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    Clinical Trial Results:
    Phase II, Multicenter, Open-label, Single Arm Trial to Evaluate the Safety and Efficacy of Oral E7080 in Medullary and Iodine-131 Refractory, Unresectable Differentiated Thyroid Cancers, Stratified by Histology.

    Summary
    EudraCT number
    		 2007-005933-12
    Trial protocol
    		 FR   PL   GB   IT  
    Global end of trial date
    29 Mar 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Apr 2020
    First version publication date
    19 Dec 2018
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    Full Data Set
    Summary report(s)
    		 E7080-G000-201 CSR Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    E7080-G000-201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00784303
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Eisai Inc.
    Sponsor organisation address
    155 Tice Boulevard, Woodcliff Lake, United States, New Jersey 07677
    Public contact
    Eisai Medical Information, Eisai Inc., 1-888 274-2378, esi_oncmedinfo@eisai.com
    Scientific contact
    Eisai Medical Information, Eisai Inc., 1-888 274-2378, esi_oncmedinfo@eisai.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Mar 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In subjects with medullary thyroid cancer [MTC] or radioiodine (131*I) refractory/resistant differentiated thyroid cancer[DTC]: • Determine the effect of E7080 on the objective response rate (ORR) based on Response Evaluation Criteria in Solid Tumors (RECIST) by independent imaging review (IIR).
    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
    06 Nov 2008
    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
    Poland: 20
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Italy: 30
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    United States: 78
    Worldwide total number of subjects
    162
    EEA total number of subjects
    69
    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)
    115
    From 65 to 84 years
    47
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 162 subjects were screened for entry into the study, of which 45 were screening failures and 117 enrolled in the study and were treated.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTC Cohort
    Arm description
    		 Subjects with radioiodine (131 I)-refractory/resistant DTC received 24 milligram (mg) lenvatinib (two 10 mg tablets and one 4 mg tablet) orally, once daily or 10 mg lenvatinib orally twice daily in 28-day treatment cycles. 58 were the total subjects in the DTC cohort: 56 subjects received 24 mg lenvatinib once daily and 2 subjects received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    LENVIMA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily, or 10 mg lenvatinib orally twice daily (20 mg total). 58 were the total subjects in the DTC cohort: 56 subjects received 24 mg lenvatinib once daily and 2 subjects received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.

    Arm title
    		 MTC Cohort
    Arm description
    		 Subjects with MTC received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily continuously in 28-day treatment cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lenvatinib
    Investigational medicinal product code
    E7080
    Other name
    LENVIMA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily given continuously in 28-day treatment cycles.

    Number of subjects in period 1 [1]
    		DTC Cohort MTC Cohort
    Started
    58
    59
    Completed
    58
    59
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects in the Baseline period are those who received the study treatment.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DTC Cohort
    Reporting group description
    		 Subjects with radioiodine (131 I)-refractory/resistant DTC received 24 milligram (mg) lenvatinib (two 10 mg tablets and one 4 mg tablet) orally, once daily or 10 mg lenvatinib orally twice daily in 28-day treatment cycles. 58 were the total subjects in the DTC cohort: 56 subjects received 24 mg lenvatinib once daily and 2 subjects received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.

    Reporting group title
    MTC Cohort
    Reporting group description
    		 Subjects with MTC received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily continuously in 28-day treatment cycles.

    Reporting group values
    		 DTC Cohort MTC Cohort Total
    Number of subjects
    		 58 59 117
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.9 ( 9.49 ) 51.6 ( 14.11 ) -
    Gender categorical
    Units: Subjects
        Female
    		 24 22 46
        Male
    		 34 37 71

    End points

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    End points reporting groups
    Reporting group title
    DTC Cohort
    Reporting group description
    		 Subjects with radioiodine (131 I)-refractory/resistant DTC received 24 milligram (mg) lenvatinib (two 10 mg tablets and one 4 mg tablet) orally, once daily or 10 mg lenvatinib orally twice daily in 28-day treatment cycles. 58 were the total subjects in the DTC cohort: 56 subjects received 24 mg lenvatinib once daily and 2 subjects received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.

    Reporting group title
    MTC Cohort
    Reporting group description
    		 Subjects with MTC received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily continuously in 28-day treatment cycles.

    Primary: ORR

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    End point title
    		 ORR [1]
    End point description
    ORR was the percentage (%) of subjects with best overall response (BOR) of complete response (CR) and partial response (PR) based on modified RECIST 1.0 for target lesions using magnetic resonance imaging/computed tomography (MRI/CT) scans, as determined by IIR. CR was defined as disappearance of all target lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of the longest diameter. ORR (CR+PR), was presented with 2-sided 95% confidence interval (CI) by the method of Clopper and Pearson. The Intent to Treat (ITT) Population included all subjects who received at least one dose of the study drug and was the primary analysis set used for efficacy analyses.
    End point type
    Primary
    End point timeframe
    From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, subject’s choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be analyzed for the end point.
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: Percentage of subjects
        number (confidence interval 90%)
    50.0 (36.6 to 63.4)
    35.6 (23.6 to 49.1)
    No statistical analyses for this end point

    Secondary: Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC)

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    End point title
    		 Plasma Pharmacokinetics (PK): Steady State Area Under the Plasma Concentration Curve (AUC)
    End point description
    Up to 9 samples per subject were obtained at specific time points. Plasma concentrations of lenvatinib were analyzed using standard analysis methods. Due to the sparse PK sampling in this study, the data were pooled with data from other Phase 1 studies conducted in subjects with solid tumors for PK model development and covariate analysis. Individual exposure (steady state AUC) to lenvatinib in MTC and DTC subjects in this study was derived based on the individual predicted steady state AUC from the final PK model. Only data for subjects taking 24 mg lenvatinib daily were reported (subjects taking 20 mg lenvatinib daily were not included in this data set). PK population included all subjects who received the 24 mg daily lenvatinib dose and had concentration values above the limit of quantification and non-missing PK sampling/dose time.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 1 (predose and at 0.5 and 2 hours postdose), Cycle 1 Day 8 (predose), Cycle 2 Day 1 (predose and at 0.5 and 2 hours postdose), and Cycle 3 Day 1 (predose and at 2 hours postdose) (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    47
    56
    Units: nanogram*hour per milliliter (ng·h/mL)
        median (full range (min-max))
    3840 (1610 to 6960)
    3350 (1040 to 6840)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Free Thyroxine (T4)

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    End point title
    		 Change From Baseline in Free Thyroxine (T4)
    End point description
    Blood samples to measure free T4 were collected at Screening (Baseline), Cycle 1 Day 15 (MTC cohort), Day 1 of Cycles 2 to 20, and Final Visit. Changes in free T4 concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. All subjects who received at least 1 dose of study drug. Only subjects with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 1 Day 15 and Cycle 20 Day 1 because no subjects were evaluable at these time points. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: picomole/liter (pmol/L)
    arithmetic mean (standard deviation)
        Cycle 1 Day 15 (n= 0, 1)
    0 ( 0 )
    -3.80 ( 99999 )
        Cycle 2 Day 1 (n= 53, 57)
    -0.46 ( 5.149 )
    -0.86 ( 3.913 )
        Cycle 3 Day 1 (n= 50, 54)
    -0.92 ( 4.985 )
    -1.00 ( 4.028 )
        Cycle 4 Day 1 (n= 48, 50)
    -1.05 ( 5.581 )
    0.34 ( 4.192 )
        Cycle 5 Day 1 (n= 46, 47)
    -1.03 ( 5.563 )
    -0.46 ( 3.878 )
        Cycle 6 Day 1 (n= 43, 45)
    -2.19 ( 5.373 )
    -0.17 ( 4.719 )
        Cycle 7 Day 1 (n= 39, 40)
    -2.32 ( 5.098 )
    -1.07 ( 5.403 )
        Cycle 8 Day 1 (n= 37, 37)
    -1.74 ( 5.504 )
    -1.13 ( 5.691 )
        Cycle 9 Day 1 (n= 30, 37)
    -0.39 ( 5.295 )
    0.52 ( 5.213 )
        Cycle 10 Day 1 (n= 30, 32)
    -0.26 ( 6.397 )
    1.33 ( 6.319 )
        Cycle 11 Day 1 (n= 30, 26)
    -0.27 ( 6.384 )
    0.30 ( 5.551 )
        Cycle 12 Day 1 (n= 30, 21)
    -1.60 ( 6.331 )
    -0.43 ( 5.380 )
        Cycle 13 Day 1 (n= 29, 19)
    -0.09 ( 5.416 )
    0.07 ( 4.347 )
        Cycle 14 Day 1 (n= 27, 14)
    -0.54 ( 5.772 )
    -0.82 ( 6.394 )
        Cycle 15 Day 1 (n= 26, 10)
    0.63 ( 6.703 )
    -1.01 ( 5.505 )
        Cycle 16 Day 1 (n= 24, 9)
    -0.98 ( 7.150 )
    0.60 ( 4.142 )
        Cycle 17 Day 1 (n= 17, 6)
    1.20 ( 7.075 )
    0.45 ( 3.528 )
        Cycle 18 Day 1 (n= 10, 6)
    0.38 ( 4.648 )
    2.17 ( 4.831 )
        Cycle 19 Day 1 (n= 4, 2)
    -0.65 ( 4.042 )
    3.25 ( 4.596 )
        Cycle 20 Day 1 (n= 0, 1)
    0 ( 0 )
    5.20 ( 99999 )
        Final Visit/Study Termination (n= 21, 22)
    -0.36 ( 6.175 )
    1.27 ( 4.584 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Free Thyroid Stimulating Hormone (TSH)

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    End point title
    		 Change From Baseline in Free Thyroid Stimulating Hormone (TSH)
    End point description
    Blood samples to measure free TSH were collected at Screening (Baseline), Cycle 1 Day 15 (MTC cohort), Day 1 of Cycles 2 to 20, and Final Visit. Changes in free TSH concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. For any free TSH result that was reported as <0.008 mIU/L, 0.004 mIU/L was used for calculating summary statistics. All subjects who received at least 1 dose of study drug. For each change from baseline assessment time point, only subjects with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 1 Day 15 and Cycle 20 Day 1 because no subjects were evaluable at these time points. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: Milli international units per litre
    arithmetic mean (standard deviation)
        Cycle 1 Day 15 (n= 0, 1)
    0 ( 0 )
    2.8030 ( 99999 )
        Cycle 2 Day 1 (n= 41, 55)
    0.4779 ( 3.07666 )
    4.1585 ( 7.34946 )
        Cycle 3 Day 1 (n= 38, 52)
    0.5161 ( 2.79122 )
    5.5788 ( 13.76600 )
        Cycle 4 Day 1 (n= 37, 48)
    0.6296 ( 2.29420 )
    2.8751 ( 6.50098 )
        Cycle 5 Day 1 (n= 35, 45)
    0.5024 ( 2.22721 )
    3.7098 ( 6.60386 )
        Cycle 6 Day 1 (n= 32, 44)
    0.8603 ( 3.09079 )
    3.9822 ( 10.65477 )
        Cycle 7 Day 1 (n= 30, 40)
    0.6660 ( 2.08608 )
    8.4308 ( 22.51715 )
        Cycle 8 Day 1 (n= 30, 37)
    0.2118 ( 3.16324 )
    11.4131 ( 32.65896 )
        Cycle 9 Day 1 (n= 25, 37)
    0.1270 ( 3.53020 )
    6.6620 ( 18.89412 )
        Cycle 10 Day 1 (n= 26, 32)
    -0.3277 ( 2.87114 )
    6.1934 ( 17.99762 )
        Cycle 11 Day 1 (n= 25, 26)
    -0.2940 ( 3.28192 )
    2.7928 ( 9.42343 )
        Cycle 12 Day 1 (n= 25, 21)
    0.3500 ( 5.43946 )
    5.1879 ( 14.81415 )
        Cycle 13 Day 1 (n= 25, 19)
    -0.2799 ( 3.31518 )
    2.0983 ( 7.03903 )
        Cycle 14 Day 1 (n= 23, 14)
    -0.6232 ( 3.09954 )
    9.6490 ( 32.48910 )
        Cycle 15 Day 1 (n= 22, 10)
    -0.5911 ( 3.21447 )
    0.9955 ( 4.93549 )
        Cycle 16 Day 1 (n= 20, 9)
    -0.3396 ( 3.68903 )
    0.2971 ( 3.33103 )
        Cycle 17 Day 1 (n= 14, 7)
    -1.0352 ( 3.92286 )
    7.4624 ( 16.18545 )
        Cycle 18 Day 1 (n= 8, 6)
    0.0331 ( 0.24520 )
    4.1232 ( 7.01461 )
        Cycle 19 Day 1 (n= 4, 2)
    0.7805 ( 1.87674 )
    -0.2080 ( 0.29698 )
        Cycle 20 Day 1 (n= 0, 1)
    0 ( 0 )
    0.0000 ( 99999 )
        Final Visit/Study Termination (n= 17, 20)
    1.0281 ( 2.07161 )
    3.4905 ( 7.39625 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only)

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    End point title
    		 Percent Change From Baseline in Concentrations of Thyroglobulin (DTC Only) [2]
    End point description
    Blood samples to obtain serum were collected at Cycle 1 Day 1 (Baseline), Day 1 of Cycles 2 to 19, Final Visit, and were analyzed for thyroglobulin concentration. Percent changes in thyroglobulin concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. All subjects who received at least 1 dose of study drug. For each change from baseline assessment time point, only subjects with both baseline and relevant visit/time point values were included. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 19, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive data was planned to be analyzed for the end point.
    End point values
    		 DTC Cohort
    Number of subjects analysed
    52
    Units: percent change
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n= 47)
    -62.21 ( 39.997 )
        Cycle 3 Day 1 (n= 44)
    -77.80 ( 22.278 )
        Cycle 4 Day 1 (n= 41)
    -79.25 ( 26.639 )
        Cycle 5 Day 1 (n= 40)
    -76.00 ( 25.085 )
        Cycle 6 Day 1 (n= 40)
    -20.36 ( 373.190 )
        Cycle 7 Day 1 (n= 30)
    -73.38 ( 45.489 )
        Cycle 8 Day 1 (n= 29)
    -79.96 ( 27.461 )
        Cycle 9 Day 1 (n= 21)
    -73.98 ( 31.366 )
        Cycle 10 Day 1 (n= 26)
    -78.26 ( 25.524 )
        Cycle 11 Day 1 (n= 28)
    -75.54 ( 37.327 )
        Cycle 12 Day 1 (n= 26)
    -73.51 ( 46.397 )
        Cycle 13 Day 1 (n= 26)
    -74.05 ( 37.091 )
        Cycle 14 Day 1 (n= 24)
    -78.70 ( 17.348 )
        Cycle 15 Day 1 (n= 23)
    -80.28 ( 16.029 )
        Cycle 16 Day 1 (n= 22)
    -76.38 ( 27.736 )
        Cycle 17 Day 1 (n= 15)
    -62.99 ( 38.740 )
        Cycle 18 Day 1 (n= 9)
    -72.67 ( 27.226 )
        Cycle 19 Day 1 (n= 4)
    -50.65 ( 46.900 )
        Final Visit/Study Termination (n= 1)
    -68.60 ( 99999 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Concentrations of Calcitonin (MTC Only)

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    End point title
    		 Percent Change From Baseline in Concentrations of Calcitonin (MTC Only) [3]
    End point description
    Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Day 1 of Cycles 2 to 20, Final Visit, and were analyzed for calcitonin concentration. Percent changes in calcitonin concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. All subjects who received at least 1 dose of study drug. For each change from baseline assessment time point, only subjects with both baseline and relevant visit/time point values were included. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive data was planned to be analyzed for the end point.
    End point values
    		 MTC Cohort
    Number of subjects analysed
    53
    Units: percent change
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n= 51)
    -42.27 ( 38.754 )
        Cycle 3 Day 1 (n= 47)
    -48.11 ( 30.976 )
        Cycle 4 Day 1 (n= 44)
    -44.54 ( 38.794 )
        Cycle 5 Day 1 (n= 40)
    -49.97 ( 34.634 )
        Cycle 6 Day 1 (n= 39)
    -41.73 ( 46.653 )
        Cycle 7 Day 1 (n= 34)
    -38.18 ( 62.721 )
        Cycle 8 Day 1 (n= 33)
    -47.29 ( 46.101 )
        Cycle 9 Day 1 (n= 29)
    -37.52 ( 72.588 )
        Cycle 10 Day 1 (n= 29)
    -39.57 ( 60.118 )
        Cycle 11 Day 1 (n= 24)
    -42.68 ( 61.797 )
        Cycle 12 Day 1 (n= 19)
    -29.25 ( 105.440 )
        Cycle 13 Day 1 (n= 17)
    -36.26 ( 89.612 )
        Cycle 14 Day 1 (n= 12)
    -18.16 ( 148.928 )
        Cycle 15 Day 1 (n= 9)
    -65.26 ( 24.553 )
        Cycle 16 Day 1 (n= 8)
    -64.24 ( 30.394 )
        Cycle 17 Day 1 (n= 7)
    -66.03 ( 23.777 )
        Cycle 18 Day 1 (n= 6)
    -64.57 ( 27.982 )
        Cycle 19 Day 1 (n= 2)
    -44.30 ( 18.668 )
        Cycle 20 Day 1 (n= 1)
    -29.40 ( 99999 )
        Final Visit/Study Termination (n= 4)
    -36.70 ( 28.296 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only)

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    End point title
    		 Percent Change From Baseline in Concentrations of Carcinoembryonic Antigen (CEA) (MTC Only) [4]
    End point description
    Blood samples were collected at Cycle 1 Day 1(Baseline), Day 1 of Cycles 2 to 20, Final Visit, and were analyzed for CEA concentration. Percent changes in CEA concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. All subjects who received at least 1 dose of study drug. For each change from baseline assessment time point, only subjects with both baseline and relevant visit/time point values were included. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Day 1 or within 72 hours prior to Day 1 of Cycles 2 to 20, and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only descriptive data was planned to be analyzed for the end point.
    End point values
    		 MTC Cohort
    Number of subjects analysed
    53
    Units: percent change
    arithmetic mean (standard deviation)
        Cycle 2 Day 1 (n= 54)
    -26.07 ( 45.864 )
        Cycle 3 Day 1 (n= 49)
    -37.68 ( 42.236 )
        Cycle 4 Day 1 (n= 46)
    -41.49 ( 48.035 )
        Cycle 5 Day 1 (n= 42)
    -44.62 ( 42.138 )
        Cycle 6 Day 1 (n= 42)
    -41.91 ( 47.388 )
        Cycle 7 Day 1 (n= 36)
    -41.39 ( 45.677 )
        Cycle 8 Day 1 (n= 34)
    -42.89 ( 47.818 )
        Cycle 9 Day 1 (n= 30)
    -49.31 ( 32.185 )
        Cycle 10 Day 1 (n= 30)
    -47.35 ( 31.621 )
        Cycle 11 Day 1 (n= 25)
    -51.75 ( 29.671 )
        Cycle 12 Day 1 (n= 20)
    -49.91 ( 32.597 )
        Cycle 13 Day 1 (n= 18)
    -46.44 ( 35.967 )
        Cycle 14 Day 1 (n= 13)
    -47.98 ( 38.324 )
        Cycle 15 Day 1 (n= 10)
    -56.62 ( 34.051 )
        Cycle 16 Day 1 (n= 9)
    -59.83 ( 34.762 )
        Cycle 17 Day 1 (n= 7)
    -53.80 ( 37.981 )
        Cycle 18 Day 1 (n= 6)
    -46.00 ( 39.905 )
        Cycle 19 Day 1 (n= 2)
    -45.65 ( 18.738 )
        Cycle 20 Day 1 (n= 1)
    -61.40 ( 99999 )
        Final Visit/Study Termination (n= 4)
    -29.43 ( 31.453 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Concentrations of Cytochrome C (CytoC)

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    End point title
    		 Change From Baseline in Concentrations of Cytochrome C (CytoC)
    End point description
    Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Cycle 1 Day 8, Cycle 2 Days 1,8 &15, Cycles 3 to 9,11,13 Day 1, Final Visit, and analyzed for CytoC concentration. Changes in CytoC concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. For results reported as below quantifiable level (BQL), zero was used for calculating summary statistics. If more than 50% of the results at a visit were BQL, then only ‘n’, ‘minimum’ and ‘maximum’ were calculated for summary statistics. All subjects who received at least 1 dose of study drug. Only subjects with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 2 Day 1, for MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 because no subject was evaluable at these time points. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 8), Cycle 2 (Days 1, 8 and 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11, & 13 (Day 1), and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    52
    54
    Units: picogram/milliliter (pg/mL)
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n= 52, 52)
    155.57 ( 825.091 )
    502.84 ( 2146.291 )
        Cycle 2 Day 1 (n= 0, 1)
    0 ( 0 )
    1679.40 ( 99999 )
        Cycle 2 Day 8 (n= 46, 49)
    -218.45 ( 591.217 )
    374.46 ( 2279.207 )
        Cycle 2 Day 15 (n= 1, 0)
    -215.50 ( 99999 )
    0 ( 0 )
        Cycle 3 Day 1 (n= 44, 47)
    -175.43 ( 435.635 )
    311.85 ( 2363.970 )
        Cycle 4 Day 1 (n= 19, 17)
    1.38 ( 268.354 )
    63.01 ( 1738.149 )
        Cycle 5 Day 1 (n= 15, 13)
    -21.32 ( 85.469 )
    1078.85 ( 3793.235 )
        Cycle 6 Day 1 (n= 14, 10)
    721.58 ( 1234.215 )
    1411.29 ( 3855.502 )
        Cycle 7 Day 1 (n= 10, 7)
    858.05 ( 1383.962 )
    2184.30 ( 4689.181 )
        Cycle 8 Day 1 (n= 10, 5)
    1358.51 ( 1364.706 )
    451.36 ( 254.305 )
        Cycle 9 Day 1 (n= 6, 5)
    1356.40 ( 913.685 )
    459.38 ( 1572.717 )
        Cycle 11 Day 1 (n= 1, 0)
    139.60 ( 99999 )
    0 ( 0 )
        Cycle 13 Day 1 (n= 1, 0)
    129.60 ( 99999 )
    0 ( 0 )
        Final Visit/Study Termination (n= 19, 23)
    249.31 ( 765.148 )
    -45.97 ( 1294.476 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Concentrations of M-30 Neo-Antigen

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    End point title
    		 Change From Baseline in Concentrations of M-30 Neo-Antigen
    End point description
    Blood samples to obtain serum were collected at Cycle 1 Day 1(Baseline), Cycle 1 Day 8, Cycle 2 Days 1,8 &15, Cycles 3 to 9,11,13 Day 1, Final Visit, and analyzed for M-30 concentration. Changes in M-30 concentration values from baseline to specific time points were calculated. Only subjects with both baseline and relevant visit values were included. For results reported as BQL, zero was used for calculating summary statistics. If more than 50% of the results at a visit were BQL, then only ‘n’, ‘minimum’ and ‘maximum’ were calculated for summary statistics. All subjects who received at least 1 dose of study drug. Only subjects with both baseline and relevant visit/time point values were included. Data not reported for DTC cohort at Cycle 2 Day 1, for MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 because no subjects were evaluable at these time points. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 8), Cycle 2 (Days 1, 8 & 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11 & 13 (Day 1) and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    52
    54
    Units: Units per liter (U/L)
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n= 52, 52)
    -5.22 ( 108.639 )
    46.32 ( 197.509 )
        Cycle 2 Day 1 (n= 0, 1)
    0 ( 0 )
    -77.80 ( 99999 )
        Cycle 2 Day 8 (n= 46, 49)
    -26.41 ( 257.723 )
    -49.33 ( 289.525 )
        Cycle 2 Day 15 (n= 1, 0)
    35.30 ( 99999 )
    0 ( 0 )
        Cycle 3 Day 1 (n= 44, 47)
    19.70 ( 296.010 )
    90.21 ( 314.343 )
        Cycle 4 Day 1 (n= 19, 17)
    -7.89 ( 336.124 )
    -97.53 ( 296.832 )
        Cycle 5 Day 1 (n= 15, 13)
    -24.83 ( 397.337 )
    -161.36 ( 265.548 )
        Cycle 6 Day 1 (n= 14, 10)
    -99.30 ( 321.554 )
    -161.30 ( 214.299 )
        Cycle 7 Day 1 (n= 10, 7)
    -168.50 ( 378.071 )
    -52.79 ( 129.671 )
        Cycle 8 Day 1 (n= 10, 5)
    -180.22 ( 386.682 )
    -92.44 ( 57.828 )
        Cycle 9 Day 1 (n= 6, 5)
    -111.92 ( 189.411 )
    -85.22 ( 161.751 )
        Cycle 11 Day 1 (n= 1, 0)
    55.00 ( 99999 )
    0 ( 0 )
        Cycle 13 Day 1 (n= 1, 0)
    -263.50 ( 99999 )
    0 ( 0 )
        Final Visit/Study Termination (n= 19, 23)
    -151.73 ( 322.159 )
    -158.99 ( 355.903 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7)

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    End point title
    		 Change From Baseline in Concentrations of Activated Caspase 3/7 (Casp 3/7)
    End point description
    Blood samples to obtain serum collected at Cycle 1 Day 1(Baseline), Cycle 1 Day 8, Cycle 2 Days 1, 8, 15, Cycles 3 to 9, 11, 13(Day 1), Final Visit, analyzed for Casp 3/7 concentration. Changes in Casp 3/7 concentration values from baseline were calculated. Only subjects with both baseline and relevant visit values were included. Concentrations of Casp 3/7 were BQL for most subjects at most time points. For results reported as BQL, zero used for calculating summary statistics. If >50% of results at visit were BQL, then only ‘n’, ‘minimum’ and ‘maximum’ were calculated for summary statistics. Subjects received at least 1 dose of study drug. Only subjects with both baseline and relevant visit/time point values included. Data not reported for DTC cohort at Cycle 2 Day 1, MTC cohort at Cycle 2 Day 15, Day 1 of Cycle 11 and 13 as no subjects were evaluable at these time points. Here “99999” refers to data not available and, therefore, 99999 is added as a space filler.
    End point type
    Secondary
    End point timeframe
    Cycle 1 (Day 8), Cycle 2 (Days 1, 8, & 15), Cycles 3, 4, 5, 6, 7, 8, 9, 11, & 13 (Day 1) and Final Visit, up to data cutoff date 11 April 2011 (Cycle length= 28 days)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: U/W
    arithmetic mean (standard deviation)
        Cycle 1 Day 8 (n= 50, 52)
    99999 ( 99999 )
    0.0030 ( 0.00610 )
        Cycle 2 Day 1 (n= 0, 1)
    0 ( 0 )
    0.0080 ( 99999 )
        Cycle 2 Day 8 (n= 44, 49)
    99999 ( 99999 )
    0.0039 ( 0.00822 )
        Cycle 2 Day 15 (n= 1, 0)
    0.0110 ( 99999 )
    0 ( 0 )
        Cycle 3 Day 1 (n= 42, 47)
    99999 ( 99999 )
    0.0026 ( 0.00691 )
        Cycle 4 Day 1 (n= 18, 17)
    99999 ( 99999 )
    0.0019 ( 0.00743 )
        Cycle 5 Day 1 (n= 15, 13)
    99999 ( 99999 )
    0.0042 ( 0.00666 )
        Cycle 6 Day 1 (n= 14, 10)
    0.0046 ( 0.00605 )
    99999 ( 99999 )
        Cycle 7 Day 1 (n= 10, 7)
    0.0058 ( 0.00496 )
    0.0044 ( 0.00692 )
        Cycle 8 Day 1 (n= 10, 5)
    0.0078 ( 0.00771 )
    99999 ( 99999 )
        Cycle 9 Day 1 (n= 6, 5)
    0.0067 ( 0.00480 )
    0.0068 ( 0.01329 )
        Cycle 11 Day 1 (n= 1, 0)
    99999 ( 99999 )
    0 ( 0 )
        Cycle 13 Day 1 (n= 1, 0)
    99999 ( 99999 )
    0 ( 0 )
        Final Visit/Study Termination (n= 18, 23)
    99999 ( 99999 )
    99999 ( 99999 )
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR) Assessed as Per IIR

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    End point title
    		 Duration of Response (DoR) Assessed as Per IIR
    End point description
    DoR was based on IIR was the time from date of the first CR or PR until the date of first documentation of disease progression or date of death, if death occurred prior to disease progression, for the subjects who had BOR of CR or PR. Subjects without progressive disease or death were censored at the date of last adequate tumor assessment. DoR= End Date - Date of first CR or PR + 1. ITT population. Subjects who were evaluable for this given measure at a given time point were included for this assessment. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    From date of the first CR or PR until the date of first documentation of disease progression or date of death, assessed up to data cutoff date 11 April 2011
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    29
    21
    Units: Months
        median (confidence interval 95%)
    12.7 (8.8 to 99999)
    99999 (5.7 to 99999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) Assessed as Per IIR

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    End point title
    		 Disease Control Rate (DCR) Assessed as Per IIR
    End point description
    DCR was the percentage of the subjects who had BOR of CR, PR, and stable disease (SD) with the minimum duration of SD lasting greater than or equal to 7 weeks, based on assessments by IIR. DCR = CR+PR+SD greater than or equal to 7 weeks. ITT population. Subjects who were evaluable for this given measure at a given time point were included for this assessment.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, subject’s choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    54
    47
    Units: Percentage of subjects
        number (confidence interval 95%)
    93.1 (83.3 to 98.1)
    79.7 (67.2 to 89.0)
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR) Assessed as Per IIR

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    End point title
    		 Clinical Benefit Rate (CBR) Assessed as Per IIR
    End point description
    CBR was the percentage of the subjects who had BOR of CR, PR, and SD with the minimum duration of SD lasting greater than or equal to 23 weeks, based on assessments by IIR. CBR = CR+PR+SD greater than or equal to 23 weeks. ITT population. Subjects who were evaluable for this given measure at a given time point were included for this assessment.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until disease progression, development of unacceptable toxicity, withdrawal of consent, subject’s choice to stop study treatment, or up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    45
    38
    Units: Percentage of subjects
        number (confidence interval 95%)
    77.6 (64.7 to 87.5)
    64.4 (50.9 to 76.4)
    No statistical analyses for this end point

    Secondary: Time to Response (TTR) Assessed as Per IIR

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    End point title
    		 Time to Response (TTR) Assessed as Per IIR
    End point description
    TTR was defined as “time from start of treatment to the time when a subject first achieves a response of PR/CR” based on assessments by IIR. TTR was only calculated for subjects with confirmed PR or CR. The Efficacy Evaluable Population included all subjects who received at least one dose of the study treatment, had a baseline and at least one posttreatment tumor response evaluation. Subjects who were evaluable for this given measure at a given time point were included for this assessment.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until date of first CR or PR, assessed up to data cutoff date 11 April 2011
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    28
    29
    Units: Months
        number (confidence interval 95%)
    3.6 (1.8 to 3.7)
    3.5 (1.9 to 3.7)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Assessed as Per IIR

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    End point title
    		 Progression Free Survival (PFS) Assessed as Per IIR
    End point description
    PFS was defined as the time from the date of treatment start until progressive disease or death from any cause in the absence of progressive disease. Disease progression was defined as at least a 20% increase in the sum of the longest diameter 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 as assessed by IIR using RECIST 1.0. The duration of PFS was calculated as end date minus date of first drug plus 1, based on assessments by IIR. PFS was calculated using Kaplan-Meier estimate and presented with 2- sided 95% Cl. ITT population. Subjects who were evaluable for this given measure at a given time point were included for this assessment. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until date of progressive disease or death from any cause, assessed up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: Months
        number (confidence interval 95%)
    12.6 (9.9 to 16.1)
    9.0 (7.0 to 99999)
    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 treatment start until death from any cause. The duration of OS was calculated as ‘end date minus date of first drug plus 1’, based on assessments by IIR. Subjects without a reported death or those lost to follow-up were censored at their last known alive date at the database cutoff. OS was calculated using Kaplan-Meier estimate and presented with 2- sided 95% Cl. ITT population. Subjects who were evaluable for this given measure at a given time point were included for this assessment. Here “99999” refers to data not available and, therefore, 99999 is added as a space-filler.
    End point type
    Secondary
    End point timeframe
    From date of treatment start until date of death from any cause, assessed up to data cutoff date 11 April 2011, for up to approximately 2 years 5 months
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: Months
        number (confidence interval 95%)
    27.7 (27.7 to 99999)
    16.6 (16.4 to 99999)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib

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    End point title
    		 Number of Subjects With Non-Serious Adverse Events (AEs) and Serious Adverse Events (SAEs) as a Measure of Safety and Tolerability of Lenvatinib
    End point description
    Safety assessments consisted of monitoring and recording all AEs (serious and non-serious) and SAEs; concomitant medications, regular monitoring of hematology, blood chemistry, and urine values; periodic measurement of vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, New York Heart Association (NYHA) assessments, electrocardiograms (ECGs), echocardiograms; and performance of physical examinations. Safety population included all subjects who received at least 1 dose of study drug and had at least 1 posttreatment safety assessment.
    End point type
    Secondary
    End point timeframe
    For each subject, from the first dose till 30 days after the last dose of study treatment (up to approximately 10 years 4 months)
    End point values
    		 DTC Cohort MTC Cohort
    Number of subjects analysed
    58
    59
    Units: Subjects
    number (not applicable)
        Non-Serious AEs
    58
    59
        SAEs
    32
    42
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For each subject, from the first dose until 30 days after the last dose of study treatment (up to approximately 10 years 4 months)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    DTC Cohort
    Reporting group description
    		 Subjects with radioiodine (131 I)-refractory/resistant DTC received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) orally, once daily or 10 mg lenvatinib orally twice daily in 28-day treatment cycles. 58 were the total subjects in the DTC cohort: 56 subjects received 24 mg lenvatinib once daily and 2 subjects received 10 mg lenvatinib twice daily (total 20 mg daily), given continuously in 28-day treatment cycles.

    Reporting group title
    MTC Cohort
    Reporting group description
    		 Subjects with MTC received 24 mg lenvatinib (two 10 mg tablets and one 4 mg tablet) given orally, once daily continuously in 28-day treatment cycles.

    Serious adverse events
    		 DTC Cohort MTC Cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    32 / 58 (55.17%)
    42 / 59 (71.19%)
         number of deaths (all causes)
    44
    37
         number of deaths resulting from adverse events
    4
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastatic pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oncologic complication
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Paraneoplastic syndrome
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pharyngeal neoplasm
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic stenosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Arterial rupture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 58 (3.45%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    4 / 4
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Local swelling
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Premature menopause
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acquired tracheo-oesophageal fistula
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    3 / 4
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Stridor
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal fistula
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Echocardiogram abnormal
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         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
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (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 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical radiculopathy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polycythaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    2 / 58 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 58 (1.72%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal fistula
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal perforation
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal spasm
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic pseudocyst
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder enlargement
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         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
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (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
    2 / 58 (3.45%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess neck
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Candida sepsis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 58 (1.72%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Implant site infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         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 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periorbital cellulitis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    0 / 58 (0.00%)
    2 / 59 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tuberculosis
         subjects affected / exposed
    1 / 58 (1.72%)
    0 / 59 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 59 (5.08%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcitoninaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DTC Cohort MTC Cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 58 (100.00%)
    59 / 59 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Hypertension
         subjects affected / exposed
    45 / 58 (77.59%)
    31 / 59 (52.54%)
         occurrences all number
    108
    74
    Hypotension
         subjects affected / exposed
    14 / 58 (24.14%)
    10 / 59 (16.95%)
         occurrences all number
    19
    19
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    14 / 58 (24.14%)
    6 / 59 (10.17%)
         occurrences all number
    36
    32
    Chest discomfort
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Chills
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    4
    5
    Fatigue
         subjects affected / exposed
    35 / 58 (60.34%)
    33 / 59 (55.93%)
         occurrences all number
    97
    84
    Influenza like illness
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 59 (10.17%)
         occurrences all number
    4
    8
    Local swelling
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Malaise
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    6
    Mucosal inflammation
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 59 (11.86%)
         occurrences all number
    7
    8
    Oedema peripheral
         subjects affected / exposed
    14 / 58 (24.14%)
    8 / 59 (13.56%)
         occurrences all number
    20
    8
    Pain
         subjects affected / exposed
    6 / 58 (10.34%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    Peripheral swelling
         subjects affected / exposed
    5 / 58 (8.62%)
    4 / 59 (6.78%)
         occurrences all number
    11
    4
    Pyrexia
         subjects affected / exposed
    15 / 58 (25.86%)
    12 / 59 (20.34%)
         occurrences all number
    21
    17
    Temperature intolerance
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    2
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    28 / 58 (48.28%)
    24 / 59 (40.68%)
         occurrences all number
    46
    38
    Dysphonia
         subjects affected / exposed
    25 / 58 (43.10%)
    20 / 59 (33.90%)
         occurrences all number
    39
    38
    Dyspnoea
         subjects affected / exposed
    20 / 58 (34.48%)
    16 / 59 (27.12%)
         occurrences all number
    32
    25
    Epistaxis
         subjects affected / exposed
    18 / 58 (31.03%)
    13 / 59 (22.03%)
         occurrences all number
    28
    21
    Haemoptysis
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 59 (13.56%)
         occurrences all number
    10
    13
    Nasal congestion
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 59 (3.39%)
         occurrences all number
    6
    2
    Nasal dryness
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    16 / 58 (27.59%)
    13 / 59 (22.03%)
         occurrences all number
    35
    25
    Pleural effusion
         subjects affected / exposed
    5 / 58 (8.62%)
    4 / 59 (6.78%)
         occurrences all number
    9
    4
    Productive cough
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 59 (5.08%)
         occurrences all number
    6
    3
    Rhinorrhoea
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 59 (5.08%)
         occurrences all number
    4
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 59 (13.56%)
         occurrences all number
    7
    9
    Confusional state
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Depression
         subjects affected / exposed
    11 / 58 (18.97%)
    5 / 59 (8.47%)
         occurrences all number
    11
    6
    Insomnia
         subjects affected / exposed
    13 / 58 (22.41%)
    7 / 59 (11.86%)
         occurrences all number
    14
    9
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    6 / 58 (10.34%)
    5 / 59 (8.47%)
         occurrences all number
    6
    5
    Alanine aminotransferase increased
         subjects affected / exposed
    7 / 58 (12.07%)
    9 / 59 (15.25%)
         occurrences all number
    17
    21
    Aspartate aminotransferase increased
         subjects affected / exposed
    9 / 58 (15.52%)
    9 / 59 (15.25%)
         occurrences all number
    15
    18
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    5
    12
    Blood bilirubin increased
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 59 (3.39%)
         occurrences all number
    6
    3
    Blood creatinine increased
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 59 (6.78%)
         occurrences all number
    4
    11
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Blood pressure increased
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 59 (6.78%)
         occurrences all number
    9
    4
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    4 / 58 (6.90%)
    13 / 59 (22.03%)
         occurrences all number
    4
    16
    Blood triglycerides increased
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    3
    5
    Blood urea increased
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    9
    2
    Blood urine present
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    5
    7
    Haemoglobin decreased
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    5
    3
    Platelet count decreased
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    7
    3
    Prothrombin time prolonged
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Weight decreased
         subjects affected / exposed
    39 / 58 (67.24%)
    29 / 59 (49.15%)
         occurrences all number
    125
    81
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    7
    Fall
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    5
    Thermal burn
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Bradycardia
         subjects affected / exposed
    5 / 58 (8.62%)
    0 / 59 (0.00%)
         occurrences all number
    6
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Tachycardia
         subjects affected / exposed
    7 / 58 (12.07%)
    7 / 59 (11.86%)
         occurrences all number
    7
    9
    Nervous system disorders
    Burning sensation
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Dizziness
         subjects affected / exposed
    10 / 58 (17.24%)
    13 / 59 (22.03%)
         occurrences all number
    14
    15
    Dysgeusia
         subjects affected / exposed
    12 / 58 (20.69%)
    9 / 59 (15.25%)
         occurrences all number
    14
    13
    Headache
         subjects affected / exposed
    27 / 58 (46.55%)
    27 / 59 (45.76%)
         occurrences all number
    49
    59
    Hyperaesthesia
         subjects affected / exposed
    1 / 58 (1.72%)
    11 / 59 (18.64%)
         occurrences all number
    1
    15
    Hypoaesthesia
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 59 (6.78%)
         occurrences all number
    5
    4
    Paraesthesia
         subjects affected / exposed
    7 / 58 (12.07%)
    1 / 59 (1.69%)
         occurrences all number
    8
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    8
    4
    Sinus headache
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    3
    2
    Somnolence
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    8
    Tremor
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    3
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    9
    Leukopenia
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Lymphadenopathy
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Lymphopenia
         subjects affected / exposed
    2 / 58 (3.45%)
    6 / 59 (10.17%)
         occurrences all number
    3
    6
    Neutropenia
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    7
    3
    Thrombocytopenia
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    3
    8
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    4
    Ear pain
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    5
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Lacrimation increased
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Vision blurred
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Visual impairment
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    4
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    8 / 58 (13.79%)
    2 / 59 (3.39%)
         occurrences all number
    12
    2
    Abdominal pain
         subjects affected / exposed
    20 / 58 (34.48%)
    19 / 59 (32.20%)
         occurrences all number
    31
    38
    Abdominal pain lower
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    2
    5
    Abdominal pain upper
         subjects affected / exposed
    18 / 58 (31.03%)
    18 / 59 (30.51%)
         occurrences all number
    33
    28
    Cheilitis
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    5
    3
    Constipation
         subjects affected / exposed
    16 / 58 (27.59%)
    17 / 59 (28.81%)
         occurrences all number
    23
    37
    Diarrhoea
         subjects affected / exposed
    40 / 58 (68.97%)
    45 / 59 (76.27%)
         occurrences all number
    146
    242
    Dry mouth
         subjects affected / exposed
    21 / 58 (36.21%)
    10 / 59 (16.95%)
         occurrences all number
    25
    11
    Dyspepsia
         subjects affected / exposed
    6 / 58 (10.34%)
    8 / 59 (13.56%)
         occurrences all number
    8
    10
    Dysphagia
         subjects affected / exposed
    14 / 58 (24.14%)
    12 / 59 (20.34%)
         occurrences all number
    17
    16
    Faeces pale
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    6
    0
    Flatulence
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    5
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 58 (8.62%)
    7 / 59 (11.86%)
         occurrences all number
    9
    11
    Gingival bleeding
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    7
    Gingival pain
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 59 (6.78%)
         occurrences all number
    1
    7
    Glossitis
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 59 (1.69%)
         occurrences all number
    5
    1
    Glossodynia
         subjects affected / exposed
    9 / 58 (15.52%)
    12 / 59 (20.34%)
         occurrences all number
    14
    17
    Haematochezia
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    2
    4
    Haemorrhoids
         subjects affected / exposed
    5 / 58 (8.62%)
    2 / 59 (3.39%)
         occurrences all number
    5
    2
    Mouth ulceration
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 59 (8.47%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    30 / 58 (51.72%)
    30 / 59 (50.85%)
         occurrences all number
    70
    82
    Oesophagitis
         subjects affected / exposed
    4 / 58 (6.90%)
    0 / 59 (0.00%)
         occurrences all number
    5
    0
    Oral discomfort
         subjects affected / exposed
    3 / 58 (5.17%)
    8 / 59 (13.56%)
         occurrences all number
    3
    10
    Oral pain
         subjects affected / exposed
    7 / 58 (12.07%)
    8 / 59 (13.56%)
         occurrences all number
    14
    11
    Stomatitis
         subjects affected / exposed
    19 / 58 (32.76%)
    15 / 59 (25.42%)
         occurrences all number
    55
    22
    Tongue disorder
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Toothache
         subjects affected / exposed
    5 / 58 (8.62%)
    6 / 59 (10.17%)
         occurrences all number
    5
    7
    Vomiting
         subjects affected / exposed
    23 / 58 (39.66%)
    25 / 59 (42.37%)
         occurrences all number
    83
    91
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    7 / 58 (12.07%)
    7 / 59 (11.86%)
         occurrences all number
    7
    7
    Blister
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    6
    Dermatitis
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Dermatitis acneiform
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    3
    Dermatitis allergic
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Dry skin
         subjects affected / exposed
    10 / 58 (17.24%)
    11 / 59 (18.64%)
         occurrences all number
    14
    17
    Erythema
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    4
    4
    Exfoliative rash
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    8
    Hair texture abnormal
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    3
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Hyperkeratosis
         subjects affected / exposed
    4 / 58 (6.90%)
    7 / 59 (11.86%)
         occurrences all number
    4
    10
    Night sweats
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    15 / 58 (25.86%)
    15 / 59 (25.42%)
         occurrences all number
    37
    45
    Pruritus
         subjects affected / exposed
    5 / 58 (8.62%)
    5 / 59 (8.47%)
         occurrences all number
    7
    6
    Rash
         subjects affected / exposed
    10 / 58 (17.24%)
    16 / 59 (27.12%)
         occurrences all number
    12
    28
    Rash macular
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Rash papular
         subjects affected / exposed
    3 / 58 (5.17%)
    6 / 59 (10.17%)
         occurrences all number
    3
    7
    Rash pruritic
         subjects affected / exposed
    3 / 58 (5.17%)
    2 / 59 (3.39%)
         occurrences all number
    4
    2
    Skin exfoliation
         subjects affected / exposed
    2 / 58 (3.45%)
    6 / 59 (10.17%)
         occurrences all number
    5
    16
    Skin fissures
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    6
    1
    Skin induration
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    6
    6
    Skin lesion
         subjects affected / exposed
    7 / 58 (12.07%)
    4 / 59 (6.78%)
         occurrences all number
    11
    6
    Skin ulcer
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 59 (1.69%)
         occurrences all number
    5
    2
    Swelling face
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    7
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    3
    3
    Haematuria
         subjects affected / exposed
    5 / 58 (8.62%)
    1 / 59 (1.69%)
         occurrences all number
    7
    2
    Pollakiuria
         subjects affected / exposed
    4 / 58 (6.90%)
    2 / 59 (3.39%)
         occurrences all number
    4
    3
    Proteinuria
         subjects affected / exposed
    41 / 58 (70.69%)
    38 / 59 (64.41%)
         occurrences all number
    195
    160
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Hypothyroidism
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    22 / 58 (37.93%)
    21 / 59 (35.59%)
         occurrences all number
    51
    51
    Arthritis
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Back pain
         subjects affected / exposed
    23 / 58 (39.66%)
    14 / 59 (23.73%)
         occurrences all number
    34
    31
    Bone pain
         subjects affected / exposed
    5 / 58 (8.62%)
    3 / 59 (5.08%)
         occurrences all number
    5
    15
    Joint stiffness
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    3
    4
    Joint swelling
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    3
    Muscle spasms
         subjects affected / exposed
    13 / 58 (22.41%)
    7 / 59 (11.86%)
         occurrences all number
    27
    11
    Muscle tightness
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 59 (6.78%)
         occurrences all number
    1
    5
    Muscular weakness
         subjects affected / exposed
    3 / 58 (5.17%)
    4 / 59 (6.78%)
         occurrences all number
    6
    5
    Musculoskeletal chest pain
         subjects affected / exposed
    14 / 58 (24.14%)
    14 / 59 (23.73%)
         occurrences all number
    14
    19
    Musculoskeletal pain
         subjects affected / exposed
    19 / 58 (32.76%)
    17 / 59 (28.81%)
         occurrences all number
    33
    24
    Musculoskeletal stiffness
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    2
    4
    Myalgia
         subjects affected / exposed
    14 / 58 (24.14%)
    14 / 59 (23.73%)
         occurrences all number
    29
    27
    Neck pain
         subjects affected / exposed
    8 / 58 (13.79%)
    9 / 59 (15.25%)
         occurrences all number
    11
    10
    Pain in extremity
         subjects affected / exposed
    19 / 58 (32.76%)
    17 / 59 (28.81%)
         occurrences all number
    46
    43
    Pain in jaw
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    2
    12
    Periarthritis
         subjects affected / exposed
    3 / 58 (5.17%)
    0 / 59 (0.00%)
         occurrences all number
    4
    0
    Flank pain
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    4
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    2
    5
    Gastroenteritis viral
         subjects affected / exposed
    4 / 58 (6.90%)
    3 / 59 (5.08%)
         occurrences all number
    5
    5
    Gingivitis
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    7
    Influenza
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 59 (11.86%)
         occurrences all number
    10
    9
    Laryngitis
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    4
    Localised infection
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    2
    8
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 58 (0.00%)
    5 / 59 (8.47%)
         occurrences all number
    0
    10
    Nasopharyngitis
         subjects affected / exposed
    2 / 58 (3.45%)
    7 / 59 (11.86%)
         occurrences all number
    3
    21
    Oral candidiasis
         subjects affected / exposed
    0 / 58 (0.00%)
    4 / 59 (6.78%)
         occurrences all number
    0
    5
    Pharyngitis
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    5
    7
    Pneumonia
         subjects affected / exposed
    4 / 58 (6.90%)
    1 / 59 (1.69%)
         occurrences all number
    6
    1
    Rash pustular
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Rhinitis
         subjects affected / exposed
    3 / 58 (5.17%)
    3 / 59 (5.08%)
         occurrences all number
    4
    3
    Sinusitis
         subjects affected / exposed
    3 / 58 (5.17%)
    6 / 59 (10.17%)
         occurrences all number
    5
    12
    Tooth abscess
         subjects affected / exposed
    4 / 58 (6.90%)
    4 / 59 (6.78%)
         occurrences all number
    4
    5
    Upper respiratory tract infection
         subjects affected / exposed
    12 / 58 (20.69%)
    12 / 59 (20.34%)
         occurrences all number
    13
    19
    Urinary tract infection
         subjects affected / exposed
    11 / 58 (18.97%)
    8 / 59 (13.56%)
         occurrences all number
    15
    17
    Vaginal infection
         subjects affected / exposed
    3 / 58 (5.17%)
    1 / 59 (1.69%)
         occurrences all number
    3
    1
    Viral infection
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    4
    Gastroenteritis
         subjects affected / exposed
    2 / 58 (3.45%)
    5 / 59 (8.47%)
         occurrences all number
    2
    5
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    32 / 58 (55.17%)
    32 / 59 (54.24%)
         occurrences all number
    61
    74
    Dehydration
         subjects affected / exposed
    9 / 58 (15.52%)
    6 / 59 (10.17%)
         occurrences all number
    10
    10
    Dyslipidaemia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    3
    3
    Hypercalcaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    4 / 59 (6.78%)
         occurrences all number
    1
    5
    Hypercholesterolaemia
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 59 (3.39%)
         occurrences all number
    15
    5
    Hyperglycaemia
         subjects affected / exposed
    4 / 58 (6.90%)
    6 / 59 (10.17%)
         occurrences all number
    13
    9
    Hyperkalaemia
         subjects affected / exposed
    2 / 58 (3.45%)
    3 / 59 (5.08%)
         occurrences all number
    4
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    6 / 58 (10.34%)
    2 / 59 (3.39%)
         occurrences all number
    22
    2
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 58 (1.72%)
    3 / 59 (5.08%)
         occurrences all number
    1
    5
    Hypocalcaemia
         subjects affected / exposed
    9 / 58 (15.52%)
    12 / 59 (20.34%)
         occurrences all number
    21
    20
    Hypoglycaemia
         subjects affected / exposed
    2 / 58 (3.45%)
    4 / 59 (6.78%)
         occurrences all number
    2
    4
    Hypokalaemia
         subjects affected / exposed
    6 / 58 (10.34%)
    7 / 59 (11.86%)
         occurrences all number
    8
    12
    Hypomagnesaemia
         subjects affected / exposed
    0 / 58 (0.00%)
    3 / 59 (5.08%)
         occurrences all number
    0
    3
    Hyponatraemia
         subjects affected / exposed
    3 / 58 (5.17%)
    5 / 59 (8.47%)
         occurrences all number
    3
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Apr 2009
    Amendment 01: The protocol was amended to remove the dose limiting toxicity component of study and changed to once daily dosing of 24 mg instead of twice daily 10 mg dosing, change the study design to Simon’s optimal two-stage design, which would have allowed for early termination of the study if the response was not sufficient, add simplified electrocardiogram (ECG) monitoring scheme, increased the timing of disease progression window to 12 months from 6 months for inclusion criteria, include proteinuria as a toxicity.
    12 Apr 2010
    Amendment 02: The protocol was amended to clarify that subjects with classical papillary thyroid cancer and minimally or widely invasive follicular thyroid cancer could have been included in the subject population, remove renal function with serum creatinine greater than (>) 1.5 upper limit normal (ULN) as an exclusion criteria, exclude subjects with greater than or equal to (>=) 1 gram (g) per (/)24 hour proteinuria, include a section on reporting overdose of study drug and include the reporting of significant treatment-emergent laboratory abnormalities as adverse events.

    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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