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    Clinical Trial Results:
    A Randomised, Double-Blind, Placebo-Controlled, Multi-Centre Phase III Study to Assess the Efficacy and Safety of Vandetanib (CAPRELSA™) 300 mg in Patients with Differentiated Thyroid Cancer That Is Either Locally Advanced or Metastatic Who Are Refractory or Unsuitable for Radioiodine (RAI) Therapy

    Summary
    EudraCT number
    		 2013-000422-58
    Trial protocol
    		 CZ   SE   IT   ES   DK   FR  
    Global end of trial date
    22 Jan 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2024
    First version publication date
    11 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4203C00011
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01876784
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Genzyme Research and Development
    Sponsor organisation address
    500 Kendall Street, Cambridge, United States, 02142
    Public contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi Aventis Recherche & Développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the efficacy (as assessed by progression free survival [PFS]) of vandetanib when compared to placebo in subjects with differentiated thyroid cancer that was either locally advanced or metastatic who were refractory or unsuitable for radioiodine therapy.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 52
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Czechia: 9
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Italy: 26
    Country: Number of subjects enrolled
    China: 22
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Japan: 40
    Country: Number of subjects enrolled
    United States: 28
    Worldwide total number of subjects
    238
    EEA total number of subjects
    118
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    117
    From 65 to 84 years
    117
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 60 active centers in 12 countries. A total of 299 subjects were screened between 17 September 2013 and 26 September 2014 of which 238 subjects were randomised.

    Pre-assignment
    Screening details
    		 A total of 235 subjects were treated in the study.

    Period 1
    Period 1 title
    Randomized Treatment Period (40 Months)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Assessor, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vandetanib
    Arm description
    		 Subjects received vandetanib 300 mg tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    SAR390530
    Other name
    CAPRELSA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vandetanib 300 mg tablet, orally once daily for up to 40 months.

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo matched to vandetanib tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received placebo matched to vandetanib 300 mg tablet, orally once daily for up to 40 months.

    Number of subjects in period 1
    		Vandetanib Placebo
    Started
    119
    119
    Treated
    117
    118
    Completed
    0
    0
    Not completed
    119
    119
         Other than specified above
    24
    25
         Consent withdrawn by subject
    20
    4
         Disease progression
    43
    81
         Development of study-specific discontinuation
    5
    2
         Death
    1
    -
         Adverse event
    22
    5
         Randomised but not treated
    2
    1
         Lost to follow-up
    1
    1
         Protocol deviation
    1
    -
    Period 2
    Period 2 title
    Open-label Period (31 Months)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Vandetanib/Vandetanib
    Arm description
    		 Subjects who completed the randomised treatment period, were offered the opportunity to continue the same vandetanib treatment in the open label period, if, in the investigator’s opinion, they received benefit and if the subject agreed and provided their informed consent to continue the open-label period for up to additional 31 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    SAR390530
    Other name
    CAPRELSA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vandetanib 300 mg tablet, orally once daily for up to additional 31 months.

    Arm title
    		 Placebo/Vandetanib
    Arm description
    		 Subjects who completed the randomised treatment period, and experienced disease progression were offered the option of treatment in open-label period with vandetanib, if in the investigator’s opinion, such treatment was of clinical benefit to the subject, and if the subject agreed and provided their informed consent to begin open-label vandetanib treatment (i.e., 300 mg tablet, orally once daily for up to 31 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    SAR390530
    Other name
    CAPRELSA
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received vandetanib 300 mg tablet, orally once daily for up to additional 31 months.

    Number of subjects in period 2
    		Vandetanib/Vandetanib Placebo/Vandetanib
    Started
    23
    74
    Completed
    0
    0
    Not completed
    23
    74
         Other than specified above
    9
    18
         Consent withdrawn by subject
    6
    8
         Development of study-specific discontinuation
    1
    5
         Death
    -
    1
         Adverse event
    2
    6
         Progressive disease
    4
    35
         Lost to follow-up
    1
    -
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    		 Subjects received vandetanib 300 mg tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vandetanib tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).

    Reporting group values
    		 Vandetanib Placebo Total
    Number of subjects
    		 119 119 238
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 64.2 ( 9.69 ) 63.2 ( 11.02 ) -
    Gender categorical
    Units: Subjects
        Female
    		 70 64 134
        Male
    		 49 55 104

    End points

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    End points reporting groups
    Reporting group title
    Vandetanib
    Reporting group description
    		 Subjects received vandetanib 300 mg tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo matched to vandetanib tablet, orally once daily until disease progression or death, in randomised treatment period (up to maximum of 40 months).
    Reporting group title
    Vandetanib/Vandetanib
    Reporting group description
    		 Subjects who completed the randomised treatment period, were offered the opportunity to continue the same vandetanib treatment in the open label period, if, in the investigator’s opinion, they received benefit and if the subject agreed and provided their informed consent to continue the open-label period for up to additional 31 months.

    Reporting group title
    Placebo/Vandetanib
    Reporting group description
    		 Subjects who completed the randomised treatment period, and experienced disease progression were offered the option of treatment in open-label period with vandetanib, if in the investigator’s opinion, such treatment was of clinical benefit to the subject, and if the subject agreed and provided their informed consent to begin open-label vandetanib treatment (i.e., 300 mg tablet, orally once daily for up to 31 months).

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    The PFS was defined as the time (in months) from randomisation until the date of first documented disease progression or death (from any cause), whichever came first. Disease progression as per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) was defined as: at least a 20% increase and absolute increase of 5 mm in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Analysis was performed by Kaplan-Meier method. Intent to treat population included all randomised subjects.
    End point type
    Primary
    End point timeframe
    Randomisation until disease progression or death, assessed every 12 weeks (up to 22 months)
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    119
    119
    Units: months
        median (confidence interval 95%)
    10.0 (6.0 to 11.1)
    5.7 (5.5 to 8.4)
    Statistical analysis title
    		 Statistical Analysis for Progression-Free Survival
    Statistical analysis description
    A multiple testing procedure (MTP) with an alpha-exhaustive recycling strategy was employed to provide adequate control of type I error.
    Comparison groups
    Placebo v Vandetanib
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.08 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.75
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 1.03
    Notes
    [1] - Threshold for significance at 0.05 level.

    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 randomisation until death due to any cause. In the absence of observation of death, survival time was censored to last date the subject was known to be alive or at the cut-off date, whichever comes first. Analysis was performed by Kaplan-Meier method. Analysis was performed on intent-to-treat population. Here, “9999” and “99999” were used as space filler which denotes median & 95% CI lower limit respectively were not estimable due to insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From randomisation to the date of death due to any cause (maximum duration: up to 42 months)
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    119
    119
    Units: months
        median (confidence interval 95%)
    9999 (31.6 to 99999)
    9999 (32.1 to 99999)
    No statistical analyses for this end point

    Secondary: Randomised Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36

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    End point title
    		 Randomised Treatment Period: Percent Change From Baseline in Tumor Size (TS) at Week 36
    End point description
    Tumor size was the sum of the longest diameters of the target lesions. Target lesions were measurable tumor lesions. Baseline was defined as the last evaluable assessment prior to starting treatment. Analysis was performed on intent-to-treat population. Here, ‘number of subjects analysed’ = subjects evaluable for this outcome measure.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 36
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    115
    116
    Units: percent change
        arithmetic mean (standard deviation)
    23.29 ( 50.059 )
    21.52 ( 25.428 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects With Objective Response

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    End point title
    		 Percentage of subjects With Objective Response
    End point description
    Objective Response was defined as the percentage (%) of subjects with complete response or partial response. Per RECIST 1.1 criteria, complete response was defined as the disappearance of all target lesions since Baseline. Any pathological lymph nodes selected as target lesions must have a reduction in short axis to less than (<)10 millimeters (mm). Partial response was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the Baseline sum of diameters. Progressive Disease was defined as at least at least a 20% increase and absolute increase of 5 mm in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Analysis was performed on intent-to-treat population. Here, ‘number of subjects analysed’ = subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    From randomisation to the date of first documented tumor progression, or death due to any cause, whichever comes first (maximum duration: up to 42 months)
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    119
    118
    Units: percentage of subjects
        number (not applicable)
    5.0
    0.0
    No statistical analyses for this end point

    Secondary: Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain

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    End point title
    		 Time to Worsening of Pain (TWP) Using Numeric Rating Scale (NRS) of Worst Pain
    End point description
    Time to worsening of pain was defined as the time interval from the date of randomisation to the date of first assessment of worsening of pain with no evidence of improvement within the next 14 days. Subjects rate their worst pain intensity during the past seven days using an 11-point NRS scale, where 0 represents “no pain” and 10 represents “pain as bad as you can imagine.” Higher scores indicated greater pain severity. TWP analysis was performed using Kaplan-Meier method. Analysis was performed on intent-to-treat population.
    End point type
    Secondary
    End point timeframe
    From randomisation to the date of first assessment of worsening of pain (maximum duration: up to 42 months)
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    119
    119
    Units: months
        median (confidence interval 95%)
    5.6 (2.9 to 8.4)
    8.3 (2.8 to 16.6)
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR)

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    End point title
    		 Duration of Response (DOR)
    End point description
    Duration of response was defined as the time from the date of first documented response until the date of documented progression or death. If subjects did not progress following a response, then their DOR used the PFS censoring time. Per RECIST 1.1, progressive disease was defined as at least a 20% increase and absolute increase of 5 mm in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. DOR analysis was performed using Kaplan-Meier method. Analysis was performed on subset of subjects with response. Here, "9999" and "99999" were used as space filler which denotes median & 95% CI upper and lower limit respectively were not estimable due an insufficient number of subjects with events.
    End point type
    Secondary
    End point timeframe
    From the date of first response to the date of first documented tumor progression or death due to any cause whichever comes first (maximum duration: up to 42 months)
    End point values
    		 Vandetanib Placebo
    Number of subjects analysed
    6
    0 [2]
    Units: months
        median (confidence interval 95%)
    99999 (-9999 to 99999)
    ( to )
    Notes
    [2] - ‘0’ signifies that no subject achieved any response, therefore DOR was not analysed.
    No statistical analyses for this end point

    Secondary: Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax)

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    End point title
    		 Randomized Treatment Period: PK Parameters: Maximum Plasma Concentration (Cmax) [3]
    End point description
    Number of participants analyzed= participants with available data for the time points.
    End point type
    Secondary
    End point timeframe
    Post-dose on Week 1 to Week 48
    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: This endpoint is applicable for Vandetanib arm.
    End point values
    		 Vandetanib
    Number of subjects analysed
    98
    Units: nanograms per millilitre
    arithmetic mean (standard deviation)
        Week 1 (n=98)
    695.1 ( 238.94 )
        Week 2 (n=95)
    846.2 ( 288.98 )
        Week 4 (n=93)
    975.7 ( 358.33 )
        Week 8 (n=90)
    1043.1 ( 395.08 )
        Week 12 (n=83)
    1041.9 ( 404.69 )
        Week 24 (n=61)
    1004.9 ( 408.34 )
        Week 36 (n=48)
    904.1 ( 312.51 )
        Week 48 (n=28)
    963.0 ( 452.4 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The data for non-serious adverse events are presented until the Last Participant Last Visit (LPLV) date i.e., 19 June 2017, up to 3 years and 9 months. Serious adverse events were collected until the end of the study, up to 8 years and 4 months.
    Adverse event reporting additional description
    Analysis was performed for safety population. For participants who continued Vandetanib after the LPLV because they still benefited of it per investigator judgment, Serious adverse events were collected as long as they received treatment. No non-serious adverse events were collected after LPLV for open label period of the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Randomized Treatment Period: Vandetanib
    Reporting group description
    		 Subjects received vandetanib 300 mg tablet, orally once daily until disease progression or death, in randomized treatment period (up to maximum of 40 months).

    Reporting group title
    Randomized Treatment Period: Placebo
    Reporting group description
    		 Subjects received placebo matched to vandetanib tablet, orally once daily until disease progression or death, in randomized treatment period (up to maximum of 40 months).

    Reporting group title
    Open-Label Treatment Period: Vandetanib/Vandetanib
    Reporting group description
    		 Subjects who completed the randomised treatment period, were offered the opportunity to continue the same vandetanib treatment in the open label period, if in the investigator’s opinion, they received benefit and if the subject agreed and provided their informed consent to continue the open-label period for up to additional 31 months.

    Reporting group title
    Open-Label Treatment Period: Placebo/Vandetanib
    Reporting group description
    		 Subjects who completed the randomized treatment period, and experienced disease progression were offered the option of treatment in open-label period with vandetanib, if, in the investigator’s opinion, such treatment was of clinical benefit to the subject, and if the subject agreed and provided their informed consent to begin open-label vandetanib treatment i.e., 300 mg tablet, orally once daily for up to 31 months.

    Serious adverse events
    		 Randomized Treatment Period: Vandetanib Randomized Treatment Period: Placebo Open-Label Treatment Period: Vandetanib/Vandetanib Open-Label Treatment Period: Placebo/Vandetanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    37 / 117 (31.62%)
    19 / 118 (16.10%)
    7 / 23 (30.43%)
    24 / 74 (32.43%)
         number of deaths (all causes)
    32
    15
    9
    27
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon Cancer
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Cancer
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma Gastric
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Neoplasm Progression
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Tumour Haemorrhage
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous Cell Carcinoma Of Lung
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Metastases To Spinal Cord
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Varicose Vein
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease Progression
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Impaired Healing
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign Prostatic Hyperplasia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Interstitial Lung Disease
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 117 (0.85%)
    3 / 118 (2.54%)
    0 / 23 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 3
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Respiratory Failure
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin Increased
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip Fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypobarism
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib Fracture
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Haemorrhage
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular Block
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Ventricular Extrasystoles
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ivth Nerve Paresis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar Insufficiency
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 117 (0.85%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone Marrow Failure
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 117 (2.56%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Photosensitivity Reaction
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Henoch-Schonlein Purpura
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis Bullous
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Rash
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stevens-Johnson Syndrome
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Cystitis Noninfective
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrotic Syndrome
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Obstruction
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Inappropriate Antidiuretic Hormone Secretion
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Muscular Weakness
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pathological Fracture
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 117 (3.42%)
    2 / 118 (1.69%)
    1 / 23 (4.35%)
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
    3 / 3
    Lung Infection
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
    Lung Abscess
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post Procedural Infection
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Infection
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 117 (0.00%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized Treatment Period: Vandetanib Randomized Treatment Period: Placebo Open-Label Treatment Period: Vandetanib/Vandetanib Open-Label Treatment Period: Placebo/Vandetanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    111 / 117 (94.87%)
    87 / 118 (73.73%)
    9 / 23 (39.13%)
    62 / 74 (83.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    48 / 117 (41.03%)
    9 / 118 (7.63%)
    0 / 23 (0.00%)
    31 / 74 (41.89%)
         occurrences all number
    53
    9
    0
    35
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    6 / 117 (5.13%)
    10 / 118 (8.47%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    7
    14
    0
    6
    Non-Cardiac Chest Pain
         subjects affected / exposed
    3 / 117 (2.56%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    3
    0
    0
    6
    Fatigue
         subjects affected / exposed
    13 / 117 (11.11%)
    13 / 118 (11.02%)
    1 / 23 (4.35%)
    14 / 74 (18.92%)
         occurrences all number
    14
    13
    1
    14
    Asthenia
         subjects affected / exposed
    21 / 117 (17.95%)
    15 / 118 (12.71%)
    1 / 23 (4.35%)
    7 / 74 (9.46%)
         occurrences all number
    27
    15
    1
    8
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    3 / 117 (2.56%)
    6 / 118 (5.08%)
    0 / 23 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    3
    7
    0
    2
    Dyspnoea
         subjects affected / exposed
    7 / 117 (5.98%)
    10 / 118 (8.47%)
    0 / 23 (0.00%)
    7 / 74 (9.46%)
         occurrences all number
    7
    10
    0
    7
    Dysphonia
         subjects affected / exposed
    3 / 117 (2.56%)
    4 / 118 (3.39%)
    0 / 23 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    3
    4
    0
    5
    Cough
         subjects affected / exposed
    11 / 117 (9.40%)
    12 / 118 (10.17%)
    1 / 23 (4.35%)
    12 / 74 (16.22%)
         occurrences all number
    11
    16
    1
    14
    Haemoptysis
         subjects affected / exposed
    4 / 117 (3.42%)
    8 / 118 (6.78%)
    0 / 23 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    5
    9
    0
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 117 (12.82%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    10 / 74 (13.51%)
         occurrences all number
    15
    2
    0
    11
    Anxiety
         subjects affected / exposed
    6 / 117 (5.13%)
    5 / 118 (4.24%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    6
    5
    0
    4
    Investigations
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    15 / 117 (12.82%)
    4 / 118 (3.39%)
    0 / 23 (0.00%)
    8 / 74 (10.81%)
         occurrences all number
    21
    7
    0
    10
    Alanine Aminotransferase Increased
         subjects affected / exposed
    16 / 117 (13.68%)
    4 / 118 (3.39%)
    0 / 23 (0.00%)
    12 / 74 (16.22%)
         occurrences all number
    23
    6
    0
    13
    Blood Creatinine Increased
         subjects affected / exposed
    7 / 117 (5.98%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    9
    1
    0
    6
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    36 / 117 (30.77%)
    4 / 118 (3.39%)
    1 / 23 (4.35%)
    20 / 74 (27.03%)
         occurrences all number
    55
    6
    1
    36
    Weight Decreased
         subjects affected / exposed
    10 / 117 (8.55%)
    3 / 118 (2.54%)
    0 / 23 (0.00%)
    7 / 74 (9.46%)
         occurrences all number
    11
    4
    0
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 117 (13.68%)
    9 / 118 (7.63%)
    0 / 23 (0.00%)
    7 / 74 (9.46%)
         occurrences all number
    23
    11
    0
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 117 (5.13%)
    6 / 118 (5.08%)
    1 / 23 (4.35%)
    0 / 74 (0.00%)
         occurrences all number
    7
    8
    1
    0
    Eye disorders
    Cornea Verticillata
         subjects affected / exposed
    9 / 117 (7.69%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    4 / 74 (5.41%)
         occurrences all number
    9
    0
    1
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    9 / 117 (7.69%)
    11 / 118 (9.32%)
    2 / 23 (8.70%)
    1 / 74 (1.35%)
         occurrences all number
    11
    13
    2
    1
    Abdominal Pain Upper
         subjects affected / exposed
    6 / 117 (5.13%)
    4 / 118 (3.39%)
    1 / 23 (4.35%)
    6 / 74 (8.11%)
         occurrences all number
    9
    4
    1
    6
    Abdominal Pain
         subjects affected / exposed
    8 / 117 (6.84%)
    8 / 118 (6.78%)
    0 / 23 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    9
    9
    0
    3
    Diarrhoea
         subjects affected / exposed
    77 / 117 (65.81%)
    24 / 118 (20.34%)
    3 / 23 (13.04%)
    39 / 74 (52.70%)
         occurrences all number
    126
    29
    5
    58
    Dry Mouth
         subjects affected / exposed
    6 / 117 (5.13%)
    2 / 118 (1.69%)
    1 / 23 (4.35%)
    4 / 74 (5.41%)
         occurrences all number
    6
    2
    1
    4
    Dyspepsia
         subjects affected / exposed
    6 / 117 (5.13%)
    3 / 118 (2.54%)
    0 / 23 (0.00%)
    2 / 74 (2.70%)
         occurrences all number
    7
    4
    0
    2
    Nausea
         subjects affected / exposed
    22 / 117 (18.80%)
    17 / 118 (14.41%)
    1 / 23 (4.35%)
    16 / 74 (21.62%)
         occurrences all number
    24
    21
    1
    20
    Vomiting
         subjects affected / exposed
    9 / 117 (7.69%)
    12 / 118 (10.17%)
    1 / 23 (4.35%)
    6 / 74 (8.11%)
         occurrences all number
    14
    15
    1
    7
    Stomatitis
         subjects affected / exposed
    6 / 117 (5.13%)
    3 / 118 (2.54%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    6
    3
    0
    4
    Hepatobiliary disorders
    Hepatic Function Abnormal
         subjects affected / exposed
    6 / 117 (5.13%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    7
    0
    0
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 117 (5.13%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    6
    3
    0
    1
    Acne
         subjects affected / exposed
    9 / 117 (7.69%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    9
    2
    0
    6
    Pruritus
         subjects affected / exposed
    6 / 117 (5.13%)
    5 / 118 (4.24%)
    1 / 23 (4.35%)
    6 / 74 (8.11%)
         occurrences all number
    6
    5
    1
    6
    Photosensitivity Reaction
         subjects affected / exposed
    14 / 117 (11.97%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    15
    0
    0
    4
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    6 / 117 (5.13%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    7
    0
    0
    5
    Erythema
         subjects affected / exposed
    5 / 117 (4.27%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    7
    2
    0
    7
    Dry Skin
         subjects affected / exposed
    18 / 117 (15.38%)
    6 / 118 (5.08%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    18
    6
    0
    4
    Dermatitis Acneiform
         subjects affected / exposed
    13 / 117 (11.11%)
    2 / 118 (1.69%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    14
    2
    0
    9
    Rash
         subjects affected / exposed
    36 / 117 (30.77%)
    6 / 118 (5.08%)
    0 / 23 (0.00%)
    19 / 74 (25.68%)
         occurrences all number
    51
    7
    0
    24
    Rash Maculo-Papular
         subjects affected / exposed
    7 / 117 (5.98%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    7
    1
    0
    5
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    8 / 117 (6.84%)
    0 / 118 (0.00%)
    1 / 23 (4.35%)
    5 / 74 (6.76%)
         occurrences all number
    8
    0
    1
    6
    Haematuria
         subjects affected / exposed
    7 / 117 (5.98%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    0 / 74 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    7 / 117 (5.98%)
    5 / 118 (4.24%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    11
    5
    0
    5
    Musculoskeletal Chest Pain
         subjects affected / exposed
    8 / 117 (6.84%)
    9 / 118 (7.63%)
    0 / 23 (0.00%)
    6 / 74 (8.11%)
         occurrences all number
    10
    9
    0
    7
    Back Pain
         subjects affected / exposed
    8 / 117 (6.84%)
    12 / 118 (10.17%)
    2 / 23 (8.70%)
    1 / 74 (1.35%)
         occurrences all number
    9
    14
    2
    1
    Musculoskeletal Pain
         subjects affected / exposed
    0 / 117 (0.00%)
    10 / 118 (8.47%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    0
    11
    0
    4
    Infections and infestations
    Paronychia
         subjects affected / exposed
    3 / 117 (2.56%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    3
    1
    0
    4
    Conjunctivitis
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
    0 / 23 (0.00%)
    5 / 74 (6.76%)
         occurrences all number
    1
    0
    0
    5
    Nasopharyngitis
         subjects affected / exposed
    8 / 117 (6.84%)
    7 / 118 (5.93%)
    0 / 23 (0.00%)
    3 / 74 (4.05%)
         occurrences all number
    10
    9
    0
    3
    Urinary Tract Infection
         subjects affected / exposed
    11 / 117 (9.40%)
    3 / 118 (2.54%)
    0 / 23 (0.00%)
    4 / 74 (5.41%)
         occurrences all number
    16
    4
    0
    5
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 117 (4.27%)
    7 / 118 (5.93%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    5
    8
    0
    2
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    21 / 117 (17.95%)
    2 / 118 (1.69%)
    1 / 23 (4.35%)
    15 / 74 (20.27%)
         occurrences all number
    23
    2
    1
    19
    Hypokalaemia
         subjects affected / exposed
    9 / 117 (7.69%)
    5 / 118 (4.24%)
    0 / 23 (0.00%)
    7 / 74 (9.46%)
         occurrences all number
    11
    5
    0
    11
    Hypomagnesaemia
         subjects affected / exposed
    9 / 117 (7.69%)
    1 / 118 (0.85%)
    0 / 23 (0.00%)
    1 / 74 (1.35%)
         occurrences all number
    19
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    17 / 117 (14.53%)
    3 / 118 (2.54%)
    1 / 23 (4.35%)
    6 / 74 (8.11%)
         occurrences all number
    18
    3
    1
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Jun 2013
    Following changes were made: The inclusion criteria were updated to include patients with follicular DTC (except minimally invasive follicular DTC); clarification was added that subjects who received blinded vandetanib prior to progression required re-consent at central confirmation of progression in order to permit dosing with open-label vandetanib.
    29 Feb 2016
    Following changes were made: The study sponsorship was transferred to Sanofi Genzyme.
    01 Jul 2016
    Following changes were made: The requirement to follow subjects for overall survival until >=50% of subjects had died was lowered to >=25% subjects’ deaths.

    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.
    This study was part of the drug acquisition where model-based PK analysis was not performed by the legacy company. Available PK descriptive statistics have been reported.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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