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    Clinical Trial Results:
    A Phase II, Randomized, Double-Blind, Placebo-Controlled Study of Oral E7080 in Addition to Best Supportive Care (BSC) versus BSC Alone in Patients with Locally Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer Who Have Failed at Least Two Systemic Anticancer Regimens

    Summary
    EudraCT number
    		 2011-002347-10
    Trial protocol
    		 HU   GB   CZ   IT   BE  
    Global end of trial date
    27 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jan 2019
    First version publication date
    19 Jan 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-703
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01529112
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Medical Research Inc.
    Sponsor organisation address
    100 Tice Boulevard, Woodcliff Lake, United States,
    Public contact
    Medical Information, Eisai Ltd, +44 08000014612, Lmedinfo@eisai.net
    Scientific contact
    Medical Information, Eisai Ltd, +44 08000014612, Lmedinfo@eisai.net
    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
    27 Jun 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Compare the overall survival (OS) of patients receiving E7080 + best supportive care (BSC) with those receiving placebo + BSC
    Protection of trial subjects
    This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Nov 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Hungary: 17
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    United States: 3
    Worldwide total number of subjects
    135
    EEA total number of subjects
    92
    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)
    73
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The participant flow is based on data cut-off date of 21 January 2014 as the study is ongoing.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer
    Blinding implementation details
    The study was unblended after primary analysis. Placebo had the same appearance of lenvatinib, but with no active pharmaceutical ingredients.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lenvatinib
    Arm description
    		 Participants received lenvatinib 24 mg orally, once daily continuously in each 28-day treatment cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received lenvatinib 24 mg orally, once daily continuously in each 28-day treatment cycle.

    Arm title
    		 Lenvatinib matched placebo
    Arm description
    		 Participants received lenvatinib matched placebo orally, once daily continuously in each 28-day treatment cycle.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received lenvatinib matched placebo orally, once daily continuously in each 28-day treatment cycle.

    Number of subjects in period 1
    		Lenvatinib Lenvatinib matched placebo
    Started
    89
    46
    Completed
    20
    5
    Not completed
    69
    41
         Consent withdrawn by subject
    7
    3
         Adverse event, non-fatal
    2
    -
         Protocol violation
    1
    -
         Death
    59
    38

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lenvatinib
    Reporting group description
    		 Participants received lenvatinib 24 mg orally, once daily continuously in each 28-day treatment cycle.

    Reporting group title
    Lenvatinib matched placebo
    Reporting group description
    		 Participants received lenvatinib matched placebo orally, once daily continuously in each 28-day treatment cycle.

    Reporting group values
    		 Lenvatinib Lenvatinib matched placebo Total
    Number of subjects
    		 89 46 135
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 63 (41 to 82) 63.5 (44 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 44 19 63
        Male
    		 45 27 72

    End points

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    End points reporting groups
    Reporting group title
    Lenvatinib
    Reporting group description
    		 Participants received lenvatinib 24 mg orally, once daily continuously in each 28-day treatment cycle.

    Reporting group title
    Lenvatinib matched placebo
    Reporting group description
    		 Participants received lenvatinib matched placebo orally, once daily continuously in each 28-day treatment cycle.

    Subject analysis set title
    Phamacokinetic Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The analysis was performed using the pharmacokinetic (PK) analysis set defined as all subjects who received at least one dose of study drug and had evaluable PK data.

    Primary: 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. The analysis was performed using the Intent-to-Treat Population, defined as all randomized subjects.
    End point type
    Primary
    End point timeframe
    From date of randomization (Day 1) until occurrence of 90 deaths in the study (cut off date 26 November 2013), approximately 22 months
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Weeks
        median (confidence interval 95%)
    38.4 (26.57 to 47.86)
    24.1 (15.29 to 36.43)
    Statistical analysis title
    		 Statistical analysis of overall survival
    Comparison groups
    Lenvatinib matched placebo v Lenvatinib
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.065
    Method
    		 based on Kaplan Meier estimation
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.45
         upper limit
    		 1.03

    Secondary: Number of participants with Treatment emergent non-serious adverse events (AEs) and Treatment emergent serious adverse events (SAEs)

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    End point title
    		 Number of participants with Treatment emergent non-serious adverse events (AEs) and Treatment emergent serious adverse events (SAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a clinical investigation participant administered with an investigational product. A SAE was defined as any untoward medical occurrence that at any dose; resulted in death, was life-threatening (i.e., the subject was at a risk of death at the time of the event; this did not include an event that hypothetically might have caused death if it had been more severe), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, or was a congenital abnormality/birth defect. In this study, treatment emergent adverse events (TEAEs) (defined as an AE (serious/non-serious) that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication) were assessed. Safety Analysis Set was used.
    End point type
    Secondary
    End point timeframe
    For each participant, from the first dose till 30 days after the last dose or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Participants
    number (not applicable)
        Treatment-emergent non-serious AEs
    83
    42
        Treatment-emergent SAEs
    46
    21
    No statistical analyses for this end point

    Secondary: 6-Month Survival rate

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    End point title
    		 6-Month Survival rate
    End point description
    Event-free survival rate was calculated using Kaplan Meier estimations. The percentage of participants with event free survival up to 6 months and the corresponding 95% confidence interval were estimated for each treatment group. The data presented is based on the data cut-off date of 26 November 2013 while the study is still ongoing. The analysis was performed using the Intent-to-Treat Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) up to 6 months
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    61.6 (50.24 to 71.1)
    49 (33.49 to 62.8)
    No statistical analyses for this end point

    Secondary: 1-year Survival rate

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    End point title
    		 1-year Survival rate
    End point description
    Event-free survival rate was calculated using Kaplan Meier estimations. The percentage of participants with event free survival up to 1 year and the corresponding 95% confidence interval were estimated for each treatment group. The data presented is based on the data cut-off date of 26 November 2013 while the study is still ongoing. The analysis was performed using the Intent-to-Treat Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) up to 1 year
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    35.8 (25.13 to 46.54)
    20.5 (9.96 to 33.74)
    No statistical analyses for this end point

    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 the randomization until the date of first documented disease progression according to Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or date of death from any cause (whichever occurred first), assessed based on investigator's assessment. Disease progression per RECIST v1.1 was defined as at least a 20% relative increase and 5 mm absolute increase in the sum of diameters of target lesions (taking as reference the smallest sum on study), recorded since the treatment started or the appearance of 1 or more new lesions. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) until date of first documentation of disease progression or death from any cause (whichever occurred first) or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Weeks
        median (confidence interval 95%)
    20.9 (15.86 to 23.86)
    7.9 (7.43 to 8.14)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    ORR, defined as the percentage of participants who had best overall response (BOR) of complete response (CR) or partial response (PR) as determined by investigator using RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. ORR = CR + PR. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing. The analysis was performed using the Intent-to-Treat Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    10.1 (4.7 to 18.3)
    2.2 (0.1 to 11.5)
    No statistical analyses for this end point

    Secondary: Response duration (RD)

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    End point title
    		 Response duration (RD)
    End point description
    Response duration, defined as the time from the date of the first assessment demonstrating a CR or PR to the date of the first assessment demonstrating progressive disease or death, whichever occurred first. This is an investigator assessed outcome, measured using RECIST 1.1. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Response duration was summarized by including only subjects with events. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing. The analysis was performed using subjects with events.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    6 [1]
    1 [2]
    Units: Weeks
        median (confidence interval 95%)
    24.2 (12.71 to 33.14)
    43.3 (43.3 to 43.3)
    Notes
    [1] - The analysis was performed using subjects with events.
    [2] - The analysis was performed using subjects with events.
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR)

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    End point title
    		 Disease control rate (DCR)
    End point description
    The percentage of participants with CR, PR, or stable disease (SD) for greater than or equal to 12 weeks. CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) had to have reduction in short axis to less than 10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. Stable disease was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum diameters while on the study. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing. The analysis was performed using the Intent-to-Treat Population, defined as all randomized subjects.
    End point type
    Secondary
    End point timeframe
    From date of randomization (Day 1) until disease progression or death, development of unacceptable toxicity, withdrawal of consent, withdrawal by Investigator, or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of Participants
        number (confidence interval 95%)
    42.7 (32.3 to 53.6)
    19.6 (9.4 to 33.9)
    No statistical analyses for this end point

    Secondary: The Percentage of participants with The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Symptom Scores Achieving Clinically Significant Deterioration on Quality of Life (QOL)

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    End point title
    		 The Percentage of participants with The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Symptom Scores Achieving Clinically Significant Deterioration on Quality of Life (QOL)
    End point description
    The EORTC QLQ-C30 symptom score, a cancer specific self-reporting questionnaire was composed of 9-symptom scales assessing fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties. All of the multi-item scales and single-item measures ranged in score from 0 to 100. For each domain and item, a linear transformation was applied to standardize the raw score to a range from 0 to 100, with a higher scale score representing a higher response level/ high level of symptomatology / problems. The data is presented as percentage of participants with EORTC QLQ-C30 symptom score achieving clinically significant deterioration on QOL. Participants were considered as deteriorated for a given symptom if the change in score from Baseline was 10 points or higher at any time point after Baseline. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing. The Intent-to-Treat population was used.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Cycle 1 (prior to treatment in Cycle 1)), every 4 weeks during treatment, and 4 weeks after completing treatment or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of participants
    number (not applicable)
        Appetite Loss (N=82, 39)
    59.8
    66.7
        Constipation (N=82, 40)
    43.9
    52.5
        Diarrhea (N=81, 40)
    48.1
    17.5
        Dyspnea (N=82, 40)
    43.9
    47.5
        Insomnia (N=82, 40)
    53.7
    35
        Nausea and Vomiting (N=82, 40)
    46.3
    40
        Pain (N= 82, 40)
    74.4
    65
        Fatigue (N= 82, 40)
    63.4
    67.5
        Financial Difficulties (N= 81, 40)
    34.6
    30
    No statistical analyses for this end point

    Secondary: The Percentage of participants with The European Organization for Research and Treatment of Cancer (EORTC) module QLQ-LC13 (lung cancer 13) Symptom Scores Achieving Clinically Significant Deterioration on QOL

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    End point title
    		 The Percentage of participants with The European Organization for Research and Treatment of Cancer (EORTC) module QLQ-LC13 (lung cancer 13) Symptom Scores Achieving Clinically Significant Deterioration on QOL
    End point description
    The EORTC module QLQ-LC13 symptom score was a self-reporting cancer-specific questionnaire composed of 13 questions incorporated into 1 multi-item scale designed to evaluate dyspnea and a series of single items assessing different types of pain, as well as, cough, hemoptysis, dysphagia, sore mouth, alopecia, and peripheral neuropathy. For each domain and item, a linear transformation was applied to standardize the raw score to a range from 0 to 100, with 100 representing the best possible function/QOL, and highest burden of symptoms for symptom domains and single items. The data is presented as percentage of participants with EORTC module QLQ-C13 symptom score achieving clinically significant deterioration on QOL. Participants were considered as deteriorated for a given symptom if the change in score from Baseline was 10 points or higher at any time point after Baseline. The data presented is based on the data cut-off date of 21 January 2014 while the study is still ongoing.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1 of Cycle 1 (prior to treatment in Cycle 1)), every 4 weeks during treatment, and 4 weeks after completing treatment or up to approximately 2 years (data cut-off date of 21 January 2014)
    End point values
    		 Lenvatinib Lenvatinib matched placebo
    Number of subjects analysed
    89
    46
    Units: Percentage of participants
    number (not applicable)
        Alopecia (Hair Loss) (N= 80, 39)
    16.3
    15.4
        Dysphagia (Trouble Swallowing) (N= 80, 39)
    43.8
    23.1
        Haemoptysis (Coughing Up Blood) (N=80, 39)
    15
    10.3
        How Much Cough (N=80, 39)
    33.8
    28.2
        Medicine For Pain (N=43, 21)
    41.9
    28.6
        Pain In Arm Or Shoulder (N=80, 39)
    55
    43.6
        Pain In Chest (N=80, 39)
    37.5
    28.2
        Pain In Other Parts Of Body (N=79, 39)
    51.9
    38.5
        Peripheral Neuropathy-Tingling Hands/Feet(N=80,39)
    36.3
    41
        Short Of Breath When Climbed Stairs (N=80, 39)
    45
    46.2
        Short Of Breath When Rested (N=80, 39)
    36.3
    41
        Short Of Breath When Walked (N=80, 39)
    45
    51.3
        Sore Mouth Or Tongue (N=80, 39)
    60
    5.1
    No statistical analyses for this end point

    Secondary: Pharmacokinetic (PK) profile of lenvatinib in subjects with Non Small Cell Lung Cancer (NSCLC)

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    End point title
    		 Pharmacokinetic (PK) profile of lenvatinib in subjects with Non Small Cell Lung Cancer (NSCLC)
    End point description
    Blood samples were collected for lenvatinib PK analysis. Lenvatinib concentrations from sparse PK sampling were measured. The data is presented as mean nanograms per milliliter +/- Standard deviation of lenvatinib serum concentration. The analysis was performed using the pharmacokinetic (PK) analysis set defined as all subjects who received at least one dose of study drug and had evaluable PK data.
    End point type
    Secondary
    End point timeframe
    Cycle 1/Day 1 (between 0.5 and 4 hours postdose and 6 and 10 hours postdose), Cycle 1/Day 15 (predose, between 0.5 and 4 hours postdose, and 6 and 10 hours postdose), and Day 1 of Cycles 2 though 4 (predose and between 2 and 12 hours postdose)
    End point values
    		 Phamacokinetic Population
    Number of subjects analysed
    67
    Units: Nanograms per milliliter
    arithmetic mean (standard deviation)
        Cycle 1 Day 1 (0.5 to 4 hours postdose); N=47
    93.4 ( 125.66 )
        Cycle 1 Day 1 (6 to 10 hours postdose); N=46
    229 ( 114.06 )
        Cycle 1 Day 15 (Pre-dose); N=43
    77.8 ( 84.73 )
        Cycle 1 Day 15 (0.5 to 4 hours postdose); N=44
    134.3 ( 119.44 )
        Cycle 1 Day 15 (6 to 10 hours postdose); N=39
    230.7 ( 106.29 )
        Cycle 2 Day 1 (Pre-dose); N=42
    68.6 ( 73.53 )
        Cycle 2 Day 1 (2 to 12 hours postdose); N=41
    260.4 ( 176.26 )
        Cycle 3 Day 1 (Pre-dose); N=34
    53.5 ( 49.2 )
        Cycle 3 Day 1 (2 to 12 hours postdose); N=31
    255.3 ( 173.79 )
        Cycle 4 Day 1 (Pre-dose); N=29
    46.2 ( 34.94 )
        Cycle 4 Day 1 (2 to 12 hours postdose); N=27
    217.7 ( 167.7 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For each participant, from the first dose till 30 days after the last dose or up to approximately 2 years (data cut-off date of 21 January 2014)
    Adverse event reporting additional description
    Treatment emergent adverse events (TEAEs), defined as an AE (serious/non-serious) that started/increased in severity on/after the first dose of study medication up to 30 days after the final dose of study medication are presented in this section.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Lenvatinib
    Reporting group description
    		 Participants received lenvatinib 24 mg orally, once daily continuously in each 28-day treatment cycle.

    Reporting group title
    Lenvatinib matched placebo
    Reporting group description
    		 Participants received lenvatinib matched placebo orally, once daily continuously in each 28-day treatment cycle.

    Serious adverse events
    		 Lenvatinib Lenvatinib matched placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    46 / 89 (51.69%)
    21 / 46 (45.65%)
         number of deaths (all causes)
    59
    38
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    4 / 89 (4.49%)
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 4
    0 / 3
    Chest pain
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Performance status decreased
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    7 / 89 (7.87%)
    4 / 46 (8.70%)
         occurrences causally related to treatment / all
    1 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Haemoptysis
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 89 (3.37%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchial polyp
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Hallucination
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Confusional state
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulseless electrical activity
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Quadriparesis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Skin and subcutaneous tissue disorders
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrotic syndrome
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate antidiuretic hormone secretion
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (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
    Muscular weakness
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 89 (1.12%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    7 / 89 (7.87%)
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 89 (2.25%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 89 (2.25%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 89 (1.12%)
    0 / 46 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cachexia
         subjects affected / exposed
    0 / 89 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lenvatinib Lenvatinib matched placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 89 (93.26%)
    42 / 46 (91.30%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    7 / 89 (7.87%)
    0 / 46 (0.00%)
         occurrences all number
    11
    0
    Weight decreased
         subjects affected / exposed
    13 / 89 (14.61%)
    0 / 46 (0.00%)
         occurrences all number
    14
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    40 / 89 (44.94%)
    4 / 46 (8.70%)
         occurrences all number
    63
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    17 / 89 (19.10%)
    6 / 46 (13.04%)
         occurrences all number
    18
    6
    Lethargy
         subjects affected / exposed
    7 / 89 (7.87%)
    2 / 46 (4.35%)
         occurrences all number
    10
    2
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 46 (0.00%)
         occurrences all number
    6
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    16 / 89 (17.98%)
    1 / 46 (2.17%)
         occurrences all number
    26
    1
    Chest pain
         subjects affected / exposed
    8 / 89 (8.99%)
    6 / 46 (13.04%)
         occurrences all number
    8
    6
    Fatigue
         subjects affected / exposed
    24 / 89 (26.97%)
    8 / 46 (17.39%)
         occurrences all number
    31
    8
    Malaise
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 46 (0.00%)
         occurrences all number
    7
    0
    Mucosal inflammation
         subjects affected / exposed
    5 / 89 (5.62%)
    0 / 46 (0.00%)
         occurrences all number
    5
    0
    Oedema peripheral
         subjects affected / exposed
    9 / 89 (10.11%)
    2 / 46 (4.35%)
         occurrences all number
    12
    3
    Pyrexia
         subjects affected / exposed
    10 / 89 (11.24%)
    4 / 46 (8.70%)
         occurrences all number
    15
    4
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 89 (1.12%)
    3 / 46 (6.52%)
         occurrences all number
    1
    3
    Abdominal pain
         subjects affected / exposed
    15 / 89 (16.85%)
    1 / 46 (2.17%)
         occurrences all number
    18
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 46 (2.17%)
         occurrences all number
    6
    1
    Constipation
         subjects affected / exposed
    17 / 89 (19.10%)
    8 / 46 (17.39%)
         occurrences all number
    19
    8
    Diarrhoea
         subjects affected / exposed
    27 / 89 (30.34%)
    3 / 46 (6.52%)
         occurrences all number
    43
    4
    Dry mouth
         subjects affected / exposed
    7 / 89 (7.87%)
    2 / 46 (4.35%)
         occurrences all number
    7
    2
    Dyspepsia
         subjects affected / exposed
    13 / 89 (14.61%)
    1 / 46 (2.17%)
         occurrences all number
    16
    1
    Nausea
         subjects affected / exposed
    26 / 89 (29.21%)
    6 / 46 (13.04%)
         occurrences all number
    36
    9
    Stomatitis
         subjects affected / exposed
    27 / 89 (30.34%)
    4 / 46 (8.70%)
         occurrences all number
    34
    4
    Vomiting
         subjects affected / exposed
    23 / 89 (25.84%)
    3 / 46 (6.52%)
         occurrences all number
    27
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    16 / 89 (17.98%)
    10 / 46 (21.74%)
         occurrences all number
    21
    12
    Dysphonia
         subjects affected / exposed
    19 / 89 (21.35%)
    0 / 46 (0.00%)
         occurrences all number
    21
    0
    Dyspnoea
         subjects affected / exposed
    16 / 89 (17.98%)
    4 / 46 (8.70%)
         occurrences all number
    18
    4
    Haemoptysis
         subjects affected / exposed
    7 / 89 (7.87%)
    1 / 46 (2.17%)
         occurrences all number
    8
    2
    Oropharyngeal pain
         subjects affected / exposed
    6 / 89 (6.74%)
    1 / 46 (2.17%)
         occurrences all number
    6
    1
    Productive cough
         subjects affected / exposed
    10 / 89 (11.24%)
    4 / 46 (8.70%)
         occurrences all number
    14
    5
    Rhinorrhoea
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 46 (2.17%)
         occurrences all number
    5
    1
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    9 / 89 (10.11%)
    0 / 46 (0.00%)
         occurrences all number
    9
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    14 / 89 (15.73%)
    0 / 46 (0.00%)
         occurrences all number
    21
    0
    Pruritus
         subjects affected / exposed
    9 / 89 (10.11%)
    1 / 46 (2.17%)
         occurrences all number
    11
    1
    Rash
         subjects affected / exposed
    5 / 89 (5.62%)
    2 / 46 (4.35%)
         occurrences all number
    9
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 89 (7.87%)
    3 / 46 (6.52%)
         occurrences all number
    7
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    33 / 89 (37.08%)
    3 / 46 (6.52%)
         occurrences all number
    66
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    17 / 89 (19.10%)
    5 / 46 (10.87%)
         occurrences all number
    23
    5
    Back pain
         subjects affected / exposed
    13 / 89 (14.61%)
    3 / 46 (6.52%)
         occurrences all number
    13
    4
    Muscular weakness
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 46 (2.17%)
         occurrences all number
    6
    1
    Musculoskeletal pain
         subjects affected / exposed
    8 / 89 (8.99%)
    3 / 46 (6.52%)
         occurrences all number
    8
    3
    Myalgia
         subjects affected / exposed
    10 / 89 (11.24%)
    1 / 46 (2.17%)
         occurrences all number
    13
    1
    Pain in extremity
         subjects affected / exposed
    5 / 89 (5.62%)
    1 / 46 (2.17%)
         occurrences all number
    7
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    31 / 89 (34.83%)
    11 / 46 (23.91%)
         occurrences all number
    36
    11

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2011
    • Clarified that in countries where erlotinib was approved and marketed for the treatment of NSCLC, subjects must have received erlotinib treatment for their NSCLC and in countries where crizotinib was approved and marketed, subjects must have received crizotinib treatment for NSCLC that was ALK-positive • PK sampling was added • Provided a new IND number on the face page (changed from 72,010 to 113,533) • New information was provided regarding drug-drug interactions with CYP3A4 inducers and inhibitors • A section on PK and pharmacodynamics was added • Some minor errors and inconsistencies were corrected
    31 Jul 2012
    • Clarified the requirement for prior erlotinib or gefitinib treatment to require prior erlotinib (or gefitinib for subjects outside the US) only for subjects with activating EGFR mutations • Added that subjects with hypertension and/or proteinuria (Grade ≥ 2) must have BP and urine protein tested (i.e., dipstick) every two weeks, or more frequently as clinically indicated • Stipulated that subjects of unknown EGFR status who had not received prior erlotinib (or gefitinib) should be tested for EGFR activating mutations prior to study entry • Clarified that the End of Treatment visit should be within 30 to 37 days after the last dose • Clarified that following dose delays, treatment could be restarted after resolution to Grade 0, Grade 1, or Baseline without waiting until the start of the next cycle. Scheduled assessments should have continued according to the initial cycle schedule (i.e., treatment assessments should not have been delayed following a dose delay) • Clarified that localized palliative radiotherapy was allowed if there was no clinical evidence of disease progression and after discussion with the Medical Monitor • Clarified RECIST language to be consistent with RECIST 1.1 • Some minor errors and inconsistencies were corrected
    16 Jan 2014
    • Updated and expanded the management of hepatotoxicity and thromboembolic events • Stipulated that survival information would continue to be collected after the unblinding of the study in order to further evaluate overall survival

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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