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    Clinical Trial Results:
    A Randomized, International, Open-Label, Multi-Centre, Phase III Study to Assess the Effect of a Patient Outreach Program on the Percentage of Time Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer Experience Grade 2 or Higher Adverse Events during the First 12 Months of Treatment with Vandetanib

    Summary
    EudraCT number
    		 2010-023428-26
    Trial protocol
    		 DE   BE   IT   AT   GB   SE   FI   GR   DK   PL   NO  
    Global end of trial date
    13 Mar 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2026
    First version publication date
    28 Mar 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D4200C00088
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01298323
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Sanofi-Genzyme Code: LPS14815
    Sponsors
    Sponsor organisation name
    Genzyme Corporation
    Sponsor organisation address
    50 Binney Street, Cambridge, Massachusetts, 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
    13 Mar 2025
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Mar 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate a decrease in the percentage of time patients with locally advanced or metastatic medullary thyroid cancer experience adverse events of Common Terminology Criteria for Adverse Event (CTCAE) grade 2 or higher in the first 12 months of receiving vandetanib with the use of a patient outreach program.
    Protection of trial subjects
    Patients 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 patient and considering the local culture. During the course of the trial, patients were provided with individual patient cards indicating the nature of the trial the patient 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
    25 Feb 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Brazil: 18
    Country: Number of subjects enrolled
    Bulgaria: 2
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    China: 16
    Country: Number of subjects enrolled
    Czechia: 4
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    India: 12
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Italy: 33
    Country: Number of subjects enrolled
    Korea, Republic of: 6
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    205
    EEA total number of subjects
    105
    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)
    161
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From 25 February 2011 to 27 April 2012, 205 patients were randomized by 33 centers in global 20 countries.

    Pre-assignment
    Screening details
    		 217 patients were screened; 205 patients were randomized in a 1:1 ratio to either Vandetanib 300 mg or Vandetanib 300 mg + Outreach Program arm in randomized treatment period for 12 months. Post completion of randomized treatment period, eligible patients entered continuing treatment period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vandetanib 300 mg
    Arm description
    		 Patients received vandetanib (3 x 100 milligram [mg] tablet form) orally, once daily for 12 months in the randomized treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    ZD6474
    Other name
    ZACTIMA™, SAR390530
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib 300 mg oral tablet was administered once daily.

    Arm title
    		 Vandetanib 300 mg + Outreach Program
    Arm description
    		 Patients received vandetanib (3 x 100 mg tablet form) orally, once daily for 12 months in the randomized treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    ZD6474
    Other name
    ZACTIMA™, SAR390530
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib 300 mg oral tablet was administered once daily.

    Number of subjects in period 1
    		Vandetanib 300 mg Vandetanib 300 mg + Outreach Program
    Started
    102
    103
    Completed
    77
    78
    Not completed
    25
    25
         Severe non-compliance to protocol
    1
    -
         Consent withdrawn by subject
    2
    2
         Adverse event, non-fatal
    1
    6
         Condition under investigation worsened
    16
    11
         Unspecified
    4
    6
         Lost to follow-up
    1
    -
    Period 2
    Period 2 title
    Continuing Treatment Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Vandetanib 300 mg
    Arm description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    ZD6474
    Other name
    ZACTIMA™, SAR390530
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib 300 mg oral tablet was administered once daily.

    Arm title
    		 Vandetanib 300 mg + Outreach Program
    Arm description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    ZD6474
    Other name
    ZACTIMA™, SAR390530
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vandetanib 300 mg oral tablet was administered once daily.

    Number of subjects in period 2 [1]
    		Vandetanib 300 mg Vandetanib 300 mg + Outreach Program
    Started
    55
    55
    Completed
    55
    55
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Patients who completed the randomized treatment and continued with vandetanib in the continuing treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vandetanib 300 mg
    Reporting group description
    		 Patients received vandetanib (3 x 100 milligram [mg] tablet form) orally, once daily for 12 months in the randomized treatment period.

    Reporting group title
    Vandetanib 300 mg + Outreach Program
    Reporting group description
    		 Patients received vandetanib (3 x 100 mg tablet form) orally, once daily for 12 months in the randomized treatment period.

    Reporting group values
    		 Vandetanib 300 mg Vandetanib 300 mg + Outreach Program Total
    Number of subjects
    		 102 103 205
    Age categorical
    Units: Subjects
        >=18 - <40 Years
    		 21 23 44
        >=40 - <65 Years
    		 65 52 117
        >=65 - <75 Years
    		 15 22 37
        >=75 Years
    		 1 6 7
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.8 ( 13.47 ) 53.0 ( 14.34 ) -
    Gender categorical
    Units: Subjects
        Female
    		 38 37 75
        Male
    		 64 66 130
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 15 19 34
        White
    		 87 84 171

    End points

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    End points reporting groups
    Reporting group title
    Vandetanib 300 mg
    Reporting group description
    		 Patients received vandetanib (3 x 100 milligram [mg] tablet form) orally, once daily for 12 months in the randomized treatment period.

    Reporting group title
    Vandetanib 300 mg + Outreach Program
    Reporting group description
    		 Patients received vandetanib (3 x 100 mg tablet form) orally, once daily for 12 months in the randomized treatment period.
    Reporting group title
    Vandetanib 300 mg
    Reporting group description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.

    Reporting group title
    Vandetanib 300 mg + Outreach Program
    Reporting group description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.

    Subject analysis set title
    Vandetanib 300 mg + Outreach Program
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients on this arm will be contacted by site personnel at week 1 and then every 2 weeks during the first 52 weeks on the study (or prior discontinuation) to detect and possibly treat adverse events sooner than they might have been without the patient outreach, and at a time of lesser CTCAE grade.

    Subject analysis set title
    Vandetanib 300 mg
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients on this arm will get a standard AE monitoring schedule, similar to that used on previous studies. Patients will be asked about any AEs at scheduled visits and will have the option to contact the investigator at any time if experiencing any AE or symptoms and discuss the best treatment options.

    Primary: Percentage of Time a Patient Experienced at Least 1 AE of CTCAE Grade >=2 in First 12 Months of Receiving Vandetanib in Patients Who Participated in Patient Outreach Program

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    End point title
    		 Percentage of Time a Patient Experienced at Least 1 AE of CTCAE Grade >=2 in First 12 Months of Receiving Vandetanib in Patients Who Participated in Patient Outreach Program
    End point description
    The primary endpoint is the percentage of time a patient experienced at least one AE of CTCAE grade 2 or higher in the first 12 months of treatment with vandetanib. If the patient discontinues treatment with vandetanib prior to the 12-month time point for any reason, this endpoint will be the time a patient experienced at least one AE of CTCAE grade 2 or higher as a percentage of the time the patient was receiving vandetanib. Number of Months Analyzed is the cumulative sum of number of months that all the participants were present in the study.
    End point type
    Primary
    End point timeframe
    12 months
    End point values
    		 Vandetanib 300 mg + Outreach Program Vandetanib 300 mg
    Number of subjects analysed
    102 [1]
    103 [2]
    Units: Percentage of days
        arithmetic mean (standard deviation)
    51.65 ( 35.548 )
    45.19 ( 36.347 )
    Notes
    [1] - Type of Units Analyzed: months= 1513
    [2] - Type of Units Analyzed: months= 1480
    Statistical analysis title
    		 Vandetanib 300mg+Outreach Program,Vandetanib 300mg
    Comparison groups
    Vandetanib 300 mg + Outreach Program v Vandetanib 300 mg
    Number of subjects included in analysis
    205
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.199 [4]
    Method
    		 t-test, 2-sided
    Parameter type
    		 t-Statistic
    Point estimate
    1.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.44
         upper limit
    		 16.37
    Notes
    [3] - Superiority or Other (legacy)
    [4] - Statistical significance threshold at this analysis was 10%.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and all-cause mortality (deaths) were collected from randomization (Day 1) up to end of follow-up for each patient, approximately 168 months. Non-serious AEs were not collected during the continuing treatment period.
    Adverse event reporting additional description
    Analysis was performed on Safety analysis set. Of 103 patients randomized to Vandetanib 300 mg + Outreach arm,all except 1 patient took part in outreach program. This patient was withdrawn due to eligibility criteria failure and could not be contacted successfully. Hence the results have been summarized under Vandetanib 300 mg for safety summaries.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1-25.1
    Reporting groups
    Reporting group title
    Randomized Treatment Period:Vandetanib 300mg+Outreach Program
    Reporting group description
    		 Patients received vandetanib (3 x 100 mg tablet form) orally, once daily for 12 months in the randomized treatment period.

    Reporting group title
    Randomized Treatment Period: Vandetanib 300 mg
    Reporting group description
    		 Patients received vandetanib (3 x 100 mg tablet form) orally, once daily for 12 months in the randomized treatment period.

    Reporting group title
    Continuing Treatment Period:Vandetanib 300mg+Outreach Program
    Reporting group description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.

    Reporting group title
    Continuing Treatment Period: Vandetanib 300 mg
    Reporting group description
    		 After completion of randomized treatment period, eligible patients entered the continuing treatment period and had the option to either permanently discontinue the study or continue taking vandetanib (3 x 100 mg tablet form) orally, once daily unless they met any criteria for discontinuation.

    Serious adverse events
    		 Randomized Treatment Period:Vandetanib 300mg+Outreach Program Randomized Treatment Period: Vandetanib 300 mg Continuing Treatment Period:Vandetanib 300mg+Outreach Program Continuing Treatment Period: Vandetanib 300 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 102 (26.47%)
    31 / 103 (30.10%)
    18 / 55 (32.73%)
    21 / 55 (38.18%)
         number of deaths (all causes)
    16
    11
    7
    7
         number of deaths resulting from adverse events
    4
    2
    5
    7
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant Neoplasm Progression
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Metastasis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Metastases To Bone
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Metastatic Pain
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Prostate Cancer
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Vascular disorders
    Aortic Dissection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 102 (1.96%)
    2 / 103 (1.94%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive Crisis
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Venous Insufficiency
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Ischaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Surgical and medical procedures
    Leg Amputation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Angioplasty
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter Site Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Chest Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 103 (1.94%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 103 (1.94%)
    2 / 55 (3.64%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Disease Progression
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    3 / 55 (5.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    3 / 3
    Sudden Death
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Respiratory, thoracic and mediastinal disorders
    Laryngeal Dyspnoea
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Haemoptysis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Dyspnoea
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    3 / 55 (5.45%)
    2 / 55 (3.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Productive Cough
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Pulmonary Embolism
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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 Failure
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Fear
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Haematocrit Increased
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Joint Dislocation
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Radius Fracture
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Angina Pectoris
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    2 / 102 (1.96%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Coronary Artery Disease
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Myocardial Infarction
         subjects affected / exposed
    2 / 102 (1.96%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid Arteriosclerosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Epilepsy
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Impairment
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Sciatica
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Migraine With Aura
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vocal Cord Paralysis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Sensorimotor Disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Ear and labyrinth disorders
    Deafness Neurosensory
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Abdominal Pain
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Anal Fistula
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Crohn's Disease
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Enteritis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Diarrhoea
         subjects affected / exposed
    3 / 102 (2.94%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric Ulcer
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Ileus Paralytic
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Haematemesis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Intestinal Obstruction
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Jejunal Perforation
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Large Intestinal Ulcer
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Perforation
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Nausea
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Pancreatitis
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 103 (1.94%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Pancreatitis Acute
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toothache
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Cholecystitis Acute
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Skin and subcutaneous tissue disorders
    Dermatitis Acneiform
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Photosensitivity Reaction
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin Necrosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder Disorder
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Glomerulonephritis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Nephrolithiasis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Ectopic Acth Syndrome
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Musculoskeletal and connective tissue disorders
    Muscle Haemorrhage
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Neck Pain
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Pathological Fracture
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Scoliosis
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Infections and infestations
    Enterocolitis Bacterial
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Appendicitis
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Anal Abscess
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Abscess Limb
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Gastroenteritis Caliciviral
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Pneumonia
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 103 (1.94%)
    2 / 55 (3.64%)
    6 / 55 (10.91%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    3 / 3
    Lung Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Herpes Zoster
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Postoperative Wound Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Subcutaneous Abscess
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Pyelonephritis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Pulmonary Tuberculosis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         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
    Urinary Tract Infection
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Tracheobronchitis
         subjects affected / exposed
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    Hypoglycaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    2 / 103 (1.94%)
    0 / 55 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 102 (0.00%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (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
    Hypercalcaemia
         subjects affected / exposed
    1 / 102 (0.98%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 102 (0.98%)
    0 / 103 (0.00%)
    0 / 55 (0.00%)
    0 / 55 (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
    0 / 102 (0.00%)
    0 / 103 (0.00%)
    1 / 55 (1.82%)
    0 / 55 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Randomized Treatment Period:Vandetanib 300mg+Outreach Program Randomized Treatment Period: Vandetanib 300 mg Continuing Treatment Period:Vandetanib 300mg+Outreach Program Continuing Treatment Period: Vandetanib 300 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    96 / 102 (94.12%)
    89 / 103 (86.41%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
    Investigations
    Electrocardiogram Qt Prolonged
         subjects affected / exposed
    9 / 102 (8.82%)
    7 / 103 (6.80%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    13
    12
    0
    0
    Blood Creatinine Increased
         subjects affected / exposed
    5 / 102 (4.90%)
    8 / 103 (7.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    5
    9
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    5 / 102 (4.90%)
    8 / 103 (7.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    6
    8
    0
    0
    Weight Decreased
         subjects affected / exposed
    12 / 102 (11.76%)
    11 / 103 (10.68%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    12
    11
    0
    0
    Alanine Aminotransferase Increased
         subjects affected / exposed
    9 / 102 (8.82%)
    10 / 103 (9.71%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    9
    10
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    35 / 102 (34.31%)
    29 / 103 (28.16%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    40
    33
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 102 (0.00%)
    6 / 103 (5.83%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    0
    6
    0
    0
    Dizziness
         subjects affected / exposed
    7 / 102 (6.86%)
    3 / 103 (2.91%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    8
    4
    0
    0
    Headache
         subjects affected / exposed
    12 / 102 (11.76%)
    8 / 103 (7.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    16
    9
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    18 / 102 (17.65%)
    17 / 103 (16.50%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    19
    17
    0
    0
    Asthenia
         subjects affected / exposed
    12 / 102 (11.76%)
    12 / 103 (11.65%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    14
    13
    0
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    8 / 102 (7.84%)
    5 / 103 (4.85%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    9
    5
    0
    0
    Diarrhoea
         subjects affected / exposed
    55 / 102 (53.92%)
    48 / 103 (46.60%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    85
    63
    0
    0
    Dry Mouth
         subjects affected / exposed
    7 / 102 (6.86%)
    4 / 103 (3.88%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    7
    4
    0
    0
    Nausea
         subjects affected / exposed
    26 / 102 (25.49%)
    18 / 103 (17.48%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    34
    20
    0
    0
    Vomiting
         subjects affected / exposed
    8 / 102 (7.84%)
    11 / 103 (10.68%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    8
    13
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal Pain
         subjects affected / exposed
    6 / 102 (5.88%)
    1 / 103 (0.97%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    7 / 102 (6.86%)
    12 / 103 (11.65%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    8
    12
    0
    0
    Dermatitis Acneiform
         subjects affected / exposed
    22 / 102 (21.57%)
    22 / 103 (21.36%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    24
    23
    0
    0
    Alopecia
         subjects affected / exposed
    2 / 102 (1.96%)
    8 / 103 (7.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    2
    8
    0
    0
    Acne
         subjects affected / exposed
    7 / 102 (6.86%)
    10 / 103 (9.71%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    9
    11
    0
    0
    Photosensitivity Reaction
         subjects affected / exposed
    13 / 102 (12.75%)
    7 / 103 (6.80%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    18
    8
    0
    0
    Rash
         subjects affected / exposed
    26 / 102 (25.49%)
    25 / 103 (24.27%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    28
    31
    0
    0
    Rash Maculo-Papular
         subjects affected / exposed
    4 / 102 (3.92%)
    7 / 103 (6.80%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    7
    0
    0
    Erythema
         subjects affected / exposed
    6 / 102 (5.88%)
    2 / 103 (1.94%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    6
    2
    0
    0
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    5 / 102 (4.90%)
    6 / 103 (5.83%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    5
    6
    0
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    11 / 102 (10.78%)
    8 / 103 (7.77%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    15
    8
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 102 (7.84%)
    9 / 103 (8.74%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    10
    9
    0
    0
    Anxiety
         subjects affected / exposed
    4 / 102 (3.92%)
    7 / 103 (6.80%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    4
    7
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    15 / 102 (14.71%)
    15 / 103 (14.56%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    16
    16
    0
    0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    9 / 102 (8.82%)
    4 / 103 (3.88%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    11
    4
    0
    0
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    13 / 102 (12.75%)
    14 / 103 (13.59%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    14
    18
    0
    0
    Decreased Appetite
         subjects affected / exposed
    13 / 102 (12.75%)
    19 / 103 (18.45%)
    0 / 55 (0.00%)
    0 / 55 (0.00%)
         occurrences all number
    15
    20
    0
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Mar 2011
    Clarified and corrected the management of vandetanib treatment in patients who developed hypertension adverse events of CTCAE grade 4 found in the clinical study protocol (CSP). Investigators that had already recruited patients in the study had been informed about this change and this guideline had been already implemented for patient safety reasons.
    19 Aug 2011
    Number of patients were increased. Dose reduction for patients with moderate renal impairment was added. CSP Appendix E was updated. Administrative changes to ensure the text was consistent or to provide clarification and correct typing errors.
    29 Feb 2016
    Genzyme assumption of responsibility for trial from AstraZeneca in cover page, header, appendices and all sections of the protocol. The Sanofi-Genzyme study code LPS14815 was added. Sections regarding investigational medicinal product and pharmacovigilance were updated to reflect the Genzyme environment. Minor typographical errors or inconsistencies were corrected.

    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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