Cycle 8 Day 1 (n=96,97)
    28.36 ( 6.204 )
    29.85 ( 4.610 )
        Cycle 9 Day 1 (n=89,92)
    28.58 ( 5.562 )
    29.84 ( 5.005 )
        Cycle 10 Day 1 (n=79,75)
    29.10 ( 5.294 )
    30.70 ( 4.297 )
        Cycle 11 Day 1 (n=68,72)
    29.56 ( 5.035 )
    30.09 ( 5.316 )
        Cycle 12 Day 1 (n=64,61)
    29.34 ( 5.149 )
    30.75 ( 5.127 )
        Cycle 13 Day 1 (n=56,53)
    29.26 ( 4.851 )
    30.93 ( 4.201 )
        Cycle 14 Day 1 (n=48,52)
    29.81 ( 4.752 )
    31.06 ( 4.830 )
        Cycle 15 Day 1 (n=44,51)
    30.09 ( 5.121 )
    30.52 ( 4.417 )
        Cycle 16 Day 1 (n=41,47)
    29.93 ( 5.293 )
    30.91 ( 4.704 )
        Cycle 17 Day 1 (n=36.40)
    29.36 ( 5.233 )
    31.52 ( 4.875 )
        Cycle 18 Day 1 (n=31,34)
    29.81 ( 4.293 )
    31.41 ( 4.639 )
        Cycle 19 Day 1 (n=27,34)
    28.48 ( 6.216 )
    30.82 ( 4.469 )
        Cycle 20 Day 1 (n=27,31)
    28.77 ( 6.058 )
    30.69 ( 4.575 )
        Cycle 21 Day 1 (n=26,28)
    29.35 ( 4.707 )
    32 ( 3.243 )
        Cycle 22 Day 1 (n=19,27)
    30.32 ( 4.978 )
    30.59 ( 5.168 )
        Cycle 23 Day 1 (n=15,24)
    30.53 ( 3.998 )
    30.29 ( 5.544 )
        Cycle 24 Day 1 (n=15,19)
    29.47 ( 5.041 )
    31.58 ( 3.977 )
        Cycle 25 Day 1 (n=12,16)
    27.92 ( 6.388 )
    31.69 ( 4.270 )
        Cycle 26 Day 1 (n=8,13)
    28.75 ( 4.862 )
    29.82 ( 6.422 )
        Cycle 27 Day 1 (n=6,7)
    29.83 ( 5.345 )
    32.86 ( 2.854 )
        Cycle 28 Day 1 (n=4,6)
    30.50 ( 4.435 )
    33.67 ( 1.862 )
        Cycle 29 Day 1 (n=4,5)
    29.50 ( 4.359 )
    33.40 ( 1.342 )
        Cycle 30 Day 1 (n=4,1)
    30.75 ( 4.031 )
    36 ( 99999 )
        Cycle 31 Day 1 (n=1,0)
    31 ( 99999 )
    99999 ( 99999 )
        Off-treatment Visit (n=78,74)
    27.42 ( 5.953 )
    27.86 ( 6.500 )
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the date of randomization until the date of death from any cause. In the absence of confirmation of death, subjects will be censored either at the date that the subject was last known to be alive or the date of data cutoff for the primary analysis, whichever comes earlier. Median OS was to be calculated using Kaplan-Meier estimate and presented with 2-sided 95% confidence interval. Here, 99999 indicates median, upper limit of 95% CI was not estimable because insufficient number of subjects had events. PPAS1 included all randomized subjects minus the 32 subjects who had received >=2 incorrect lenvatinib doses due to IxRS issues. As pre-specified in the protocol, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death from any cause, or up to date of data cut off for the primary analysis (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    156
    155
    Units: months
        median (confidence interval 95%)
    27.0 (18.3 to 99999)
    99999 (23.8 to 99999)
    No statistical analyses for this end point

    Secondary: HRQoL assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scores

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    End point title
    		 HRQoL assessed by European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30 scores
    End point description
    In EQ-5D-3L, subjects rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). Summed score ranges from 5-15, "5" =no problems "15" =severe problems in 5 dimensions. EQ-5D index calculated by applying preference-based weights (tariffs) to scores of 5 health state dimensions. Index values range from -1 to 1, 0 =health state equivalent to death and 1=perfect health. EQ-5D-3L also included EQVAS ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease in EQ-5D-3L =improvement. Total index EQ-5D-3L score was weighted with range of -0.594 (worst) to 1.0 (best). QoL analysis set. "N"=subjects evaluable for endpoint; "n”=subjects evaluable at given time points and 99999=no data was calculated due to less subjects. As pre-specified in protocol, data for this endpoint was collected and analyzed till primary analysis only.
    End point type
    Secondary
    End point timeframe
    At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    171
    162
    Units: score on a scale
    arithmetic mean (standard deviation)
        Global Health Status/QoL; Baseline(n=171,162)
    63.35 ( 22.020 )
    63.58 ( 21.340 )
        Global Health Status/QoL;Cycle 2 Day 1(n=157,151)
    58.60 ( 21.234 )
    60.93 ( 20.280 )
        Global Health Status/QoL;Cycle 3 Day 1(n=149,142)
    56.43 ( 24.065 )
    61.85 ( 20.202 )
        Global Health Status/QoL;Cycle 4 Day 1(n=133,136)
    58.71 ( 19.754 )
    62.62 ( 19.641 )
        Global Health Status/QoL;Cycle 5 Day 1(n=127,126)
    59.38 ( 21.670 )
    63.76 ( 20.339 )
        Global Health Status/QoL;Cycle 6 Day 1(n=120,119)
    58.75 ( 21.028 )
    63.73 ( 19.756 )
        Global Health Status/QoL;Cycle 7 Day 1(n=107,105)
    58.72 ( 20.134 )
    62.54 ( 20.153 )
        Global Health Status/QoL;Cycle 8 Day 1(n=97,97)
    58.68 ( 20.409 )
    62.11 ( 20.271 )
        Global Health Status/QoL;Cycle 9 Day 1(n=91,92)
    58.97 ( 18.726 )
    63.77 ( 20.429 )
        Global Health Status/QoL;Cycle 10 Day 1(n=80,74)
    63.13 ( 19.612 )
    66.44 ( 19.012 )
        Global Health Status/QoL;Cycle 11 Day 1(n=69,72)
    60.87 ( 18.705 )
    65.86 ( 21.173 )
        Global Health Status/QoL;Cycle 12 Day 1(n=64,60)
    57.81 ( 18.891 )
    66.94 ( 18.409 )
        Global Health Status/QoL;Cycle 13 Day 1(n=55,55)
    59.39 ( 19.047 )
    68.94 ( 18.388 )
        Global Health Status/QoL;Cycle 14 Day 1(n=49,52)
    61.56 ( 17.498 )
    70.35 ( 15.605 )
        Global Health Status/QoL;Cycle 15 Day 1(n=43,51)
    62.98 ( 16.795 )
    66.83 ( 16.955 )
        Global Health Status/QoL;Cycle 16 Day 1(n=41,47)
    61.59 ( 17.567 )
    64.54 ( 19.386 )
        Global Health Status/QoL;Cycle 17 Day 1(n=36,40)
    60.88 ( 16.882 )
    67.71 ( 18.794 )
        Global Health Status/QoL;Cycle 18 Day 1(n=31,34)
    59.68 ( 16.258 )
    68.38 ( 17.859 )
        Global Health Status/QoL;Cycle 19 Day 1(n=27,34)
    58.33 ( 19.747 )
    66.67 ( 15.215 )
        Global Health Status/QoL;Cycle 20 Day 1(n=27,31)
    58.95 ( 18.479 )
    66.40 ( 15.736 )
        Global Health Status/QoL;Cycle 21 Day 1(n=26,28)
    57.05 ( 18.362 )
    71.13 ( 15.463 )
        Global Health Status/QoL;Cycle 22 Day 1(n=19,27)
    62.72 ( 14.532 )
    66.05 ( 17.438 )
        Global Health Status/QoL;Cycle 23 Day 1(n=15,24)
    60 ( 15.494 )
    66.67 ( 14.948 )
        Global Health Status/QoL;Cycle 24 Day 1 (n=15,19)
    64.44 ( 17.385 )
    65.79 ( 18.818 )
        Global Health Status/QoL;Cycle 25 Day 1(n=12,16)
    58.33 ( 16.667 )
    69.79 ( 14.868 )
        Global Health Status/QoL;Cycle 26 Day 1(n=8,13)
    59.38 ( 15.064 )
    60.90 ( 18.442 )
        Global Health Status/QoL;Cycle 27 Day 1(n=6,7)
    59.72 ( 18.572 )
    71.43 ( 18.545 )
        Global Health Status/QoL;Cycle 28 Day 1(n=4,6)
    58.33 ( 21.517 )
    77.78 ( 13.608 )
        Global Health Status/QoL;Cycle 29 Day 1(n=4,5)
    56.25 ( 18.478 )
    75 ( 16.667 )
        Global Health Status/QoL;Cycle 30 Day 1(n-4,1)
    54.17 ( 15.957 )
    66.67 ( 99999 )
        Global Health Status/QoL;Cycle 31 Day 19(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Global Health Status/QoL;Off-treatment(n=80,73)
    51.04 ( 23.133 )
    56.05 ( 22.363 )
        Physical Functioning; Baseline(n=171,162)
    76.36 ( 19.282 )
    76.60 ( 21.855 )
        Physical Functioning; Cycle 2 Day 1(n=158,150)
    73.54 ( 19.857 )
    75.38 ( 19.706 )
        Physical Functioning; Cycle 3 Day 1(n=148,142)
    72.74 ( 21.227 )
    76.15 ( 19.160 )
        Physical Functioning; Cycle 4 Day 1(n=135,137)
    70.90 ( 20.873 )
    75.40 ( 20.155 )
        Physical Functioning; Cycle 5 Day 1(n=128,127)
    72.80 ( 19.284 )
    77.85 ( 18.342 )
        Physical Functioning; Cycle 6 Day 1(n=123,120)
    72.17 ( 21.694 )
    77.76 ( 18.562 )
        Physical Functioning; Cycle 7 Day 1(n=107,105)
    73.02 ( 20.769 )
    78.41 ( 18.034 )
        Physical Functioning; Cycle 8 Day 1(n=98,97)
    72.77 ( 20.422 )
    79.11 ( 17.707 )
        Physical Functioning; Cycle 9 Day 1(n=91,92)
    74.54 ( 19.389 )
    80.60 ( 16.041 )
        Physical Functioning; Cycle 10 Day 1(n=81,75)
    75.06 ( 18.908 )
    81.20 ( 16.271 )
        Physical Functioning; Cycle 11 Day 1(n=69,71)
    73.72 ( 18.073 )
    81.13 ( 16.638 )
        Physical Functioning; Cycle 12 Day 1(n=65,62)
    75.52 ( 17.080 )
    83.01 ( 15.254 )
        Physical Functioning; Cycle 13 Day 1(n=55,55)
    74.55 ( 17.874 )
    80.24 ( 16.873 )
        Physical Functioning; Cycle 14 Day 1(n=49,53)
    75.78 ( 16.925 )
    82.39 ( 16.387 )
        Physical Functioning; Cycle 15 Day 1(n=44,51)
    75.45 ( 16.629 )
    80.92 ( 17.283 )
        Physical Functioning; Cycle 16 Day 1(n=41,47)
    73.46 ( 17.129 )
    81.74 ( 15.982 )
        Physical Functioning; Cycle 17 Day 1(n=36,40)
    71.85 ( 17.896 )
    82.33 ( 15.657 )
        Physical Functioning; Cycle 18 Day 1(n=31,34)
    75.48 ( 17.838 )
    81.52 ( 16.135 )
        Physical Functioning; Cycle 19 Day 1(n=27,34)
    76.67 ( 15.771 )
    81.57 ( 16.002 )
        Physical Functioning; Cycle 20 Day 1(n=27,31)
    73.09 ( 22.071 )
    82.80 ( 13.854 )
        Physical Functioning; Cycle 21 Day 1(n=26,28)
    74.62 ( 18.668 )
    84.29 ( 12.335 )
        Physical Functioning; Cycle 22 Day 1(n=19,27)
    80.35 ( 14.483 )
    82.72 ( 15.164 )
        Physical Functioning; Cycle 23 Day 1(n=15,24)
    79.56 ( 14.357 )
    81.39 ( 17.248 )
        Physical Functioning; Cycle 24 Day 1(n=15,19)
    77.33 ( 16.676 )
    83.86 ( 13.755 )
        Physical Functioning; Cycle 25 Day 1(n=12,16)
    72.78 ( 15.688 )
    84.17 ( 15.753 )
        Physical Functioning; Cycle 26 Day 1(n=8,13)
    76.67 ( 6.172 )
    71.79 ( 29.833 )
        Physical Functioning; Cycle 27 Day 1(n=6,7)
    76.67 ( 6.992 )
    85.71 ( 16.523 )
        Physical Functioning; Cycle 28 Day 1(n=4,6)
    78.33 ( 3.333 )
    90 ( 15.635 )
        Physical Functioning; Cycle 29 Day 1(n=4,5)
    78.33 ( 3.333 )
    86.67 ( 16.330 )
        Physical Functioning; Cycle 30 Day 1(n=4,1)
    76.67 ( 3.849 )
    100 ( 99999 )
        Physical Functioning; Cycle 31 Day 1(n=1,0)
    80 ( 99999 )
    99999 ( 99999 )
        Physical Functioning; Off-treatment(n=80,74)
    64.50 ( 25.891 )
    70.41 ( 25.139 )
        Role Functioning; Baseline(n=171,162)
    73.78 ( 27.471 )
    75.72 ( 27.932 )
        Role Functioning; Cycle 2 Day 1(n=158,150)
    68.25 ( 27.951 )
    69.33 ( 27.449 )
        Role Functioning; Cycle 3 Day 1(n=148,142)
    67 ( 28.136 )
    72.18 ( 25.630 )
        Role Functioning; Cycle 4 Day 1(n=135,137)
    66.67 ( 27.993 )
    73.60 ( 26.169 )
        Role Functioning; Cycle 5 Day 1(n=128,127)
    67.32 ( 28.479 )
    72.44 ( 25.143 )
        Role Functioning; Cycle 6 Day 1(n=123,120)
    68.16 ( 27.245 )
    73.75 ( 27.557 )
        Role Functioning; Cycle 7 Day 1(n=107,105)
    66.51 ( 27.424 )
    73.97 ( 25.205 )
        Role Functioning; Cycle 8 Day 1(n=98,97)
    68.20 ( 27.712 )
    75.60 ( 26.139 )
        Role Functioning; Cycle 9 Day 1(n=91,92)
    67.58 ( 26.101 )
    75.91 ( 25.242 )
        Role Functioning; Cycle 10 Day 1(n=81,75)
    68.52 ( 27.131 )
    76.89 ( 24.027 )
        Role Functioning; Cycle 11 Day 1(n=69,71)
    69.57 ( 25.237 )
    79.11 ( 23.691 )
        Role Functioning; Cycle 12 Day 1(n=65,62)
    70.51 ( 24.785 )
    80.91 ( 22.953 )
        Role Functioning; Cycle 13 Day 1(n=56,55)
    69.64 ( 24.434 )
    80 ( 24.721 )
        Role Functioning; Cycle 14 Day 1(n=49,53)
    71.09 ( 24.242 )
    81.13 ( 23.121 )
        Role Functioning; Cycle 15 Day 1(n=44,51)
    72.73 ( 22.184 )
    74.84 ( 25.685 )
        Role Functioning; Cycle 16 Day 1(n=41,47)
    70.33 ( 23.426 )
    79.08 ( 21.272 )
        Role Functioning; Cycle 17 Day 1(n=36,40)
    65.74 ( 22.868 )
    83.75 ( 18.292 )
        Role Functioning; Cycle 18 Day 1(n=31,34)
    67.74 ( 20.609 )
    82.35 ( 22.073 )
        Role Functioning; Cycle 19 Day 1(n=27,34)
    67.28 ( 28.300 )
    77.45 ( 23.883 )
        Role Functioning; Cycle 20 Day 1(n=27,31)
    70.37 ( 23.266 )
    79.57 ( 24.612 )
        Role Functioning; Cycle 21 Day 1(n=26,28)
    69.23 ( 21.956 )
    81.55 ( 19.948 )
        Role Functioning; Cycle 22 Day 1(n=19,27)
    75.44 ( 20.313 )
    77.78 ( 22.169 )
        Role Functioning; Cycle 23 Day 1(n=15,24)
    73.33 ( 25.040 )
    79.86 ( 23.560 )
        Role Functioning; Cycle 24 Day 1(n=15,19)
    78.89 ( 16.019 )
    83.33 ( 19.245 )
        Role Functioning; Cycle 25 Day 1(n=12,16)
    77.78 ( 17.885 )
    82.29 ( 23.936 )
        Role Functioning; Cycle 26 Day 1(n=8,13)
    75 ( 12.599 )
    69.23 ( 31.066 )
        Role Functioning; Cycle 27 Day 1(n=6,7)
    77.78 ( 13.608 )
    90.48 ( 16.265 )
        Role Functioning; Cycle 28 Day 1(n=4,6)
    79.17 ( 15.957 )
    97.22 ( 6.804 )
        Role Functioning; Cycle 29 Day 1(n=4,5)
    75 ( 9.623 )
    96.67 ( 7.454 )
        Role Functioning; Cycle 30 Day 1(n=4,1)
    87.50 ( 15.957 )
    100 ( 99999 )
        Role Functioning; Cycle 31 Day 1(n=1,0)
    66.67 ( 99999 )
    99999 ( 99999 )
        Role Functioning; Off-treatment(n=79,74)
    60.97 ( 31.790 )
    63.51 ( 31.656 )
        Emotional Functioning; Baseline(n=171,162)
    79.35 ( 19.704 )
    80.06 ( 19.729 )
        Emotional Functioning; Cycle 2 Day 1(n=157,151)
    79.41 ( 19.465 )
    82.06 ( 19.167 )
        Emotional Functioning; Cycle 3 Day 1(n=149,141)
    78.47 ( 21.642 )
    82.90 ( 19.314 )
        Emotional Functioning; Cycle 4 Day 1(n=133,136)
    78.26 ( 18.854 )
    84.19 ( 18.517 )
        Emotional Functioning; Cycle 5 Day 1(n=127,126)
    75.85 ( 21.767 )
    84.52 ( 15.766 )
        Emotional Functioning; Cycle 6 Day 1(n=121,119)
    80.60 ( 18.703 )
    84.38 ( 18.365 )
        Emotional Functioning; Cycle 7 Day 1(n=107,105)
    77.18 ( 19.571 )
    84.29 ( 16.356 )
        Emotional Functioning; Cycle 8 Day 1(n=98,97)
    79.08 ( 19.744 )
    84.88 ( 18.215 )
        Emotional Functioning; Cycle 9 Day 1(n=91,92)
    78.75 ( 22.127 )
    85.96 ( 17.512 )
        Emotional Functioning; Cycle 10 Day 1(n=81,74)
    80.04 ( 19.440 )
    87.84 ( 15.433 )
        Emotional Functioning; Cycle 11 Day 1(n=69,72)
    82.25 ( 20.558 )
    87.15 ( 16.247 )
        Emotional Functioning; Cycle 12 Day 1(n=64,60)
    81.51 ( 19.157 )
    86.67 ( 15.358 )
        Emotional Functioning; Cycle 13 Day 1(n=56,55)
    79.32 ( 17.908 )
    87.27 ( 15.783 )
        Emotional Functioning; Cycle 14 Day 1(n=49,52)
    81.35 ( 16.782 )
    87.50 ( 17.110 )
        Emotional Functioning; Cycle 15 Day 1(n=44,51)
    80.30 ( 18.336 )
    87.25 ( 15.398 )
        Emotional Functioning; Cycle 16 Day 1(n=41,47)
    81.50 ( 17.432 )
    87.41 ( 14.935 )
        Emotional Functioning; Cycle 17 Day 1(n=36,40)
    79.63 ( 19.664 )
    87.08 ( 16.118 )
        Emotional Functioning; Cycle 18 Day 1(n=31,34)
    81.90 ( 15.330 )
    86.76 ( 16.555 )
        Emotional Functioning; Cycle 19 Day 1(n=27,34)
    81.17 ( 15.945 )
    84.80 ( 18.403 )
        Emotional Functioning; Cycle 20 Day 1(n=27,31)
    80.25 ( 17.925 )
    86.56 ( 17.437 )
        Emotional Functioning; Cycle 21 Day 1(n=26,28)
    81.73 ( 15.279 )
    88.99 ( 14.174 )
        Emotional Functioning; Cycle 22 Day 1(n=19,27)
    85.09 ( 16.096 )
    89.20 ( 15.644 )
        Emotional Functioning; Cycle 23 Day 1(n=15,24)
    86.67 ( 15.366 )
    87.15 ( 15.922 )
        Emotional Functioning; Cycle 24 Day 1(n=15,19)
    88.89 ( 14.319 )
    87.28 ( 13.712 )
        Emotional Functioning; Cycle 25 Day 1(n=12,16)
    83.33 ( 18.119 )
    90.63 ( 12.500 )
        Emotional Functioning; Cycle 26 Day 1(n=8,13)
    77.08 ( 23.038 )
    85.26 ( 23.362 )
        Emotional Functioning; Cycle 27 Day 1(n=6,7)
    80.56 ( 16.387 )
    95.24 ( 12.599 )
        Emotional Functioning; Cycle 28 Day 1(n=4,6)
    75 ( 16.667 )
    100 ( 0 )
        Emotional Functioning; Cycle 29 Day 1(n=4,5)
    75 ( 16.667 )
    100 ( 0 )
        Emotional Functioning; Cycle 30 Day 1(n=4,1)
    75 ( 16.667 )
    100 ( 99999 )
        Emotional Functioning; Cycle 31 Day 1(n=1,0)
    66.67 ( 99999 )
    99999 ( 99999 )
        Emotional Functioning;Off-treatment Visit(n=80,74)
    69.62 ( 27.304 )
    73.87 ( 25.145 )
        Cognitive Functioning; Baseline(n=171,162)
    87.91 ( 15.764 )
    89.51 ( 15.529 )
        Cognitive Functioning; Cycle 2 Day 1(n=157,151)
    87.15 ( 15.661 )
    88.85 ( 18.025 )
        Cognitive Functioning; Cycle 3 Day 1(n=149,141)
    84.45 ( 19.049 )
    87.47 ( 17.946 )
        Cognitive Functioning; Cycle 4 Day 1(n=133,136)
    83.58 ( 19.461 )
    90.32 ( 13.692 )
        Cognitive Functioning; Cycle 5 Day 1(n=127,126)
    83.99 ( 17.239 )
    87.43 ( 17.086 )
        Cognitive Functioning; Cycle 6 Day 1(n=121,119)
    84.71 ( 16.886 )
    87.68 ( 18.470 )
        Cognitive Functioning; Cycle 7 Day 1(n=107,105)
    82.40 ( 18.855 )
    87.94 ( 14.708 )
        Cognitive Functioning; Cycle 8 Day 1(n=98,97)
    81.97 ( 21.227 )
    88.49 ( 16.380 )
        Cognitive Functioning; Cycle 9 Day 1(n=91,92)
    83.70 ( 18.084 )
    87.68 ( 17.095 )
        Cognitive Functioning; Cycle 10 Day 1(n=81,75)
    85.39 ( 17.947 )
    90.44 ( 13.747 )
        Cognitive Functioning; Cycle 11 Day 1(n=69,72)
    84.06 ( 18.176 )
    88.89 ( 15.824 )
        Cognitive Functioning; Cycle 12 Day 1(n=64,60)
    85.42 ( 16.400 )
    88.61 ( 17.758 )
        Cognitive Functioning; Cycle 13 Day 1(n=56,55)
    83.93 ( 17.685 )
    89.70 ( 12.624 )
        Cognitive Functioning; Cycle 14 Day 1(n=49,52)
    85.71 ( 18.634 )
    87.18 ( 16.375 )
        Cognitive Functioning; Cycle 15 Day 1(n=44,51)
    84.85 ( 18.264 )
    83.99 ( 17.308 )
        Cognitive Functioning; Cycle 16 Day 1(n=41,47)
    83.74 ( 18.062 )
    89.36 ( 13.649 )
        Cognitive Functioning; Cycle 17 Day 1(n=36,40)
    82.87 ( 18.033 )
    89.58 ( 14.465 )
        Cognitive Functioning; Cycle 18 Day 1(n=31,34)
    83.87 ( 17.994 )
    90.20 ( 15.417 )
        Cognitive Functioning; Cycle 19 Day 1(n=27,34)
    80.25 ( 18.511 )
    89.22 ( 14.727 )
        Cognitive Functioning; Cycle 20 Day 1(n=27,31)
    82.10 ( 17.250 )
    91.94 ( 12.073 )
        Cognitive Functioning; Cycle 21 Day 1(n=26,28)
    81.41 ( 19.623 )
    88.10 ( 12.715 )
        Cognitive Functioning; Cycle 22 Day 1(n=19,27)
    88.60 ( 14.754 )
    90.12 ( 12.454 )
        Cognitive Functioning; Cycle 23 Day 1(n=15,24)
    83.33 ( 16.667 )
    88.19 ( 14.311 )
        Cognitive Functioning; Cycle 24 Day 1(n=15,19)
    84.44 ( 16.019 )
    92.11 ( 8.550 )
        Cognitive Functioning; Cycle 25 Day 1(n=12,16)
    84.72 ( 15.006 )
    98.96 ( 4.167 )
        Cognitive Functioning; Cycle 26 Day 1(n=8,13)
    89.58 ( 12.400 )
    92.31 ( 11.004 )
        Cognitive Functioning; Cycle 27 Day 1(n=6,7)
    83.33 ( 14.907 )
    95.24 ( 12.599 )
        Cognitive Functioning; Cycle 28 Day 1(n=4,6)
    91.67 ( 9.623 )
    100 ( 0 )
        Cognitive Functioning; Cycle 29 Day 1(n=4,5)
    91.67 ( 9.623 )
    100 ( 0 )
        Cognitive Functioning; Cycle 30 Day 1(n=4,1)
    87.50 ( 15.957 )
    100 ( 99999 )
        Cognitive Functioning; Cycle 31 Day 1(n=1,0)
    83.33 ( 99999 )
    99999 ( 99999 )
        Cognitive Functioning; Off-treatment(n=80,74)
    75.21 ( 25.846 )
    80.41 ( 23.304 )
        Social Functioning; Baseline(n=171,162)
    77.29 ( 25.678 )
    78.29 ( 27.243 )
        Social Functioning; Cycle 2 Day 1(n=157,151)
    73.46 ( 25.386 )
    77.15 ( 27.190 )
        Social Functioning; Cycle 3 Day 1(n=149,141)
    72.04 ( 26.229 )
    77.19 ( 25.309 )
        Social Functioning; Cycle 4 Day 1(n=133,136)
    71.43 ( 24.837 )
    77.33 ( 25.311 )
        Social Functioning; Cycle 5 Day 1(n=127,126)
    71.78 ( 25.589 )
    79.63 ( 23.934 )
        Social Functioning; Cycle 6 Day 1(n=121,119)
    70.80 ( 26.812 )
    78.71 ( 25.758 )
        Social Functioning; Cycle 7 Day 1(n=106,105)
    71.70 ( 26.544 )
    77.30 ( 24.691 )
        Social Functioning; Cycle 8 Day 1(n=98,97)
    70.24 ( 28.139 )
    79.04 ( 24.565 )
        Social Functioning; Cycle 9 Day 1(n=91,92)
    72.16 ( 25.946 )
    78.62 ( 20.573 )
        Social Functioning; Cycle 10 Day 1(n=81,74)
    72.43 ( 28.156 )
    85.14 ( 19.422 )
        Social Functioning; Cycle 11 Day 1(n=69,72)
    73.91 ( 25.801 )
    85.19 ( 19.086 )
        Social Functioning; Cycle 12 Day 1(n=64,60)
    76.56 ( 24.073 )
    83.89 ( 23.161 )
        Social Functioning; Cycle 13 Day 1(n=56,55)
    72.92 ( 23.476 )
    83.94 ( 21.508 )
        Social Functioning; Cycle 14 Day 1(n=49,52)
    72.79 ( 22.997 )
    83.97 ( 19.792 )
        Social Functioning; Cycle 15 Day 1(n=44,51)
    72.73 ( 25.942 )
    81.37 ( 22.273 )
        Social Functioning; Cycle 16 Day 1(n=41,46)
    73.17 ( 24.403 )
    80.80 ( 22.489 )
        Social Functioning; Cycle 17 Day 1(n=36,40)
    70.37 ( 22.222 )
    80.42 ( 24.134 )
        Social Functioning; Cycle 18 Day 1(n=31,34)
    76.88 ( 20.493 )
    82.84 ( 21.116 )
        Social Functioning; Cycle 19 Day 1(n=27,34)
    74.07 ( 22.329 )
    80.88 ( 25.667 )
        Social Functioning; Cycle 20 Day 1(n=27,31)
    75.31 ( 24.183 )
    81.72 ( 22.092 )
        Social Functioning; Cycle 21 Day 1(n=26,28)
    73.72 ( 18.362 )
    82.14 ( 24.398 )
        Social Functioning; Cycle 22 Day 1(n=19,27)
    79.82 ( 17.194 )
    82.10 ( 20.634 )
        Social Functioning; Cycle 23 Day 1(n=15,24)
    82.22 ( 18.330 )
    83.33 ( 22.522 )
        Social Functioning; Cycle 24 Day 1(n=15,19)
    83.33 ( 17.817 )
    84.21 ( 19.621 )
        Social Functioning; Cycle 25 Day 1(n=12,16)
    87.50 ( 12.563 )
    84.38 ( 18.727 )
        Social Functioning; Cycle 26 Day 1(n=8,13)
    83.33 ( 15.430 )
    76.92 ( 31.578 )
        Social Functioning; Cycle 27 Day 1(n=6,7)
    80.56 ( 12.546 )
    95.24 ( 12.599 )
        Social Functioning; Cycle 28 Day 1(n=4,6)
    83.33 ( 19.245 )
    100 ( 0 )
        Social Functioning; Cycle 29 Day 1(n=4,5)
    79.17 ( 15.957 )
    100 ( 0 )
        Social Functioning; Cycle 30 Day 1(n=4,1)
    70.83 ( 8.333 )
    100 ( 99999 )
        Social Functioning; Cycle 31 Day 1(n=1,0)
    100 ( 99999 )
    99999 ( 99999 )
        Social Functioning; Off-treatment(n=80,73)
    64.58 ( 31.419 )
    66.89 ( 32.453 )
        Fatigue Score; Baseline(n=171,162)
    31.32 ( 21.379 )
    31.76 ( 25.224 )
        Fatigue Score; Cycle 2 Day 1(n=158,150)
    39.21 ( 22.171 )
    36.74 ( 23.665 )
        Fatigue Score; Cycle 3 Day 1(n=148,142)
    40.09 ( 24.095 )
    36.62 ( 24.031 )
        Fatigue Score; Cycle 4 Day 1(n=135,137)
    40.21 ( 23.504 )
    32.68 ( 23.829 )
        Fatigue Score; Cycle 5 Day 1(n=128,127)
    37.54 ( 23.329 )
    35.17 ( 22.431 )
        Fatigue Score; Cycle 6 Day 1(n=123,120)
    38.80 ( 23.246 )
    33.19 ( 23.696 )
        Fatigue Score; Cycle 7 Day 1(n=107,105)
    38.06 ( 21.850 )
    30.79 ( 21.859 )
        Fatigue Score; Cycle 8 Day 1(n=97,97)
    36.14 ( 22.852 )
    30.81 ( 23.268 )
        Fatigue Score; Cycle 9 Day 1(n=91,92)
    35.90 ( 21.281 )
    30.80 ( 21.293 )
        Fatigue Score; Cycle 10 Day 1(n=81,75)
    34.57 ( 22.635 )
    27.11 ( 20.278 )
        Fatigue Score; Cycle 11 Day 1(n=69,71)
    32.37 ( 20.851 )
    27.46 ( 22.788 )
        Fatigue Score; Cycle 12 Day 1(n=65,62)
    32.82 ( 20.264 )
    23.48 ( 21.302 )
        Fatigue Score; Cycle 13 Day 1(n=56,55)
    35.52 ( 18.882 )
    25.05 ( 21.300 )
        Fatigue Score; Cycle 14 Day 1(n=49,53)
    30.84 ( 21.429 )
    25.58 ( 20.276 )
        Fatigue Score; Cycle 15 Day 1(n=44,51)
    28.03 ( 20.682 )
    28.98 ( 23.315 )
        Fatigue Score; Cycle 16 Day 1(n=41,47)
    33.33 ( 22.361 )
    25.53 ( 20.581 )
        Fatigue Score; Cycle 17 Day 1(n=36,40)
    33.33 ( 21.902 )
    25 ( 20.090 )
        Fatigue Score; Cycle 18 Day 1(n=31,34)
    34.05 ( 22.024 )
    24.84 ( 19.546 )
        Fatigue Score; Cycle 19 Day 1(n=27,34)
    37.04 ( 23.061 )
    27.45 ( 22.595 )
        Fatigue Score; Cycle 20 Day 1(n=27,31)
    34.57 ( 19.812 )
    27.24 ( 22.192 )
        Fatigue Score; Cycle 21 Day 1(n=26,28)
    34.19 ( 20.828 )
    23.02 ( 17.088 )
        Fatigue Score; Cycle 22 Day 1(n=19,27)
    26.32 ( 18.596 )
    26.75 ( 20.033 )
        Fatigue Score; Cycle 23 Day 1(n=15,24)
    26.67 ( 20.053 )
    29.17 ( 21.934 )
        Fatigue Score; Cycle 24 Day 1(n=15,19)
    28.15 ( 20.082 )
    26.90 ( 17.496 )
        Fatigue Score; Cycle 25 Day 1(n=12,16)
    33.33 ( 19.534 )
    25.69 ( 19.338 )
        Fatigue Score; Cycle 26 Day 1(n=8,13)
    26.39 ( 17.755 )
    37.61 ( 28.160 )
        Fatigue Score; Cycle 27 Day 1(n=6,7)
    27.78 ( 16.851 )
    20.63 ( 20.716 )
        Fatigue Score; Cycle 28 Day 1(n=4,6)
    22.22 ( 15.713 )
    16.67 ( 19.563 )
        Fatigue Score; Cycle 29 Day 1(n=4,5)
    22.22 ( 15.713 )
    15.56 ( 14.907 )
        Fatigue Score; Cycle 30 Day 1(n=4,1)
    25 ( 16.667 )
    11.11 ( 99999 )
        Fatigue Score; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Fatigue Score; Off-treatment Visit(n=80,74)
    43.47 ( 28.173 )
    38.89 ( 28.977 )
        Nausea and Vomiting; Baseline(n=171,162)
    7.60 ( 17.265 )
    6.28 ( 14.510 )
        Nausea and Vomiting; Cycle 2 Day 1(n=158,150)
    11.50 ( 18.229 )
    9.56 ( 17.943 )
        Nausea and Vomiting; Cycle 3 Day 1(n=148,142)
    14.86 ( 24.057 )
    9.74 ( 18.219 )
        Nausea and Vomiting; Cycle 4 Day 1(n=135,137)
    15.80 ( 21.386 )
    12.17 ( 18.906 )
        Nausea and Vomiting; Cycle 5 Day 1(n=127,127)
    12.07 ( 17.017 )
    11.42 ( 18.270 )
        Nausea and Vomiting; Cycle 6 Day 1(n=123,120)
    12.74 ( 19.215 )
    10.14 ( 18.996 )
        Nausea and Vomiting; Cycle 7 Day 1(n=107,105)
    12.46 ( 18.612 )
    8.57 ( 13.696 )
        Nausea and Vomiting; Cycle 8 Day 1(n=98,97)
    13.10 ( 21.836 )
    10.14 ( 15.508 )
        Nausea and Vomiting; Cycle 9 Day 1(n=91,92)
    12.27 ( 20.005 )
    9.96 ( 17.306 )
        Nausea and Vomiting; Cycle 10 Day 1(n=81,75)
    15.02 ( 22.299 )
    7.78 ( 16.287 )
        Nausea and Vomiting; Cycle 11 Day 1(n=69,71)
    11.11 ( 18.002 )
    8.69 ( 15.394 )
        Nausea and Vomiting; Cycle 12 Day 1(n=65,62)
    12.82 ( 19.042 )
    6.99 ( 14.645 )
        Nausea and Vomiting; Cycle 13 Day 1(n=56,55)
    12.20 ( 18.934 )
    6.97 ( 13.867 )
        Nausea and Vomiting; Cycle 14 Day 1(n=49,53)
    14.97 ( 21.849 )
    7.55 ( 16.527 )
        Nausea and Vomiting; Cycle 15 Day 1(n=44,51)
    14.02 ( 20.631 )
    8.82 ( 15.038 )
        Nausea and Vomiting; Cycle 16 Day 1(n=41,47)
    11.38 ( 19.874 )
    9.22 ( 15.467 )
        Nausea and Vomiting; Cycle 17 Day 1(n=36,40)
    14.35 ( 22.940 )
    5 ( 13.183 )
        Nausea and Vomiting; Cycle 18 Day 1(n=31,34)
    10.75 ( 22.587 )
    9.31 ( 15.457 )
        Nausea and Vomiting; Cycle 19 Day 1(n=27,34)
    16.67 ( 27.347 )
    7.35 ( 15.457 )
        Nausea and Vomiting; Cycle 20 Day 1(n=27,31)
    16.67 ( 23.113 )
    10.22 ( 15.915 )
        Nausea and Vomiting; Cycle 21 Day 1(n=26,28)
    12.82 ( 20.714 )
    7.74 ( 12.408 )
        Nausea and Vomiting; Cycle 22 Day 1(n=19,27)
    7.02 ( 11.541 )
    8.64 ( 13.374 )
        Nausea and Vomiting; Cycle 23 Day 1(n=15,24)
    5.56 ( 12.062 )
    6.25 ( 11.849 )
        Nausea and Vomiting; Cycle 24 Day 1(n=15,19)
    6.67 ( 13.801 )
    7.89 ( 17.004 )
        Nausea and Vomiting; Cycle 25 Day 1(n=12,16)
    13.89 ( 21.122 )
    2.08 ( 8.333 )
        Nausea and Vomiting; Cycle 26 Day 1(n=8,13)
    4.17 ( 7.715 )
    14.10 ( 24.387 )
        Nausea and Vomiting; Cycle 27 Day 1(n=6,7)
    5.56 ( 13.608 )
    16.67 ( 28.868 )
        Nausea and Vomiting; Cycle 28 Day 1(n=4,6)
    12.50 ( 15.957 )
    8.33 ( 20.412 )
        Nausea and Vomiting; Cycle 29 Day 1(n=4,5)
    16.67 ( 13.608 )
    0 ( 0 )
        Nausea and Vomiting; Cycle 30 Day 1(n=4,1)
    8.33 ( 16.667 )
    0 ( 99999 )
        Nausea and Vomiting; Cycle 31 Day 1(n=1,0)
    16.67 ( 99999 )
    99999 ( 99999 )
        Nausea and Vomiting; Off-treatment(n=80,74)
    13.33 ( 22.564 )
    6.76 ( 13.207 )
        Pain Score; Baseline(n=171,162)
    23.39 ( 25.410 )
    23.77 ( 26.323 )
        Pain Score; Cycle 2 Day 1(n=158,151)
    26.79 ( 25.850 )
    27.04 ( 23.862 )
        Pain Score; Cycle 3 Day 1(n=149,142)
    27.63 ( 24.103 )
    25 ( 24.046 )
        Pain Score; Cycle 4 Day 1(n=135,137)
    26.67 ( 24.788 )
    22.87 ( 21.486 )
        Pain Score; Cycle 5 Day 1(n=128,127)
    29.04 ( 26.805 )
    22.97 ( 22.314 )
        Pain Score; Cycle 6 Day 1(n=123,120)
    26.29 ( 24.887 )
    22.50 ( 25.716 )
        Pain Score; Cycle 7 Day 1(n=107,105)
    28.04 ( 23.189 )
    23.65 ( 22.142 )
        Pain Score; Cycle 8 Day 1(n=98,97)
    27.38 ( 23.722 )
    23.20 ( 24.949 )
        Pain Score; Cycle 9 Day 1(n=91,92)
    27.11 ( 23.393 )
    21.01 ( 20.053 )
        Pain Score; Cycle 10 Day 1(n=81,75)
    26.95 ( 22.603 )
    19.33 ( 18.792 )
        Pain Score; Cycle 11 Day 1(n=69,72)
    27.29 ( 22.319 )
    18.06 ( 20.508 )
        Pain Score; Cycle 12 Day 1(n=65,62)
    26.41 ( 21.018 )
    18.55 ( 19.814 )
        Pain Score; Cycle 13 Day 1(n=56,55)
    24.40 ( 20.092 )
    18.48 ( 20.203 )
        Pain Score; Cycle 14 Day 1(n=49,53)
    22.11 ( 22.666 )
    16.04 ( 19.601 )
        Pain Score; Cycle 15 Day 1(n=44,53)
    24.24 ( 23.966 )
    17.65 ( 18.078 )
        Pain Score; Cycle 16 Day 1(n=41,47)
    29.67 ( 25.417 )
    18.44 ( 20.628 )
        Pain Score; Cycle 17 Day 1(n=36,40)
    27.78 ( 25.198 )
    17.50 ( 19.954 )
        Pain Score; Cycle 18 Day 1(n=31,34)
    25.27 ( 20.125 )
    16.67 ( 18.803 )
        Pain Score; Cycle 19 Day 1(n=27,34)
    31.48 ( 23.266 )
    19.61 ( 22.274 )
        Pain Score; Cycle 20 Day 1(n=27,31)
    29.63 ( 23.266 )
    19.35 ( 21.558 )
        Pain Score; Cycle 21 Day 1(n=26,28)
    26.92 ( 23.131 )
    17.86 ( 21.721 )
        Pain Score; Cycle 22 Day 1(n=19,27)
    23.68 ( 17.843 )
    22.84 ( 24.085 )
        Pain Score; Cycle 23 Day 1(n=15,24)
    21.11 ( 14.729 )
    18.06 ( 23.527 )
        Pain Score; Cycle 24 Day 1(n=15,19)
    22.22 ( 20.574 )
    14.91 ( 19.160 )
        Pain Score; Cycle 25 Day 1(n=12,16)
    27.78 ( 23.925 )
    15.63 ( 19.691 )
        Pain Score; Cycle 26 Day 1(n=8,13)
    27.08 ( 21.708 )
    21.79 ( 27.542 )
        Pain Score; Cycle 27 Day 1(n=6,7)
    25 ( 20.412 )
    11.90 ( 24.934 )
        Pain Score; Cycle 28 Day 1(n=4,6)
    25 ( 21.517 )
    2.78 ( 6.804 )
        Pain Score; Cycle 29 Day 1(n=4,5)
    25 ( 21.517 )
    6.67 ( 14.907 )
        Pain Score; Cycle 30 Day 1(n=4,1)
    25 ( 16.667 )
    0 ( 99999 )
        Pain Score; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Pain Score; Off-treatment Visit(n=80,74)
    28.33 ( 27.354 )
    27.70 ( 28.171 )
        Dyspnea; Baseline(n=170,162)
    21.18 ( 25.562 )
    22.22 ( 26.006 )
        Dyspnea; Cycle 2 Day 1(n=157,150)
    18.90 ( 24.248 )
    19.56 ( 23.865 )
        Dyspnea; Cycle 3 Day 1(n=147,142)
    20.63 ( 24.155 )
    19.72 ( 23.871 )
        Dyspnea; Cycle 4 Day 1(n=134,137)
    19.90 ( 24.224 )
    17.52 ( 20.643 )
        Dyspnea; Cycle 5 Day 1(n=127,127)
    19.16 ( 23.201 )
    15.75 ( 20.925 )
        Dyspnea; Cycle 6 Day 1(n=122,120)
    16.67 ( 21.104 )
    18.89 ( 23.957 )
        Dyspnea; Cycle 7 Day 1(n=105,105)
    19.37 ( 23.922 )
    15.87 ( 21.728 )
        Dyspnea; Cycle 8 Day 1(n=97,97)
    19.24 ( 23.489 )
    14.09 ( 20.319 )
        Dyspnea; Cycle 9 Day 1(n=90,92)
    15.93 ( 20.740 )
    14.49 ( 21.712 )
        Dyspnea; Cycle 10 Day 1(n=80,75)
    17.92 ( 21.832 )
    11.56 ( 19.369 )
        Dyspnea; Cycle 11 Day 1(n=68,71)
    18.63 ( 23.310 )
    15.02 ( 23.764 )
        Dyspnea; Cycle 12 Day 1(n=64,62)
    13.54 ( 21.998 )
    12.90 ( 22.057 )
        Dyspnea; Cycle 13 Day 1(n=56,55)
    13.69 ( 20.867 )
    10.91 ( 20.341 )
        Dyspnea; Cycle 14 Day 1(n=49,53)
    15.65 ( 21.626 )
    10.69 ( 20.437 )
        Dyspnea; Cycle 15 Day 1(n=44,51)
    15.15 ( 19.628 )
    12.42 ( 21.040 )
        Dyspnea; Cycle 16 Day 1(n=41,47)
    16.26 ( 22.512 )
    9.93 ( 16.904 )
        Dyspnea; Cycle 17 Day 1(n=36,40)
    15.74 ( 20.293 )
    10 ( 20.255 )
        Dyspnea; Cycle 18 Day 1(n=31,34)
    16.13 ( 20.854 )
    10.78 ( 17.829 )
        Dyspnea; Cycle 19 Day 1(n=26,34)
    15.38 ( 21.563 )
    9.80 ( 17.465 )
        Dyspnea; Cycle 20 Day 1(n=27,31)
    23.46 ( 20.286 )
    11.83 ( 16.212 )
        Dyspnea; Cycle 21 Day 1(n=26,28)
    15.38 ( 16.946 )
    7.14 ( 13.929 )
        Dyspnea; Cycle 22 Day 1(n=19,27)
    17.54 ( 20.393 )
    12.35 ( 18.829 )
        Dyspnea; Cycle 23 Day 1(n=15,24)
    13.33 ( 21.082 )
    11.11 ( 18.822 )
        Dyspnea; Cycle 24 Day 1(n=15,19)
    20 ( 21.082 )
    12.28 ( 16.520 )
        Dyspnea; Cycle 25 Day 1(n=12,16)
    22.22 ( 29.588 )
    8.33 ( 14.907 )
        Dyspnea; Cycle 26 Day 1(n=8,13)
    16.67 ( 17.817 )
    15.38 ( 22.008 )
        Dyspnea; Cycle 27 Day 1(n=6,7)
    11.11 ( 17.213 )
    14.29 ( 17.817 )
        Dyspnea; Cycle 28 Day 1(n=4,6)
    16.67 ( 19.245 )
    16.67 ( 18.257 )
        Dyspnea; Cycle 29 Day 1(n=4,5)
    25 ( 16.667 )
    20 ( 18.257 )
        Dyspnea; Cycle 30 Day 1(n=4,1)
    16.67 ( 19.245 )
    0 ( 99999 )
        Dyspnea; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Dyspnea; Off-treatment Visit(n=77,74)
    24.68 ( 27.254 )
    21.62 ( 28.898 )
        Insomnia; Baseline (n=169,162)
    23.08 ( 26.972 )
    22.84 ( 27.671 )
        Insomnia; Cycle 2 Day 1(n=157,149)
    26.11 ( 27.038 )
    19.91 ( 25.386 )
        Insomnia; Cycle 3 Day 1(n=147,142)
    30.39 ( 29.435 )
    23 ( 25.477 )
        Insomnia; Cycle 4 Day 1(n=133,137)
    26.57 ( 28.057 )
    20.19 ( 24.036 )
        Insomnia; Cycle 5 Day 1(n=126,127)
    23.02 ( 26.487 )
    22.05 ( 24.205 )
        Insomnia; Cycle 6 Day 1(n=122,120)
    24.86 ( 26.955 )
    17.50 ( 22.019 )
        Insomnia; Cycle 7 Day 1(n=105,105)
    25.08 ( 27.651 )
    20 ( 25.149 )
        Insomnia; Cycle 8 Day 1(n=97,97)
    26.46 ( 28.843 )
    19.59 ( 25.346 )
        Insomnia; Cycle 9 Day 1(n=90,92)
    25.56 ( 27.392 )
    16.67 ( 21.255 )
        Insomnia; Cycle 10 Day 1(n=80,75)
    24.58 ( 25.844 )
    18.22 ( 22.789 )
        Insomnia; Cycle 11 Day 1(n=68,71)
    24.02 ( 26.918 )
    17.37 ( 24.468 )
        Insomnia; Cycle 12 Day 1(n=64,62)
    23.44 ( 23.518 )
    13.98 ( 22.216 )
        Insomnia; Cycle 13 Day 1(n=56,55)
    21.43 ( 21.489 )
    13.33 ( 21.849 )
        Insomnia; Cycle 14 Day 1(n=48,53)
    18.06 ( 23.778 )
    11.95 ( 21.774 )
        Insomnia; Cycle 15 Day 1(n=44,50)
    18.94 ( 20.832 )
    16 ( 23.561 )
        Insomnia; Cycle 16 Day 1(n=41,47)
    20.33 ( 20.921 )
    14.89 ( 21.768 )
        Insomnia; Cycle 17 Day 1(n=36,40)
    17.59 ( 16.877 )
    13.33 ( 21.082 )
        Insomnia; Cycle 18 Day 1(n=31,34)
    27.96 ( 25.958 )
    11.76 ( 19.903 )
        Insomnia; Cycle 19 Day 1(n=27,34)
    24.69 ( 25.474 )
    13.73 ( 21.893 )
        Insomnia; Cycle 20 Day 1(n=27,31)
    25.93 ( 25.036 )
    12.90 ( 20.507 )
        Insomnia; Cycle 21 Day 1(n=26,28)
    23.08 ( 27.919 )
    10.71 ( 18.265 )
        Insomnia; Cycle 22 Day 1(n=19,27)
    21.05 ( 19.909 )
    6.17 ( 16.111 )
        Insomnia; Cycle 23 Day 1(n=15,24)
    26.67 ( 22.537 )
    11.11 ( 23.399 )
        Insomnia; Cycle 24 Day 1(n=15,19)
    24.44 ( 26.627 )
    12.28 ( 19.909 )
        Insomnia; Cycle 25 Day 1(n=12,16)
    16.67 ( 17.408 )
    12.50 ( 20.638 )
        Insomnia; Cycle 26 Day 1(n=8,13)
    16.67 ( 17.817 )
    20.51 ( 32.026 )
        Insomnia; Cycle 27 Day 1(n=6,7)
    22.22 ( 17.213 )
    9.52 ( 16.265 )
        Insomnia; Cycle 28 Day 1(n=4,6)
    25 ( 16.667 )
    11.11 ( 17.213 )
        Insomnia; Cycle 29 Day 1(n=4,5)
    25 ( 16.667 )
    13.33 ( 18.257 )
        Insomnia; Cycle 30 Day 1(n=4,1)
    25 ( 16.667 )
    0 ( 99999 )
        Insomnia; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Insomnia; Off-treatment Visit(n=78,74)
    32.05 ( 32.430 )
    28.83 ( 31.850 )
        Appetite Loss; Baseline(n=171,162)
    15.79 ( 24.606 )
    18.31 ( 27.060 )
        Appetite Loss; Cycle 2 Day 1(n=158,150)
    26.79 ( 31.129 )
    27.56 ( 32.020 )
        Appetite Loss; Cycle 3 Day 1(n=147,142)
    31.97 ( 31.905 )
    29.81 ( 31.687 )
        Appetite Loss; Cycle 4 Day 1(n=134,137)
    32.09 ( 31.239 )
    30.90 ( 32.749 )
        Appetite Loss; Cycle 5 Day 1(n=128,125)
    30.47 ( 29.881 )
    30.67 ( 32.129 )
        Appetite Loss; Cycle 6 Day 1(n=123,120)
    30.35 ( 31.365 )
    26.11 ( 29.996 )
        Appetite Loss; Cycle 7 Day 1(n=107,105)
    29.28 ( 31.956 )
    26.98 ( 28.154 )
        Appetite Loss; Cycle 8 Day 1(n=98,96)
    29.25 ( 31.483 )
    25.00 ( 26.491 )
        Appetite Loss; Cycle 9 Day 1(n=91,92)
    29.30 ( 30.565 )
    25.36 ( 27.678 )
        Appetite Loss; Cycle 10 Day 1(n=81,75)
    27.57 ( 29.716 )
    22.22 ( 22.815 )
        Appetite Loss; Cycle 11 Day 1(n=69,71)
    24.15 ( 27.938 )
    22.07 ( 26.988 )
        Appetite Loss; Cycle 12 Day 1(n=65,62)
    22.05 ( 24.493 )
    18.82 ( 25.336 )
        Appetite Loss; Cycle 13 Day 1(n=56,54)
    23.21 ( 25.362 )
    17.28 ( 21.221 )
        Appetite Loss; Cycle 14 Day 1(n=49,53)
    19.73 ( 24.456 )
    17.61 ( 24.111 )
        Appetite Loss; Cycle 15 Day 1(n=44,51)
    17.42 ( 23.282 )
    24.18 ( 30.608 )
        Appetite Loss; Cycle 16 Day 1(n=41,47)
    23.58 ( 27.125 )
    22.70 ( 27.014 )
        Appetite Loss; Cycle 17 Day 1(n=36,40)
    20.37 ( 21.496 )
    22.50 ( 25.473 )
        Appetite Loss; Cycle 18 Day 1(n=31,33)
    19.35 ( 22.401 )
    22.22 ( 24.533 )
        Appetite Loss; Cycle 19 Day 1(n=27,34)
    19.75 ( 23.130 )
    20.59 ( 25.969 )
        Appetite Loss; Cycle 20 Day 1(n=27,31)
    23.46 ( 25.844 )
    21.51 ( 30.488 )
        Appetite Loss; Cycle 21 Day 1(n=26,28)
    23.08 ( 20.590 )
    15.48 ( 21.242 )
        Appetite Loss; Cycle 22 Day 1(n=19,27)
    17.54 ( 20.393 )
    17.28 ( 25.099 )
        Appetite Loss; Cycle 23 Day 1(n=15,24)
    17.78 ( 24.774 )
    20.83 ( 27.474 )
        Appetite Loss; Cycle 24 Day 1(n=15,19)
    13.33 ( 24.560 )
    15.79 ( 25.744 )
        Appetite Loss; Cycle 25 Day 1(n=12,16)
    19.44 ( 22.285 )
    18.75 ( 29.736 )
        Appetite Loss; Cycle 26 Day 1(n=8,13)
    29.17 ( 27.817 )
    23.08 ( 34.385 )
        Appetite Loss; Cycle 27 Day 1(n=6,7)
    16.67 ( 18.257 )
    9.52 ( 16.265 )
        Appetite Loss; Cycle 28 Day 1(n=4,6)
    8.33 ( 16.667 )
    11.11 ( 17.213 )
        Appetite Loss; Cycle 29 Day 1(n=4,5)
    16.67 ( 19.245 )
    0 ( 0 )
        Appetite Loss; Cycle 30 Day 1(n=4,1)
    8.33 ( 16.667 )
    0 ( 99999 )
        Appetite Loss; Cycle 31 Day 1(n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Appetite Loss Score; Off-treatment(n=80,74)
    29.58 ( 31.820 )
    25.23 ( 32.082 )
        Constipation; Baseline(n=171,162)
    15.98 ( 24.876 )
    12.55 ( 23.501 )
        Constipation; Cycle 2 Day 1(n=157,150)
    10.40 ( 20.274 )
    11.11 ( 21.035 )
        Constipation; Cycle 3 Day 1(n=147,142)
    9.52 ( 20.644 )
    10.80 ( 20.456 )
        Constipation; Cycle 4 Day 1(n=135,136)
    11.11 ( 21.930 )
    9.80 ( 19.081 )
        Constipation; Cycle 5 Day 1(n=128,125)
    12.24 ( 20.438 )
    9.87 ( 19.411 )
        Constipation; Cycle 6 Day 1(n=122,118)
    8.47 ( 16.905 )
    8.47 ( 19.090 )
        Constipation; Cycle 7 Day 1(n=106,103)
    11.01 ( 22.874 )
    7.44 ( 16.785 )
        Constipation; Cycle 8 Day 1(n=97,97)
    9.62 ( 18.608 )
    7.22 ( 14.614 )
        Constipation; Cycle 9 Day 1(n=91,92)
    6.23 ( 15.644 )
    9.42 ( 19.967 )
        Constipation; Cycle 10 Day 1(n=81,75)
    6.58 ( 13.354 )
    8.00 ( 18.042 )
        Constipation; Cycle 11 Day 1(n=69,71)
    6.76 ( 15.739 )
    7.98 ( 18.227 )
        Constipation; Cycle 12 Day 1(n=65,62)
    5.64 ( 13.906 )
    9.68 ( 18.492 )
        Constipation; Cycle 13 Day 1(n=55,55)
    3.64 ( 12.294 )
    9.09 ( 18.653 )
        Constipation; Cycle 14 Day 1(n=49,52)
    5.44 ( 14.186 )
    7.69 ( 16.978 )
        Constipation; Cycle 15 Day 1(n=43,50)
    5.43 ( 17.714 )
    9.33 ( 19.095 )
        Constipation; Cycle 16 Day 1(n=39,47)
    5.98 ( 16.879 )
    9.93 ( 18.277 )
        Constipation; Cycle 17 Day 1(n=36,40)
    11.11 ( 22.537 )
    5.00 ( 12.054 )
        Constipation; Cycle 18 Day 1(n=31,34)
    7.53 ( 14.167 )
    7.84 ( 16.532 )
        Constipation; Cycle 19 Day 1(n=27,34)
    9.88 ( 18.057 )
    9.80 ( 20.969 )
        Constipation; Cycle 20 Day 1(n=27,31)
    8.64 ( 17.523 )
    8.60 ( 22.718 )
        Constipation; Cycle 21 Day 1(n=26,28)
    8.97 ( 17.783 )
    7.14 ( 16.623 )
        Constipation; Cycle 22 Day 1(n=19,27)
    7.02 ( 13.962 )
    7.41 ( 19.245 )
        Constipation; Cycle 23 Day 1(n=15,24)
    6.67 ( 13.801 )
    11.11 ( 21.234 )
        Constipation; Cycle 24 Day 1(n=15,19)
    4.44 ( 17.213 )
    8.77 ( 21.779 )
        Constipation; Cycle 25 Day 1(n=12,16)
    5.56 ( 12.975 )
    18.75 ( 29.736 )
        Constipation; Cycle 26 Day 1(n=8,13)
    8.33 ( 15.430 )
    15.38 ( 25.875 )
        Constipation; Cycle 27 Day 1(n=6,7)
    16.67 ( 27.889 )
    0 ( 0 )
        Constipation; Cycle 28 Day 1(n=4,6)
    25.00 ( 31.914 )
    0 ( 0 )
        Constipation; Cycle 29 Day 1(n=4,5)
    25.00 ( 31.914 )
    0 ( 0 )
        Constipation; Cycle 30 Day 1(n=4,1)
    16.67 ( 33.333 )
    0 ( 99999 )
        Constipation; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Constipation; Off-treatment(n=80,74)
    13.33 ( 23.481 )
    12.61 ( 21.863 )
        Diarrhea; Baseline(n=171,162)
    6.43 ( 15.045 )
    6.79 ( 15.823 )
        Diarrhea; Cycle 2 Day 1(n=157,151)
    22.29 ( 29.572 )
    17.66 ( 26.333 )
        Diarrhea; Cycle 3 Day 1(n=149,141)
    32.21 ( 30.858 )
    27.19 ( 32.023 )
        Diarrhea; Cycle 4 Day 1(n=133,136)
    35.59 ( 33.634 )
    29.41 ( 28.991 )
        Diarrhea; Cycle 5 Day 1(n=127,125)
    28.61 ( 28.085 )
    29.33 ( 29.207 )
        Diarrhea; Cycle 6 Day 1(n=121,119)
    31.96 ( 30.550 )
    26.89 ( 27.541 )
        Diarrhea; Cycle 7 Day 1(n=107,105)
    33.64 ( 31.885 )
    31.75 ( 27.881 )
        Diarrhea; Cycle 8 Day 1(n=97,97)
    29.55 ( 28.818 )
    31.27 ( 28.793 )
        Diarrhea; Cycle 9 Day 1(n=91,92)
    34.43 ( 33.129 )
    28.62 ( 28.637 )
        Diarrhea; Cycle 10 Day 1(n=81,75)
    29.22 ( 29.992 )
    29.33 ( 25.088 )
        Diarrhea; Cycle 11 Day 1(n=69,72)
    28.02 ( 28.367 )
    26.85 ( 26.619 )
        Diarrhea; Cycle 12 Day 1(n=62,60)
    28.49 ( 31.273 )
    22.78 ( 23.363 )
        Diarrhea; Cycle 13 Day 1(n=56,55)
    26.19 ( 28.223 )
    23.03 ( 25.558 )
        Diarrhea; Cycle 14 Day 1(n=49,52)
    26.53 ( 25.440 )
    24.36 ( 22.008 )
        Diarrhea; Cycle 15 Day 1(n=44,51)
    29.55 ( 29.828 )
    30.07 ( 26.038 )
        Diarrhea; Cycle 16 Day 1(n=41,47)
    20.33 ( 27.767 )
    23.40 ( 21.886 )
        Diarrhea; Cycle 17 Day 1(n=36,40)
    21.30 ( 24.107 )
    29.17 ( 28.432 )
        Diarrhea; Cycle 18 Day 1(n=31,34)
    21.51 ( 25.164 )
    25.49 ( 23.296 )
        Diarrhea; Cycle 19 Day 1(n=27,34)
    23.46 ( 28.963 )
    21.57 ( 21.528 )
        Diarrhea; Cycle 20 Day 1(n=27,31)
    19.75 ( 23.130 )
    22.58 ( 23.392 )
        Diarrhea; Cycle 21 Day 1(n=26,28)
    20.51 ( 26.795 )
    21.43 ( 18.624 )
        Diarrhea; Cycle 22 Day 1(n=19,27)
    17.54 ( 20.393 )
    24.69 ( 19.812 )
        Diarrhea; Cycle 23 Day 1(n=15,24)
    15.56 ( 17.213 )
    22.22 ( 16.051 )
        Diarrhea; Cycle 24 Day 1(n=15,19)
    11.11 ( 16.265 )
    19.30 ( 16.909 )
        Diarrhea; Cycle 25 Day 1(n=12,16)
    19.44 ( 22.285 )
    18.75 ( 17.078 )
        Diarrhea; Cycle 26 Day 1(n=8,13)
    25.00 ( 29.547 )
    17.95 ( 17.296 )
        Diarrhea; Cycle 27 Day 1(n=6,7)
    33.33 ( 21.082 )
    33.33 ( 19.245 )
        Diarrhea; Cycle 28 Day 1(n=4,6)
    16.67 ( 19.245 )
    22.22 ( 17.213 )
        Diarrhea; Cycle 29 Day 1(n=4,5)
    8.33 ( 16.667 )
    20.00 ( 18.257 )
        Diarrhea; Cycle 30 Day 1(n=4,1)
    16.67 ( 19.245 )
    0 ( 99999 )
        Diarrhea; Cycle 31 Day 1(n=1,0)
    33.33 ( 99999 )
    99999 ( 99999 )
        Diarrhea; Off-treatment(n=80,74)
    18.33 ( 25.380 )
    12.16 ( 19.565 )
        Financial Difficulties; Baseline(n=170,162)
    21.76 ( 28.382 )
    20.37 ( 29.076 )
        Financial Difficulties; Cycle 2 Day 1(n=155,151)
    21.08 ( 28.177 )
    15.01 ( 24.852 )
        Financial Difficulties; Cycle 3 Day 1(n=147,141)
    23.13 ( 27.201 )
    18.20 ( 27.451 )
        Financial Difficulties; Cycle 4 Day 1(n=131,134)
    22.90 ( 27.761 )
    16.42 ( 25.113 )
        Financial Difficulties; Cycle 5 Day 1(n=125,126)
    22.93 ( 28.213 )
    18.78 ( 29.058 )
        Financial Difficulties; Cycle 6 Day 1(n=120,118)
    25.00 ( 27.416 )
    17.80 ( 25.666 )
        Financial Difficulties; Cycle 7 Day 1(n=105,105)
    30.16 ( 31.866 )
    15.87 ( 24.062 )
        Financial Difficulties; Cycle 8 Day 1(n=97,97)
    25.43 ( 29.176 )
    17.53 ( 24.576 )
        Financial Difficulties; Cycle 9 Day 1(n=90,90)
    25.56 ( 30.002 )
    16.67 ( 23.440 )
        Financial Difficulties; Cycle 10 Day 1(n=80,73)
    22.50 ( 27.952 )
    17.35 ( 24.913 )
        Financial Difficulties; Cycle 11 Day 1(n=66,72)
    26.26 ( 30.108 )
    16.20 ( 24.382 )
        Financial Difficulties; Cycle 12 Day 1(n=63,60)
    24.87 ( 28.061 )
    16.11 ( 24.156 )
        Financial Difficulties; Cycle 13 Day 1(n=55,54)
    23.03 ( 26.351 )
    19.14 ( 25.577 )
        Financial Difficulties; Cycle 14 Day 1(n=48,52)
    20.83 ( 22.413 )
    17.31 ( 25.127 )
        Financial Difficulties; Cycle 15 Day 1(n=43,51)
    21.71 ( 27.103 )
    19.61 ( 26.813 )
        Financial Difficulties; Cycle 16 Day 1(n=40,47)
    21.67 ( 25.654 )
    17.02 ( 24.937 )
        Financial Difficulties; Cycle 17 Day 1(n=35,40)
    23.81 ( 27.501 )
    19.17 ( 27.099 )
        Financial Difficulties; Cycle 18 Day 1(n=31,34)
    17.20 ( 18.995 )
    19.61 ( 28.566 )
        Financial Difficulties; Cycle 19 Day 1(n=27,34)
    18.52 ( 19.245 )
    20.59 ( 28.444 )
        Financial Difficulties; Cycle 20 Day 1(n=27,31)
    16.05 ( 21.424 )
    20.43 ( 30.644 )
        Financial Difficulties; Cycle 21 Day 1(n=26,28)
    19.23 ( 21.444 )
    20.24 ( 27.725 )
        Financial Difficulties; Cycle 22 Day 1(n=19,27)
    24.56 ( 24.450 )
    20.99 ( 29.451 )
        Financial Difficulties; Cycle 23 Day 1(n=15,24)
    17.78 ( 17.213 )
    23.61 ( 31.819 )
        Financial Difficulties; Cycle 24 Day 1(n=15,19)
    17.78 ( 21.331 )
    19.30 ( 25.618 )
        Financial Difficulties; Cycle 25 Day 1(n=12,16)
    16.67 ( 22.473 )
    16.67 ( 24.343 )
        Financial Difficulties; Cycle 26 Day 1(n=8,13)
    20.83 ( 24.801 )
    20.51 ( 32.026 )
        Financial Difficulties; Cycle 27 Day 1(n=6,7)
    16.67 ( 18.257 )
    0 ( 0 )
        Financial Difficulties; Cycle 28 Day 1(n=4,6)
    25.00 ( 16.667 )
    0 ( 0 )
        Financial Difficulties; Cycle 29 Day 1(n=4,5)
    25.00 ( 16.667 )
    0 ( 0 )
        Financial Difficulties; Cycle 30 Day 1(n=4,1)
    25.00 ( 16.667 )
    0 ( 99999 )
        Financial Difficulties; Cycle 31 Day 1(n=1,0)
    0 ( 99999 )
    99999 ( 99999 )
        Financial Difficulties; Off-treatment(n=79,73)
    31.65 ( 32.423 )
    25.11 ( 30.318 )
    No statistical analyses for this end point

    Secondary: HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)

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    End point title
    		 HRQoL Assessed by European Quality of Life (EuroQol) Five-Dimensional, 3-Level (EQ-5D-3L) Index Score and Visual Analogue Scale (VAS)
    End point description
    In EQ-5D-3L, subjects rate 5 dimensions of health (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) by choosing from 3 answering options (1=no problems; 2=some problems; 3=extreme problems). Summed score ranges from 5-15, "5" =no problems "15" =severe problems in 5 dimensions. EQ-5D index calculated by applying preference-based weights (tariffs) to scores of 5 health state dimensions. Index values range from -1 to 1, 0 =health state equivalent to death and 1=perfect health. EQ-5D-3L also included EQVAS ranges between 100 (best imaginable health) and 0 (worst imaginable health). Decrease in EQ-5D-3L =improvement. Total index EQ-5D-3L score was weighted with range of -0.594 (worst) to 1.0 (best). QoL analysis set. "N"=subjects evaluable for endpoint; "n”=subjects evaluable at given time points and 99999=no data was calculated due to less subjects. As pre-specified in protocol, data for this endpoint was collected and analyzed till primary analysis only.
    End point type
    Secondary
    End point timeframe
    At baseline (prior to first dose of study drug), on Day 1 of each subsequent cycle (cycle length =28 days), and at the Off-treatment visit (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    168
    161
    Units: score on a scale
    arithmetic mean (standard deviation)
        EQ-5D Index Score; Baseline(n=168,161)
    0.76 ( 0.216 )
    0.78 ( 0.232 )
        EQ-5D Index Score; Cycle 2 Day 1(n=151,147)
    0.76 ( 0.178 )
    0.76 ( 0.230 )
        EQ-5D Index Score; Cycle 3 Day 1(n=144,134)
    0.73 ( 0.232 )
    0.78 ( 0.239 )
        EQ-5D Index Score; Cycle 4 Day 1(n=131,131)
    0.73 ( 0.213 )
    0.78 ( 0.236 )
        EQ-5D Index Score; Cycle 5 Day 1(n=124,124)
    0.73 ( 0.212 )
    0.78 ( 0.199 )
        EQ-5D Index Score; Cycle 6 Day 1(n=121,114)
    0.73 ( 0.220 )
    0.77 ( 0.225 )
        EQ-5D Index Score; Cycle 7 Day 1(n=103,102)
    0.71 ( 0.219 )
    0.78 ( 0.196 )
        EQ-5D Index Score; Cycle 8 Day 1(n=95,95)
    0.75 ( 0.187 )
    0.80 ( 0.187 )
        EQ-5D Index Score; Cycle 9 Day 1(n=87,89)
    0.73 ( 0.192 )
    0.79 ( 0.192 )
        EQ-5D Index Score; Cycle 10 Day 1(n=77,71)
    0.76 ( 0.186 )
    0.81 ( 0.177 )
        EQ-5D Index Score; Cycle 11 Day 1(n=67,70)
    0.77 ( 0.185 )
    0.82 ( 0.82 )
        EQ-5D Index Score; Cycle 12 Day 1(n=64,59)
    0.77 ( 0.173 )
    0.83 ( 0.161 )
        EQ-5D Index Score; Cycle 13 Day 1(n=56,54)
    0.76 ( 0.157 )
    0.82 ( 0.179 )
        EQ-5D Index Score; Cycle 14 Day 1(n=49,51)
    0.77 ( 0.186 )
    0.83 ( 0.163 )
        EQ-5D Index Score; Cycle 15 Day 1(n=43,49)
    0.76 ( 0.191 )
    0.81 ( 0.165 )
        EQ-5D Index Score; Cycle 16 Day 1(n=40,46)
    0.73 ( 0.179 )
    0.81 ( 0.212 )
        EQ-5D Index Score; Cycle 17 Day 1(n=37,39)
    0.73 ( 0.211 )
    0.83 ( 0.158 )
        EQ-5D Index Score; Cycle 18 Day 1(n=31,33)
    0.76 ( 0.148 )
    0.84 ( 0.177 )
        EQ-5D Index Score; Cycle 19 Day 1(n=26,33)
    0.69 ( 0.266 )
    0.79 ( 0.205 )
        EQ-5D Index Score; Cycle 20 Day 1(n=27,30)
    0.70 ( 0.259 )
    0.82 ( 0.167 )
        EQ-5D Index Score; Cycle 21 Day 1(n=26,28)
    0.73 ( 0.223 )
    0.83 ( 0.180 )
        EQ-5D Index Score; Cycle 22 Day 1(n=19,27)
    0.74 ( 0.157 )
    0.85 ( 0.173 )
        EQ-5D Index Score; Cycle 23 Day 1(n=14,24)
    0.74 ( 0.149 )
    0.82 ( 0.242 )
        EQ-5D Index Score; Cycle 24 Day 1(n=15,18)
    0.75 ( 0.172 )
    0.84 ( 0.156 )
        EQ-5D Index Score; Cycle 25 Day 1(n=12,16)
    0.70 ( 0.245 )
    0.83 ( 0.175 )
        EQ-5D Index Score; Cycle 26 Day 1(n=8,13)
    0.72 ( 0.170 )
    0.73 ( 0.438 )
        EQ-5D Index Score; Cycle 27 Day 1(n=6,6)
    0.77 ( 0.135 )
    0.93 ( 0.117 )
        EQ-5D Index Score; Cycle 28 Day 1(n=4,5)
    0.73 ( 0.112 )
    0.97 ( 0.067 )
        EQ-5D Index Score; Cycle 29 Day 1(n=4,4)
    0.74 ( 0.120 )
    0.96 ( 0.075 )
        EQ-5D Index Score; Cycle 30 Day 1(n=4,1)
    0.61 ( 0.391 )
    1 ( 99999 )
        EQ-5D Index Score; Cycle 31 Day 1(n=1,0)
    0.87 ( 99999 )
    99999 ( 99999 )
        EQ-5D Index Score; Off-treatment Visit(n=77,72)
    0.61 ( 0.331 )
    0.68 ( 0.314 )
        EQ-VAS Score; Baseline(n=167,161)
    68.57 ( 18.348 )
    70.01 ( 20.552 )
        EQ-VAS Score; Cycle 2 Day 1(n=149,147)
    66.05 ( 18.531 )
    69.52 ( 19.155 )
        EQ-VAS Score; Cycle 3 Day 1(n=145,137)
    66.22 ( 17.804 )
    70.71 ( 17.648 )
        EQ-VAS Score; Cycle 4 Day 1(n=130,133)
    65.69 ( 18.265 )
    69.66 ( 17.784 )
        EQ-VAS Score; Cycle 5 Day 1(n=122,125)
    65.86 ( 18.908 )
    70.30 ( 19.492 )
        EQ-VAS Score; Cycle 6 Day 1(n=118,116)
    65.53 ( 20.027 )
    71.73 ( 17.366 )
        EQ-VAS Score; Cycle 7 Day 1(n=102,104)
    65.74 ( 18.063 )
    70.39 ( 19.387 )
        EQ-VAS Score; Cycle 8 Day 1(n=97,95)
    64.16 ( 18.969 )
    70.40 ( 20.130 )
        EQ-VAS Score; Cycle 9 Day 1(n=90,90)
    65.51 ( 17.670 )
    69.92 ( 19.452 )
        EQ-VAS Score; Cycle 10 Day 1(n=77,73)
    66.92 ( 17.747 )
    73.18 ( 20.167 )
        EQ-VAS Score; Cycle 11 Day 1(n=69,71)
    67.74 ( 16.850 )
    73.21 ( 19.310 )
        EQ-VAS Score; Cycle 12 Day 1(n=65,61)
    66.46 ( 18.680 )
    74.46 ( 17.139 )
        EQ-VAS Score; Cycle 13 Day 1(n=56,55)
    65.64 ( 19.690 )
    74.35 ( 17.766 )
        EQ-VAS Score; Cycle 14 Day 1(n=49,53)
    66.41 ( 17.839 )
    74.40 ( 17.678 )
        EQ-VAS Score; Cycle 15 Day 1(n=44,50)
    67.05 ( 17.847 )
    72.58 ( 19.060 )
        EQ-VAS Score; Cycle 16 Day 1(n=41,46)
    66.54 ( 18.118 )
    72.80 ( 17.733 )
        EQ-VAS Score; Cycle 17 Day 1(n=37,40)
    65.78 ( 17.755 )
    73.80 ( 17.593 )
        EQ-VAS Score; Cycle 18 Day 1(n=30,34)
    64.70 ( 18.170 )
    73.71 ( 16.665 )
        EQ-VAS Score; Cycle 19 Day 1(n=26,34)
    62.15 ( 20.676 )
    71.76 ( 19.272 )
        EQ-VAS Score; Cycle 20 Day 1(n=27,30)
    62.70 ( 19.779 )
    72.07 ( 19.293 )
        EQ-VAS Score; Cycle 21 Day 1(n=26,28)
    62.12 ( 17.974 )
    76.46 ( 16.836 )
        EQ-VAS Score; Cycle 22 Day 1(n=19,27)
    65.21 ( 14.722 )
    74.44 ( 16.860 )
        EQ-VAS Score; Cycle 23 Day 1(n=15,24)
    67.73 ( 15.650 )
    73.67 ( 17.704 )
        EQ-VAS Score; Cycle 24 Day 1(n=15,19)
    65.27 ( 19.381 )
    71.21 ( 21.212 )
        EQ-VAS Score; Cycle 25 Day 1(n=12,16)
    60.58 ( 19.313 )
    72.81 ( 16.897 )
        EQ-VAS Score; Cycle 26 Day 1(n=8,13)
    64.13 ( 16.313 )
    65.23 ( 25.652 )
        EQ-VAS Score; Cycle 27 Day 1(n=6,7)
    61.83 ( 18.357 )
    77.43 ( 16.762 )
        EQ-VAS Score; Cycle 28 Day 1(n=4,6)
    54.25 ( 8.694 )
    77.50 ( 20.907 )
        EQ-VAS Score; Cycle 29 Day 1(n=4,5)
    52.75 ( 12.093 )
    74 ( 21.036 )
        EQ-VAS Score; Cycle 30 Day 1(n=4,1)
    51.75 ( 11.295 )
    50 ( 99999 )
        EQ-VAS Score; Cycle 31 Day 1(n=1,0)
    35 ( 99999 )
    99999 ( 99999 )
        EQ-VAS Score; Off-treatment Visit(n=77,73)
    58.48 ( 23.516 )
    62.66 ( 22.252 )
    No statistical analyses for this end point

    Secondary: Progression-free Survival After Next Line of Therapy (PFS2)

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    End point title
    		 Progression-free Survival After Next Line of Therapy (PFS2)
    End point description
    PFS2, defined as the time from randomization to the date of PD after next line of therapy or death from any cause, whichever occurred first based on investigator assessment according to RECIST v1.1. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. Median PFS2 was analyzed using the Kaplan-Meier product-limit estimates for each treatment group and presented with 2-sided 95% CI. PPAS1 included all randomized subjects minus the 32 subjects who had received >=2 incorrect lenvatinib doses due to IxRS issues. As pre-specified in protocol, data for this secondary endpoint was collected and analyzed till the primary analysis only.
    End point type
    Secondary
    End point timeframe
    From the time of randomization to the date of PD after next line of therapy or death from any cause or the date of data cutoff for the primary analysis, whichever occurs first (up to 29 months)
    End point values
    		 Lenvatinib 14 mg + Everolimus 5 mg Lenvatinib 18 mg + Everolimus 5 mg
    Number of subjects analysed
    156
    155
    Units: months
        median (confidence interval 95%)
    18.2 (13.1 to 22.5)
    19.5 (14.1 to 23.8)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of first dose of study drug up to 28 days after last dose of study drug (up to 71 months)
    Adverse event reporting additional description
    Reported deaths included all anticipated and unanticipated deaths due to any cause in the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Lenvatinib 18 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 18 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose for in a 28-day treatment cycle until PD, development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first.

    Reporting group title
    Lenvatinib 14 mg + Everolimus 5 mg
    Reporting group description
    		 Subjects received lenvatinib 14 mg, capsule, orally, once daily along with everolimus 5 mg, tablet, orally, once daily as the starting dose for in a 28-day treatment cycle until progressive disease (PD), development of unacceptable toxicity, subject requested to discontinue treatment, withdrew consent or lost to follow-up, until the end of the study, or until study termination by the sponsor, whichever occurred first. If there were no intolerable Grade 2 or any >= Grade 3 TEAEs that required dose reduction in the first 28-day cycle (that is, the first 4 weeks of treatment), lenvatinib dose was escalated to 18 mg once daily (along with everolimus 5 mg) beginning in Cycle 2 or later (cycle length = 28 days) during randomization phase.

    Serious adverse events
    		 Lenvatinib 18 mg + Everolimus 5 mg Lenvatinib 14 mg + Everolimus 5 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 168 (51.79%)
    92 / 173 (53.18%)
         number of deaths (all causes)
    60
    71
         number of deaths resulting from adverse events
    17
    24
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion malignant
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to lung
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Malignant pleural effusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 168 (2.98%)
    5 / 173 (2.89%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    Cholangiocarcinoma
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cancer fatigue
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic renal cell carcinoma
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic thrombosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 168 (1.19%)
    3 / 173 (1.73%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 168 (0.60%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Fatigue
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Localised oedema
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyrexia
         subjects affected / exposed
    1 / 168 (0.60%)
    4 / 173 (2.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    3 / 168 (1.79%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cough
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrothorax
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    3 / 168 (1.79%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pneumonitis
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Pneumothorax
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    3 / 168 (1.79%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 168 (1.79%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Troponin increased
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    4 / 168 (2.38%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Amylase increased
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulna fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiovascular disorder
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiopulmonary failure
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic vein thrombosis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 168 (1.19%)
    3 / 173 (1.73%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal fistula
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous ulcer
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    6 / 168 (3.57%)
    11 / 173 (6.36%)
         occurrences causally related to treatment / all
    3 / 6
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Large intestine perforation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 168 (1.19%)
    6 / 173 (3.47%)
         occurrences causally related to treatment / all
    1 / 3
    7 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faeces hard
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stenosis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder obstruction
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant biliary obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Acute febrile neutrophilic dermatosis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis acneiform
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Livedo reticularis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus bladder
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    6 / 168 (3.57%)
    3 / 173 (1.73%)
         occurrences causally related to treatment / all
    7 / 10
    2 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pathological fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture pain
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma muscle
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib deformity
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cholecystitis infective
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendiceal abscess
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bacteraemia
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paracancerous pneumonia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphangitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 168 (0.60%)
    4 / 173 (2.31%)
         occurrences causally related to treatment / all
    0 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes virus infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal sepsis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Large intestine infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung abscess
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic sinusitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perihepatic abscess
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perineal abscess
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 168 (4.17%)
    13 / 173 (7.51%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 17
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Pneumonia fungal
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 168 (1.19%)
    3 / 173 (1.73%)
         occurrences causally related to treatment / all
    1 / 2
    3 / 5
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Septic shock
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral diarrhoea
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 168 (0.60%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 173 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 173 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 173 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lenvatinib 18 mg + Everolimus 5 mg Lenvatinib 14 mg + Everolimus 5 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    166 / 168 (98.81%)
    172 / 173 (99.42%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    10 / 168 (5.95%)
    7 / 173 (4.05%)
         occurrences all number
    16
    7
    Hypertension
         subjects affected / exposed
    59 / 168 (35.12%)
    54 / 173 (31.21%)
         occurrences all number
    101
    113
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    16 / 168 (9.52%)
    17 / 173 (9.83%)
         occurrences all number
    21
    22
    Oedema peripheral
         subjects affected / exposed
    23 / 168 (13.69%)
    21 / 173 (12.14%)
         occurrences all number
    44
    31
    Fatigue
         subjects affected / exposed
    50 / 168 (29.76%)
    51 / 173 (29.48%)
         occurrences all number
    104
    93
    Asthenia
         subjects affected / exposed
    39 / 168 (23.21%)
    42 / 173 (24.28%)
         occurrences all number
    100
    104
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    24 / 168 (14.29%)
    26 / 173 (15.03%)
         occurrences all number
    28
    36
    Cough
         subjects affected / exposed
    30 / 168 (17.86%)
    13 / 173 (7.51%)
         occurrences all number
    47
    16
    Dysphonia
         subjects affected / exposed
    24 / 168 (14.29%)
    20 / 173 (11.56%)
         occurrences all number
    25
    28
    Dyspnoea
         subjects affected / exposed
    25 / 168 (14.88%)
    15 / 173 (8.67%)
         occurrences all number
    33
    23
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 168 (9.52%)
    12 / 173 (6.94%)
         occurrences all number
    19
    14
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    14 / 168 (8.33%)
    11 / 173 (6.36%)
         occurrences all number
    21
    21
    Amylase increased
         subjects affected / exposed
    8 / 168 (4.76%)
    9 / 173 (5.20%)
         occurrences all number
    12
    15
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 168 (7.14%)
    13 / 173 (7.51%)
         occurrences all number
    16
    17
    Blood alkaline phosphatase increased
         subjects affected / exposed
    9 / 168 (5.36%)
    11 / 173 (6.36%)
         occurrences all number
    12
    11
    Blood cholesterol increased
         subjects affected / exposed
    22 / 168 (13.10%)
    13 / 173 (7.51%)
         occurrences all number
    37
    19
    Blood creatinine increased
         subjects affected / exposed
    25 / 168 (14.88%)
    23 / 173 (13.29%)
         occurrences all number
    42
    30
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    5 / 168 (2.98%)
    11 / 173 (6.36%)
         occurrences all number
    6
    17
    Blood triglycerides increased
         subjects affected / exposed
    13 / 168 (7.74%)
    7 / 173 (4.05%)
         occurrences all number
    36
    19
    Lipase increased
         subjects affected / exposed
    16 / 168 (9.52%)
    18 / 173 (10.40%)
         occurrences all number
    26
    33
    Platelet count decreased
         subjects affected / exposed
    12 / 168 (7.14%)
    9 / 173 (5.20%)
         occurrences all number
    20
    22
    Weight decreased
         subjects affected / exposed
    41 / 168 (24.40%)
    36 / 173 (20.81%)
         occurrences all number
    73
    63
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 168 (11.90%)
    24 / 173 (13.87%)
         occurrences all number
    28
    34
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    10 / 168 (5.95%)
    10 / 173 (5.78%)
         occurrences all number
    29
    13
    Anaemia
         subjects affected / exposed
    29 / 168 (17.26%)
    37 / 173 (21.39%)
         occurrences all number
    74
    56
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    123 / 168 (73.21%)
    117 / 173 (67.63%)
         occurrences all number
    394
    352
    Constipation
         subjects affected / exposed
    25 / 168 (14.88%)
    22 / 173 (12.72%)
         occurrences all number
    32
    25
    Abdominal pain upper
         subjects affected / exposed
    13 / 168 (7.74%)
    15 / 173 (8.67%)
         occurrences all number
    21
    20
    Abdominal pain
         subjects affected / exposed
    28 / 168 (16.67%)
    29 / 173 (16.76%)
         occurrences all number
    40
    46
    Vomiting
         subjects affected / exposed
    43 / 168 (25.60%)
    41 / 173 (23.70%)
         occurrences all number
    85
    85
    Toothache
         subjects affected / exposed
    11 / 168 (6.55%)
    8 / 173 (4.62%)
         occurrences all number
    11
    10
    Stomatitis
         subjects affected / exposed
    49 / 168 (29.17%)
    61 / 173 (35.26%)
         occurrences all number
    92
    120
    Nausea
         subjects affected / exposed
    52 / 168 (30.95%)
    54 / 173 (31.21%)
         occurrences all number
    103
    104
    Dyspepsia
         subjects affected / exposed
    15 / 168 (8.93%)
    14 / 173 (8.09%)
         occurrences all number
    23
    21
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    29 / 168 (17.26%)
    28 / 173 (16.18%)
         occurrences all number
    43
    41
    Pruritus
         subjects affected / exposed
    12 / 168 (7.14%)
    6 / 173 (3.47%)
         occurrences all number
    12
    9
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    26 / 168 (15.48%)
    24 / 173 (13.87%)
         occurrences all number
    26
    36
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    66 / 168 (39.29%)
    40 / 173 (23.12%)
         occurrences all number
    186
    133
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    9 / 168 (5.36%)
    5 / 173 (2.89%)
         occurrences all number
    11
    6
    Hypothyroidism
         subjects affected / exposed
    35 / 168 (20.83%)
    30 / 173 (17.34%)
         occurrences all number
    42
    38
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 168 (10.12%)
    23 / 173 (13.29%)
         occurrences all number
    31
    29
    Back pain
         subjects affected / exposed
    17 / 168 (10.12%)
    18 / 173 (10.40%)
         occurrences all number
    26
    23
    Musculoskeletal chest pain
         subjects affected / exposed
    12 / 168 (7.14%)
    9 / 173 (5.20%)
         occurrences all number
    16
    9
    Musculoskeletal pain
         subjects affected / exposed
    5 / 168 (2.98%)
    12 / 173 (6.94%)
         occurrences all number
    8
    20
    Pain in extremity
         subjects affected / exposed
    13 / 168 (7.74%)
    8 / 173 (4.62%)
         occurrences all number
    19
    9
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 168 (5.36%)
    4 / 173 (2.31%)
         occurrences all number
    12
    4
    Urinary tract infection
         subjects affected / exposed
    9 / 168 (5.36%)
    11 / 173 (6.36%)
         occurrences all number
    14
    16
    Pneumonia
         subjects affected / exposed
    6 / 168 (3.57%)
    9 / 173 (5.20%)
         occurrences all number
    6
    9
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    57 / 168 (33.93%)
    64 / 173 (36.99%)
         occurrences all number
    137
    130
    Hypercholesterolaemia
         subjects affected / exposed
    26 / 168 (15.48%)
    31 / 173 (17.92%)
         occurrences all number
    49
    64
    Hyperglycaemia
         subjects affected / exposed
    12 / 168 (7.14%)
    13 / 173 (7.51%)
         occurrences all number
    36
    20
    Hypertriglyceridaemia
         subjects affected / exposed
    38 / 168 (22.62%)
    37 / 173 (21.39%)
         occurrences all number
    136
    112
    Hypoalbuminaemia
         subjects affected / exposed
    10 / 168 (5.95%)
    8 / 173 (4.62%)
         occurrences all number
    18
    10
    Hypocalcaemia
         subjects affected / exposed
    13 / 168 (7.74%)
    7 / 173 (4.05%)
         occurrences all number
    21
    11
    Hypokalaemia
         subjects affected / exposed
    19 / 168 (11.31%)
    10 / 173 (5.78%)
         occurrences all number
    31
    12
    Hypomagnesaemia
         subjects affected / exposed
    11 / 168 (6.55%)
    11 / 173 (6.36%)
         occurrences all number
    23
    11
    Hyponatraemia
         subjects affected / exposed
    13 / 168 (7.74%)
    11 / 173 (6.36%)
         occurrences all number
    26
    18
    Hypophosphataemia
         subjects affected / exposed
    11 / 168 (6.55%)
    16 / 173 (9.25%)
         occurrences all number
    19
    24
    Dehydration
         subjects affected / exposed
    5 / 168 (2.98%)
    9 / 173 (5.20%)
         occurrences all number
    9
    12
    Hyperkalaemia
         subjects affected / exposed
    10 / 168 (5.95%)
    9 / 173 (5.20%)
         occurrences all number
    12
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Apr 2017
    Protocol amendment 1: Changes included: added safety results regarding dose modifications and reasons for treatment discontinuation due to toxicity. Added details on sensitivity analysis to be performed for primary endpoints to explore homogeneity of treatment effect across study centers/regions. Added details/explanation on estimation of non-inferiority margin.
    12 Jul 2017
    Protocol amendment 2: Changes included: removed all references related to central imaging from synopsis and protocol. Revised following statement in the Synopsis and Protocol: "The analysis will be detailed in the biomarker analysis plan (BAP) and reported separately”.
    23 May 2018
    Protocol amendment 3: Changes included: removed all references related to pharmacogenetic (PG) sampling and testing from synopsis and protocol. New paragraph was added for consistency of prior anticancer regimens. Made clarifications to footnotes in the Schedule of Procedures/Assessments.
    23 Jul 2018
    Protocol amendment 4: Changes included: revised text to reflect change from double-blind to open-label study design. Revised text regarding lenvatinib dispensing instructions.
    18 Oct 2018
    Protocol amendment 5: Changes included: clarified that lenvatinib in plasma and everolimus in blood will be used for PK assessments, and that PK assessments will be done using the population PK approach. Updated total sample size to approximately 338 subjects (169 subjects in each arm). Full Analysis set changed from primary analysis set to a secondary analysis set.
    04 Jan 2019
    Protocol amendment 6: Changes included: added an exploratory objective: to explore tumor response parameters (ORR24W, ORR, PFS) based on blinded independent imaging review (IIR) for efficacy assessment. Added exploratory endpoints: tumor response endpoints ORR24W, ORR, and PFS based on IIR assessment. These endpoints were defined in the same way as those based on the investigator assessments. Added statistical analyses for the IIR assessments: exploratory efficacy response endpoints ORR24W, ORR, and PFS based on IIR assessment were summarized using the same statistical methods as those used for the same response parameters based on the investigator assessments.
    07 Feb 2020
    Protocol amendment 7: Changes included: clarified that the data cutoff for the primary analysis refers to the statistical end of the study for analysis purposes (end of the Randomization Phase) and that the End of Study refers to the last subject last visit after which all subjects will have completed their off-treatment visits.

    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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