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    Clinical Trial Results:
    A single arm, open-label, phase II, multicentre study, to assess the safety of vismodegib (GDC-0449) in patient with locally advanced or metastatic basal cell carcinoma (BCC)

    Summary
    EudraCT number
    		 2011-000195-34
    Trial protocol
    		 SE   AT   DE   BG   GB   BE   IT   ES   NL   SI   DK   HU   CZ   GR   SK   IE   PT   PL   NO   LT   FI   EE  
    Global end of trial date

    Results information
    Results version number
    		 v1
    This version publication date
    20 Apr 2016
    First version publication date
    08 Aug 2015
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    MO25616
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01367665
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG , 41 61 6878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline , F. Hoffmann-La Roche AG , 41 61 6878333, global.trial_information@roche.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?
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Results analysis stage
    Analysis stage
    Interim
    Date of interim/final analysis
    06 Nov 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Nov 2013
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This single-arm, open-label, multi-center study will evaluate the safety and efficacy of vismodegib (GDC-0449) in patients with locally advanced or metastatic basal cell carcinoma. Patients will receive oral doses of vismodegib 150 mg once daily until disease progression or unacceptable toxicity.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the “Declaration of Helsinki” and Good Clinical Practice (GCP).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 3
    Country: Number of subjects enrolled
    Austria: 60
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Canada: 25
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 179
    Country: Number of subjects enrolled
    Germany: 55
    Country: Number of subjects enrolled
    Israel: 4
    Country: Number of subjects enrolled
    Italy: 75
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Russian Federation: 5
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 17
    Country: Number of subjects enrolled
    Switzerland: 7
    Country: Number of subjects enrolled
    United Kingdom: 12
    Worldwide total number of subjects
    501
    EEA total number of subjects
    456
    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)
    193
    From 65 to 84 years
    211
    85 years and over
    97

    Subject disposition

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    Recruitment
    Recruitment details
    		 Enrollment at interim analysis Secondary outcomes are not being assessed because it's an interim safety analysis.

    Pre-assignment
    Screening details
    		 Potential participants will undergo the following screening procedures no more than 28 days prior to Day 1, Cycle 1 (unless they have already been conducted during this time period as part of the patient’s routine clinical care)

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Vismodegib - Locally Advanced
    Arm description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator.

    Arm title
    		 Vismodegib - Metastatic
    Arm description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity
    Arm type
    		 Experimental

    Investigational medicinal product name
    Vismodegib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator.

    Number of subjects in period 1
    		Vismodegib - Locally Advanced Vismodegib - Metastatic
    Started
    470
    31
    Completed
    93
    7
    Not completed
    377
    24
         Adverse event, serious fatal
    9
    1
         Consent withdrawn by subject
    60
    2
         Progression of Disease
    55
    15
         Adverse event, non-fatal
    173
    5
         Investigator Request
    13
    1
         Other
    62
    -
         Lost to follow-up
    4
    -
         Not treated
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Vismodegib - Locally Advanced
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Reporting group title
    Vismodegib - Metastatic
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Reporting group values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic Total
    Number of subjects
    		 470 31 501
    Age, Customized
    Units: years
        Adults (18-64 years)
    		 176 17 193
        From 65-84 years
    		 199 12 211
        85 years and over
    		 95 2 97
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69 ± 17.07 64.9 ± 12.86 -
    Gender, Male/Female
    Units: participants
        Female
    		 190 12 202
        Male
    		 280 19 299
    Region of Enrollment
    The numbers of patients enrolled per country is referred to the Interim analysis, not the total number enrolled in the study.
    Units: Subjects
        Russian Federation
    		 4 1 5
        Sweden
    		 16 1 17
        Austria
    		 57 3 60
        Netherlands
    		 5 0 5
        Bulgaria
    		 14 1 15
        France
    		 177 2 179
        United Kingdom
    		 10 2 12
        Switzerland
    		 7 0 7
        Spain
    		 32 2 34
        New Zealand
    		 1 0 1
        Canada
    		 22 3 25
        Belgium
    		 1 2 3
        Denmark
    		 1 0 1
        Italy
    		 69 6 75
        Israel
    		 4 0 4
        Australia
    		 2 1 3
        Germany
    		 48 7 55

    End points

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    End points reporting groups
    Reporting group title
    Vismodegib - Locally Advanced
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Reporting group title
    Vismodegib - Metastatic
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Primary: Percentage of participants who experienced at least 1 adverse event

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    End point title
    		 Percentage of participants who experienced at least 1 adverse event [1]
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to the data cut-off of 06 Nov 2013 (up to 2 years, 6 months)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No additional statistical analyses have been specified for this primary end point.
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    461 [2]
    31 [3]
    Units: percentage of participants
    number (not applicable)
        Any AEs
    98.3
    100
        Any TEAEs
    98.1
    100
        Any TEAEs with maximum severity of Grade 3
    31.8
    51.6
        Any TEAEs with maximum severity of Grade 4
    4.9
    3.2
        Any Serious TEAEs
    20.5
    35.5
        Any drug-related TEAEs
    92.3
    87.1
        Any serious drug-related TEAEs
    6.6
    6.5
        Any TEAEs leading to study drug interruption
    35.4
    45.2
        Any TEAEs leading to study drug discontinuation
    38
    16.1
        Any TEAEs leading to death
    4.1
    6.5
    Notes
    [2] - Safety population: All participants who received at least 1 dose of study medication.
    [3] - Safety population: All participants who received at least 1 dose of study medication.
    No statistical analyses for this end point

    Secondary: Symptoms in metastatic BCC patients: M.D. Anderson Symptom Inventory (MDASI)

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    End point title
    		 Symptoms in metastatic BCC patients: M.D. Anderson Symptom Inventory (MDASI)
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: units
    Notes
    [4] - This is an interim safety analysis, efficacy is not reported at this time.
    [5] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Quality of life: Skindex-16 questionnaire

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    End point title
    		 Quality of life: Skindex-16 questionnaire
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: units
    Notes
    [6] - This is an interim safety analysis, efficacy is not reported at this time.
    [7] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Tumor response rate according to Response Evaluation Criteria in Solid Tumors (RECIST)

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    End point title
    		 Tumor response rate according to Response Evaluation Criteria in Solid Tumors (RECIST)
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: units
    Notes
    [8] - This is an interim safety analysis, efficacy is not reported at this time.
    [9] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Time to response

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    End point title
    		 Time to response
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [10]
    0 [11]
    Units: units
    Notes
    [10] - This is an interim safety analysis, efficacy is not reported at this time.
    [11] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Duration of response

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    End point title
    		 Duration of response
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [12]
    0 [13]
    Units: units
    Notes
    [12] - This is an interim safety analysis, efficacy is not reported at this time.
    [13] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [14]
    0 [15]
    Units: units
    Notes
    [14] - This is an interim safety analysis, efficacy is not reported at this time.
    [15] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Note: This is an interim safety analysis, efficacy is not reported at this time.
    End point type
    Secondary
    End point timeframe
    Until disease progression or unacceptable toxicity (approximately 2 years)
    End point values
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Number of subjects analysed
    0 [16]
    0 [17]
    Units: units
    Notes
    [16] - This is an interim safety analysis, efficacy is not reported at this time.
    [17] - This is an interim safety analysis, efficacy is not reported at this time.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline to the data cut-off of 06 Nov 2013 (up to 2 years, 6 months)
    Adverse event reporting additional description
    Safety population: First 500 patients who received at least 1 dose of study medication and had 1 year follow-up.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Vismodegib - Locally Advanced
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Reporting group title
    Vismodegib - Metastatic
    Reporting group description
    		 Participants received vismodegib 150 mg orally once a day until one of the following occurs: Disease progression, intolerable toxicity most probably attributable to vismodegib, consent withdrawal, death, study termination by the Sponsor, or other reason deemed by the Investigator. vismodegib: 150 mg once daily until disease progression or unacceptable toxicity

    Serious adverse events
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Total subjects affected by serious adverse events
         subjects affected / exposed
    96 / 469 (20.47%)
    11 / 31 (35.48%)
         number of deaths (all causes)
    19
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    BREAST CANCER RECURRENT
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC CANCER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED NEOPLASM
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIP SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM MALIGNANT
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    METASTATIC SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NON−SMALL CELL LUNG CANCER METASTATIC
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PLASMA CELL MYELOMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL ADENOCARCINOMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SQUAMOUS CELL CARCINOMA
         subjects affected / exposed
    4 / 469 (0.85%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SQUAMOUS CELL CARCINOMA OF SKIN
         subjects affected / exposed
    3 / 469 (0.64%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    ARTERIAL HAEMORRHAGE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    7 / 469 (1.49%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    4 / 8
    0 / 0
         deaths causally related to treatment / all
    1 / 3
    0 / 0
    MULTI−ORGAN FAILURE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    TERMINAL STATE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLESTASIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATOTOXICITY
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE PULMONARY OEDEMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISORIENTATION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSAMINASES INCREASED
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    EYEBALL AVULSION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMORAL NECK FRACTURE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FOREIGN BODY
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INCISIONAL HERNIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROCEDURAL INTESTINAL PERFORATION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRAUMATIC HAEMATOMA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC ARREST
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    ATRIOVENTRICULAR BLOCK FIRST DEGREE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CARDIAC FAILURE CONGESTIVE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CARDIO−RESPIRATORY ARREST
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    DILATATION VENTRICULAR
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    4 / 469 (0.85%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    SICK SINUS SYNDROME
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    CONVULSION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    1 / 469 (0.21%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSGEUSIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EMBOLIC STROKE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ISCHAEMIC STROKE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NERVOUS SYSTEM DISORDER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL HERNIA OBSTRUCTIVE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC ULCER HAEMORRHAGE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS EROSIVE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MELAENA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHARYNGO−OESOPHAGEAL DIVERTICULUM
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DERMATITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN ULCER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE CHRONIC
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETHRAL STENOSIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY RETENTION
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL DISORDER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ABSCESS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APPENDICITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL INFECTION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRAIN ABSCESS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CLOSTRIDIUM COLITIS
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYSTITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOCARDITIS BACTERIAL
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENTEROCOCCAL SEPSIS
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS CLOSTRIDIAL
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GROIN ABSCESS
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED SKIN ULCER
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOCALISED INFECTION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    8 / 469 (1.71%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    PYELONEPHRITIS
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SOFT TISSUE INFECTION
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    2 / 469 (0.43%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    CACHEXIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DECREASED APPETITE
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    4 / 469 (0.85%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERKALAEMIA
         subjects affected / exposed
    0 / 469 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    1 / 469 (0.21%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Vismodegib - Locally Advanced Vismodegib - Metastatic
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    442 / 469 (94.24%)
    29 / 31 (93.55%)
    Investigations
    WEIGHT DECREASED
         subjects affected / exposed
    154 / 469 (32.84%)
    8 / 31 (25.81%)
         occurrences all number
    281
    11
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    18 / 469 (3.84%)
    2 / 31 (6.45%)
         occurrences all number
    23
    7
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    17 / 469 (3.62%)
    3 / 31 (9.68%)
         occurrences all number
    21
    7
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    3 / 469 (0.64%)
    3 / 31 (9.68%)
         occurrences all number
    3
    6
    GAMMA−GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    16 / 469 (3.41%)
    4 / 31 (12.90%)
         occurrences all number
    23
    9
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    17 / 469 (3.62%)
    5 / 31 (16.13%)
         occurrences all number
    32
    5
    Nervous system disorders
    AGEUSIA
         subjects affected / exposed
    106 / 469 (22.60%)
    6 / 31 (19.35%)
         occurrences all number
    143
    6
    DIZZINESS
         subjects affected / exposed
    23 / 469 (4.90%)
    2 / 31 (6.45%)
         occurrences all number
    25
    3
    DYSGEUSIA
         subjects affected / exposed
    252 / 469 (53.73%)
    17 / 31 (54.84%)
         occurrences all number
    428
    30
    HEADACHE
         subjects affected / exposed
    32 / 469 (6.82%)
    2 / 31 (6.45%)
         occurrences all number
    37
    3
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    137 / 469 (29.21%)
    3 / 31 (9.68%)
         occurrences all number
    219
    3
    FATIGUE
         subjects affected / exposed
    73 / 469 (15.57%)
    6 / 31 (19.35%)
         occurrences all number
    106
    13
    CHEST DISCOMFORT
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    2
    OEDEMA PERIPHERAL
         subjects affected / exposed
    15 / 469 (3.20%)
    2 / 31 (6.45%)
         occurrences all number
    16
    3
    PAIN
         subjects affected / exposed
    5 / 469 (1.07%)
    2 / 31 (6.45%)
         occurrences all number
    5
    2
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    24 / 469 (5.12%)
    3 / 31 (9.68%)
         occurrences all number
    32
    4
    CONSTIPATION
         subjects affected / exposed
    37 / 469 (7.89%)
    6 / 31 (19.35%)
         occurrences all number
    52
    7
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    32 / 469 (6.82%)
    2 / 31 (6.45%)
         occurrences all number
    40
    4
    DIARRHOEA
         subjects affected / exposed
    80 / 469 (17.06%)
    6 / 31 (19.35%)
         occurrences all number
    99
    16
    NAUSEA
         subjects affected / exposed
    74 / 469 (15.78%)
    5 / 31 (16.13%)
         occurrences all number
    96
    10
    VOMITING
         subjects affected / exposed
    38 / 469 (8.10%)
    1 / 31 (3.23%)
         occurrences all number
    50
    2
    DRY MOUTH
         subjects affected / exposed
    12 / 469 (2.56%)
    2 / 31 (6.45%)
         occurrences all number
    12
    2
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    16 / 469 (3.41%)
    3 / 31 (9.68%)
         occurrences all number
    16
    3
    DYSPNOEA
         subjects affected / exposed
    8 / 469 (1.71%)
    4 / 31 (12.90%)
         occurrences all number
    9
    4
    PRODUCTIVE COUGH
         subjects affected / exposed
    1 / 469 (0.21%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    Skin and subcutaneous tissue disorders
    ALOPECIA
         subjects affected / exposed
    288 / 469 (61.41%)
    17 / 31 (54.84%)
         occurrences all number
    405
    27
    PRURITUS
         subjects affected / exposed
    31 / 469 (6.61%)
    3 / 31 (9.68%)
         occurrences all number
    37
    3
    ACTINIC KERATOSIS
         subjects affected / exposed
    19 / 469 (4.05%)
    3 / 31 (9.68%)
         occurrences all number
    22
    3
    DERMATITIS ACNEIFORM
         subjects affected / exposed
    6 / 469 (1.28%)
    3 / 31 (9.68%)
         occurrences all number
    6
    3
    HYPERKERATOSIS
         subjects affected / exposed
    9 / 469 (1.92%)
    2 / 31 (6.45%)
         occurrences all number
    11
    5
    SKIN EROSION
         subjects affected / exposed
    1 / 469 (0.21%)
    2 / 31 (6.45%)
         occurrences all number
    1
    2
    SKIN ULCER
         subjects affected / exposed
    4 / 469 (0.85%)
    2 / 31 (6.45%)
         occurrences all number
    4
    2
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    10 / 469 (2.13%)
    3 / 31 (9.68%)
         occurrences all number
    12
    3
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    43 / 469 (9.17%)
    2 / 31 (6.45%)
         occurrences all number
    60
    3
    BACK PAIN
         subjects affected / exposed
    23 / 469 (4.90%)
    4 / 31 (12.90%)
         occurrences all number
    26
    4
    MUSCLE SPASMS
         subjects affected / exposed
    299 / 469 (63.75%)
    17 / 31 (54.84%)
         occurrences all number
    654
    44
    SPINAL PAIN
         subjects affected / exposed
    0 / 469 (0.00%)
    2 / 31 (6.45%)
         occurrences all number
    0
    5
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    8 / 469 (1.71%)
    2 / 31 (6.45%)
         occurrences all number
    9
    2
    MYALGIA
         subjects affected / exposed
    34 / 469 (7.25%)
    4 / 31 (12.90%)
         occurrences all number
    49
    6
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    26 / 469 (5.54%)
    4 / 31 (12.90%)
         occurrences all number
    36
    5
    FOLLICULITIS
         subjects affected / exposed
    17 / 469 (3.62%)
    2 / 31 (6.45%)
         occurrences all number
    21
    2
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    120 / 469 (25.59%)
    6 / 31 (19.35%)
         occurrences all number
    170
    6
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    3 / 469 (0.64%)
    2 / 31 (6.45%)
         occurrences all number
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Jan 2009
    Key changes to the protocol included increasing the number of patients to be enrolled from 150 to 550 patients. The length of study was amended to include an end of treatment phase visit when a patient received their last dose of vismodegib and thereafter discontinued vismodegib (regardless of when it occurred), and one Safety Follow-Up Visit 30 days after the last dose of vismodegib
    08 Nov 2012
    Key changes to the protocol included increasing the number of patients to be enrolled from 550 to 800 patients. The length of study was amended to include five safety follow-up visits 1 month, 3 months, 6 months, 9 months and 12 months after the last dose of vismodegib (+/-5 days). Clarification was added regarding use of contraceptive methods during the study. Further details on the frequency of interim analyses and Data Safety Monitoring Board (DSMB) Committee reviews were also added to this version of the protocol.
    08 May 2013
    Key changes to the protocol included increasing the number of patients to be enrolled from 800 to approximately 1200 patients. In addition, this amendment included increased number of interim analyses and increased stringency of contraception requirements. Following a request by the EMA, disease symptoms and tumor tissue of patients with metastatic disease were to be assessed following approval of this version of the protocol.
    03 Oct 2013
    (EU) Key changes to the protocol included extension of enrollment to accrue additional patients with metastatic BCC to allow for an extension of enrollment above the 1200 patients previously planned in order to ensure that 10 − 15 patients with metastatic BCC were evaluated according to Protocol Amendment version 4 (dated 8 May 2013), which included additional assessments for metastatic BCC patients. In addition, post-treatment PK testing in a sub cohort of patients for a period of 12 months to further characterize the PK profile of vismodegib up to 12 months after dosing cessation, and PK testing for patients with persistent vismodegib related AEs (6 months after discontinution of vismodegib) to further assess vismodegib exposure in these patients, were added during this amendment.
    20 Nov 2013
    (Rest of the world) Key changes to the protocol included extension of enrollment to accrue additional patients with metastatic BCC to allow for an extension of enrollment above the 1200 patients previously planned in order to ensure that 10 − 15 patients with metastatic BCC were evaluated according to Protocol Amendment version 4 (dated 8 May 2013), which included additional assessments for metastatic BCC patients. In addition, post-treatment PK testing in a sub cohort of patients for a period of 12 months to further characterize the PK profile of vismodegib up to 12 months after dosing cessation, and PK testing for patients with persistent vismodegib related AEs (6 months after discontinution of vismodegib) to further assess vismodegib exposure in these patients, were added during this amendment.

    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
    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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