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    Clinical Trial Results:
    A phase III randomized sequential open-label study to evaluate the efficacy and safety of sorafenib followed by sunitinib versus sunitinib followed by sorafenib in the treatment of first-line advanced / metastatic renal cell carcinoma

    Summary
    EudraCT number
    		 2008-005011-18
    Trial protocol
    		 NL   DE   AT  
    Global end of trial date
    31 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jan 2017
    First version publication date
    13 Jan 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    09072008-13772
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00732914
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Deutsche Krebsgesellschaft Sponsor GmbH
    Sponsor organisation address
    Staudernheimer Str. 17, Odernheim am Glan, Germany, 55571
    Public contact
    Projektmanagement, Deutsche Krebsgesellschaft Sponsor GmbH, 49 30 322932935, neugebauer@krebsgesellschaft.de
    Scientific contact
    Bereich Klinische Studien, Deutsche Krebsgesellschaft e. V., 49 30 322932935, neugebauer@krebsgesellschaft.de
    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
    03 Apr 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Oct 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary: To evaluate if progression-free survival from randomization to progression or death during second-line therapy (total PFS) of sorafenib followed by sunitinib is at least as effective as sunitinib followed by sorafenib
    Protection of trial subjects
    This study was conducted in compliance with local legal and regulatory requirements and in conformance with Good Clinical Practice standards. All subjects were fully informed about nature, scope and possible consequences of the clinical trial in a language appropriate for the subject.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2009
    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
    Netherlands: 48
    Country: Number of subjects enrolled
    Austria: 29
    Country: Number of subjects enrolled
    Germany: 288
    Worldwide total number of subjects
    365
    EEA total number of subjects
    365
    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)
    182
    From 65 to 84 years
    183
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was performed in 96 centers in three countries (Germany, Austria, Netherlands). A total of 365 patients were enrolled between 19 Feb 2009 and 30 Dec 2011.

    Pre-assignment
    Screening details
    		 The following steps were performed before randomization: check for inclusion/exclusion criteria, contraindications, medical history of the subjects and signing informed consent forms.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Sorafenib followed by sunitinib
    Arm description
    		 In the experimental group (Group A), patients took per oral 400 mg of sorafenib twice daily (BID) until DP (first-line treatment) followed by 50 mg of sunitinib once daily (QD) in cycles of 6 weeks (4 weeks on and 2 weeks off)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nexavar®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (2 x 200 mg tablets) taken twice daily

    Investigational medicinal product name
    Sutent®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Other use
    Dosage and administration details
    50 mg per oral taken daily for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks.

    Arm title
    		 Sunitinib followed by sorafenib
    Arm description
    		 In the control group (Group B), patients took per oral 50 mg of sunitinib QD in cycles of 6 weeks (4 weeks on and 2 weeks off) until DP (first-line treatment) followed by 400 mg of sorafenib BID (second-line treatment)
    Arm type
    		 Control

    Investigational medicinal product name
    Nexavar®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg (2 x 200 mg tablets) taken twice daily

    Investigational medicinal product name
    Sutent®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Other use
    Dosage and administration details
    50 mg per oral taken daily for 4 consecutive weeks, followed by a 2-week rest period (schedule 4/2) to comprise a complete cycle of 6 weeks.

    Number of subjects in period 1
    		Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Started
    182
    183
    Sorafenib treatment
    177
    76
    Sunitinib treatment
    103
    176
    Completed
    0
    0
    Not completed
    182
    183
         Consent withdrawn by subject
    8
    7
         Physician decision
    3
    4
         Study closed, patient stops study medication
    1
    -
         Other reason
    25
    31
         Patient died
    74
    69
         Lost to follow-up
    8
    7
         Screening failure / no randomization
    1
    -
         Reason missing
    62
    65

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Sorafenib followed by sunitinib
    Reporting group description
    		 In the experimental group (Group A), patients took per oral 400 mg of sorafenib twice daily (BID) until DP (first-line treatment) followed by 50 mg of sunitinib once daily (QD) in cycles of 6 weeks (4 weeks on and 2 weeks off)

    Reporting group title
    Sunitinib followed by sorafenib
    Reporting group description
    		 In the control group (Group B), patients took per oral 50 mg of sunitinib QD in cycles of 6 weeks (4 weeks on and 2 weeks off) until DP (first-line treatment) followed by 400 mg of sorafenib BID (second-line treatment)

    Reporting group values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib Total
    Number of subjects
    		 182 183 365
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (39 to 84) 65 (40 to 83) -
    Gender categorical
    Units: Subjects
        Female
    		 43 48 91
        Male
    		 139 135 274
    MSKCC risk score
    Memorial Sloan Kettering Cancer Center
    Units: Subjects
        High
    		 1 1 2
        Intermediate
    		 108 94 202
        Low
    		 71 82 153
        Unknown
    		 2 4 6
        Missing
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Sorafenib followed by sunitinib
    Reporting group description
    		 In the experimental group (Group A), patients took per oral 400 mg of sorafenib twice daily (BID) until DP (first-line treatment) followed by 50 mg of sunitinib once daily (QD) in cycles of 6 weeks (4 weeks on and 2 weeks off)

    Reporting group title
    Sunitinib followed by sorafenib
    Reporting group description
    		 In the control group (Group B), patients took per oral 50 mg of sunitinib QD in cycles of 6 weeks (4 weeks on and 2 weeks off) until DP (first-line treatment) followed by 400 mg of sorafenib BID (second-line treatment)

    Primary: Total Progression-free Survival

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    End point title
    		 Total Progression-free Survival
    End point description
    End point type
    Primary
    End point timeframe
    Progression-free survival from first treatment to progression or death during second-line therapy (total PFS)
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: days
        median (confidence interval 95%)
    379 (298 to 474)
    431 (292 to 524)
    Statistical analysis title
    		 Analysis of Primary Endpoint
    Statistical analysis description
    The primary endpoint is to evaluate if total PFS of sorafenib followed by sunitinib is superior compared to sunitinib followed by sorafenib. A Comparison between the two treatment groups was performed on basis of Kaplan-Meier estimates.
    Comparison groups
    Sorafenib followed by sunitinib v Sunitinib followed by sorafenib
    Number of subjects included in analysis
    353
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5398
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.014
    Confidence interval
         level
    		 95%
         sides
    1-sided
         lower limit
    		 -
         upper limit
    		 1.266

    Secondary: Total Time to Progression (TTP)

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    End point title
    		 Total Time to Progression (TTP)
    End point description
    End point type
    Secondary
    End point timeframe
    Time from first treatment to progression during second-line therapy (total time to progression [TTP])
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    182
    183
    Units: days
    455
    521
    No statistical analyses for this end point

    Secondary: Time to First-line Treatment Failure

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    End point title
    		 Time to First-line Treatment Failure
    End point description
    End point type
    Secondary
    End point timeframe
    Time to first-line treatment failure (progression, death, discontinuation due to toxicity) descriptively in each group
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: days
    181
    267
    No statistical analyses for this end point

    Secondary: PFS in First-line Treatment

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    End point title
    		 PFS in First-line Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Progression-free survival in first-line treatment
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: days
    174
    266
    No statistical analyses for this end point

    Secondary: PFS in Second-line Treatment

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    End point title
    		 PFS in Second-line Treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Progression-free survival in second-line treatment
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: days
    164
    85
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall survival, descriptively (data cut-off same as for primary endpoint)
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: days
    959
    907
    No statistical analyses for this end point

    Secondary: Response Rates and Disease Control Rate - First-line treatment

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    End point title
    		 Response Rates and Disease Control Rate - First-line treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Disease control rate (DCR); Response rates in first-line treatment (complete response (CR), partial response (PR), stable disease (SD) according to RECIST)
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: percent
    number (not applicable)
        Complete Response (CR)
    0.028
    0.034
        Partial Response (PR)
    0.282
    0.256
        Stable Disease (SD)
    0.384
    0.347
        Disease Control Rate (CDR)
    0.695
    0.636
    No statistical analyses for this end point

    Secondary: Response Rates and Disease Control Rate - Second-line treatment

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    End point title
    		 Response Rates and Disease Control Rate - Second-line treatment
    End point description
    End point type
    Secondary
    End point timeframe
    Disease control rate (DCR); Response rates in second-line treatment (complete response (CR), partial response (PR), stable disease (SD) according to RECIST)
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    103
    76
    Units: percent
    number (not applicable)
        Complete Response (CR)
    0.01
    0.013
        Partial Response (PR)
    0.165
    0.053
        Stable Disease (SD)
    0.311
    0.25
        Disease Control Rate (DCR)
    0.485
    0.316
    No statistical analyses for this end point

    Secondary: Response Rates and Disease Control Rate - Overall

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    End point title
    		 Response Rates and Disease Control Rate - Overall
    End point description
    End point type
    Secondary
    End point timeframe
    Disease control rate (DCR); Response rates overall (complete response (CR), partial response (PR), stable disease (SD) according to RECIST)
    End point values
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Number of subjects analysed
    177
    176
    Units: percent
    number (not applicable)
        Complete Response (CR)
    0.034
    0.04
        Partial Response (PR)
    0.328
    0.267
        Stable Disease (SD)
    0.356
    0.364
        Disease Control Rate (DCR)
    0.718
    0.67
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    On treatment and post treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Sorafenib followed by sunitinib
    Reporting group description
    		 In the experimental group (Group A), patients took per oral 400 mg of sorafenib twice daily (BID) until DP (first-line treatment) followed by 50 mg of sunitinib once daily (QD) in cycles of 6 weeks (4 weeks on and 2 weeks off)

    Reporting group title
    Sunitinib followed by sorafenib
    Reporting group description
    		 In the control group (Group B), patients took per oral 50 mg of sunitinib QD in cycles of 6 weeks (4 weeks on and 2 weeks off) until DP (first-line treatment) followed by 400 mg of sorafenib BID (second-line treatment)

    Serious adverse events
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    111 / 177 (62.71%)
    93 / 176 (52.84%)
         number of deaths (all causes)
    17
    26
         number of deaths resulting from adverse events
    2
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    3 / 177 (1.69%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Metastases to meninges
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hair follicle tumour benign
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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
    2 / 177 (1.13%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Tumour haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Basal cell carcinoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour necrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to bone
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign pancreatic neoplasm
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac myxoma
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 177 (2.26%)
    6 / 176 (3.41%)
         occurrences causally related to treatment / all
    3 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Knee arthroplasty
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stent insertion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracotomy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoadjuvant therapy
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour excision
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Central venous catheterisation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenectomy
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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
    Chest pain
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    2 / 177 (1.13%)
    13 / 176 (7.39%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    0 / 11
    Pyrexia
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    7 / 177 (3.95%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    2 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    3 / 177 (1.69%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Death
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Spinal pain
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriogram coronary
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Imaging procedure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament sprain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic haematoma
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (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
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 177 (0.00%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 177 (0.56%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrospinal fluid leakage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiplegia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Thalamic infarction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Monoparesis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebellar haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Guillain-Barre syndrome
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic vein thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Visual impairment
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyphaema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Papilloedema
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Melaena
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 177 (1.69%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 177 (1.13%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 176 (1.14%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal haemorrhagic
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    3 / 177 (1.69%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatitis allergic
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug eruption
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Prerenal failure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    3 / 177 (1.69%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary retention
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Toxic nodular goitre
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pathological fracture
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteolysis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pyelonephritis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 177 (5.08%)
    7 / 176 (3.98%)
         occurrences causally related to treatment / all
    2 / 9
    1 / 7
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Anal abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periumbilical abscess
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intertrigo
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Serratia infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 176 (1.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastroenteritis
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diverticulitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess jaw
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (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
    Dehydration
         subjects affected / exposed
    1 / 177 (0.56%)
    4 / 176 (2.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 176 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 176 (0.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Sorafenib followed by sunitinib Sunitinib followed by sorafenib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    172 / 177 (97.18%)
    172 / 176 (97.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    65 / 177 (36.72%)
    64 / 176 (36.36%)
         occurrences all number
    83
    73
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    9 / 177 (5.08%)
    6 / 176 (3.41%)
         occurrences all number
    9
    7
    Asthenia
         subjects affected / exposed
    11 / 177 (6.21%)
    8 / 176 (4.55%)
         occurrences all number
    12
    9
    Disease progression
         subjects affected / exposed
    2 / 177 (1.13%)
    15 / 176 (8.52%)
         occurrences all number
    3
    15
    Fatigue
         subjects affected / exposed
    71 / 177 (40.11%)
    77 / 176 (43.75%)
         occurrences all number
    110
    107
    General physical health deterioration
         subjects affected / exposed
    13 / 177 (7.34%)
    13 / 176 (7.39%)
         occurrences all number
    21
    17
    Mucosal inflammation
         subjects affected / exposed
    21 / 177 (11.86%)
    34 / 176 (19.32%)
         occurrences all number
    28
    48
    Oedema
         subjects affected / exposed
    9 / 177 (5.08%)
    10 / 176 (5.68%)
         occurrences all number
    11
    17
    Oedema peripheral
         subjects affected / exposed
    14 / 177 (7.91%)
    8 / 176 (4.55%)
         occurrences all number
    20
    14
    Pain
         subjects affected / exposed
    42 / 177 (23.73%)
    27 / 176 (15.34%)
         occurrences all number
    51
    38
    Pyrexia
         subjects affected / exposed
    24 / 177 (13.56%)
    15 / 176 (8.52%)
         occurrences all number
    27
    15
    Unevaluable event
         subjects affected / exposed
    9 / 177 (5.08%)
    11 / 176 (6.25%)
         occurrences all number
    17
    17
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    19 / 177 (10.73%)
    24 / 176 (13.64%)
         occurrences all number
    21
    29
    Dysphonia
         subjects affected / exposed
    19 / 177 (10.73%)
    10 / 176 (5.68%)
         occurrences all number
    22
    12
    Dyspnoea
         subjects affected / exposed
    20 / 177 (11.30%)
    25 / 176 (14.20%)
         occurrences all number
    23
    34
    Epistaxis
         subjects affected / exposed
    15 / 177 (8.47%)
    20 / 176 (11.36%)
         occurrences all number
    19
    24
    Psychiatric disorders
    Depression
         subjects affected / exposed
    9 / 177 (5.08%)
    9 / 176 (5.11%)
         occurrences all number
    12
    9
    Insomnia
         subjects affected / exposed
    9 / 177 (5.08%)
    14 / 176 (7.95%)
         occurrences all number
    11
    14
    Investigations
    Weight decreased
         subjects affected / exposed
    28 / 177 (15.82%)
    21 / 176 (11.93%)
         occurrences all number
    31
    23
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    15 / 177 (8.47%)
    13 / 176 (7.39%)
         occurrences all number
    18
    16
    Dysgeusia
         subjects affected / exposed
    24 / 177 (13.56%)
    41 / 176 (23.30%)
         occurrences all number
    35
    57
    Headache
         subjects affected / exposed
    20 / 177 (11.30%)
    26 / 176 (14.77%)
         occurrences all number
    33
    34
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 177 (9.60%)
    8 / 176 (4.55%)
         occurrences all number
    22
    19
    Leukopenia
         subjects affected / exposed
    2 / 177 (1.13%)
    10 / 176 (5.68%)
         occurrences all number
    27
    14
    Thrombocytopenia
         subjects affected / exposed
    3 / 177 (1.69%)
    11 / 176 (6.25%)
         occurrences all number
    7
    23
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 177 (7.34%)
    13 / 176 (7.39%)
         occurrences all number
    19
    16
    Abdominal pain upper
         subjects affected / exposed
    11 / 177 (6.21%)
    11 / 176 (6.25%)
         occurrences all number
    11
    15
    Constipation
         subjects affected / exposed
    23 / 177 (12.99%)
    19 / 176 (10.80%)
         occurrences all number
    31
    21
    Diarrhoea
         subjects affected / exposed
    101 / 177 (57.06%)
    84 / 176 (47.73%)
         occurrences all number
    220
    179
    Dry mouth
         subjects affected / exposed
    4 / 177 (2.26%)
    12 / 176 (6.82%)
         occurrences all number
    4
    13
    Dyspepsia
         subjects affected / exposed
    21 / 177 (11.86%)
    31 / 176 (17.61%)
         occurrences all number
    29
    41
    Nausea
         subjects affected / exposed
    50 / 177 (28.25%)
    57 / 176 (32.39%)
         occurrences all number
    83
    76
    Stomatitis
         subjects affected / exposed
    23 / 177 (12.99%)
    38 / 176 (21.59%)
         occurrences all number
    39
    58
    Vomiting
         subjects affected / exposed
    26 / 177 (14.69%)
    38 / 176 (21.59%)
         occurrences all number
    46
    56
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    1 / 177 (0.56%)
    9 / 176 (5.11%)
         occurrences all number
    1
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    57 / 177 (32.20%)
    13 / 176 (7.39%)
         occurrences all number
    67
    14
    Dry skin
         subjects affected / exposed
    21 / 177 (11.86%)
    16 / 176 (9.09%)
         occurrences all number
    22
    17
    Erythema
         subjects affected / exposed
    19 / 177 (10.73%)
    10 / 176 (5.68%)
         occurrences all number
    20
    11
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    70 / 177 (39.55%)
    49 / 176 (27.84%)
         occurrences all number
    124
    95
    Pruritus
         subjects affected / exposed
    23 / 177 (12.99%)
    19 / 176 (10.80%)
         occurrences all number
    45
    19
    Rash
         subjects affected / exposed
    54 / 177 (30.51%)
    22 / 176 (12.50%)
         occurrences all number
    71
    30
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    13 / 177 (7.34%)
    18 / 176 (10.23%)
         occurrences all number
    13
    19
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    21 / 177 (11.86%)
    15 / 176 (8.52%)
         occurrences all number
    28
    20
    Back pain
         subjects affected / exposed
    16 / 177 (9.04%)
    17 / 176 (9.66%)
         occurrences all number
    17
    21
    Muscle spasms
         subjects affected / exposed
    11 / 177 (6.21%)
    4 / 176 (2.27%)
         occurrences all number
    14
    6
    Pain in extremity
         subjects affected / exposed
    15 / 177 (8.47%)
    14 / 176 (7.95%)
         occurrences all number
    22
    24
    Infections and infestations
    Cystitis
         subjects affected / exposed
    7 / 177 (3.95%)
    9 / 176 (5.11%)
         occurrences all number
    7
    10
    Infection
         subjects affected / exposed
    11 / 177 (6.21%)
    7 / 176 (3.98%)
         occurrences all number
    14
    9
    Nasopharyngitis
         subjects affected / exposed
    12 / 177 (6.78%)
    17 / 176 (9.66%)
         occurrences all number
    15
    20
    Pneumonia
         subjects affected / exposed
    9 / 177 (5.08%)
    9 / 176 (5.11%)
         occurrences all number
    10
    10
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    47 / 177 (26.55%)
    38 / 176 (21.59%)
         occurrences all number
    66
    60
    Hypokalaemia
         subjects affected / exposed
    10 / 177 (5.65%)
    4 / 176 (2.27%)
         occurrences all number
    11
    4

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2008
    Shorten the treatment-free period between first and second line treatment parts of this study from at least two to at least one week. Justification: The treatment-free period was introduced into the protocol to avoid additive toxicity from both drugs and to provide the patient with time for recreation between the treatment sections of first and second line. However, there can be circumstances that demand a rapid change from first to second line treatment. In those cases a treatment interruption of two weeks is deemed too long. Instead, one week between first and second line treatment is considered to be acceptable also from the pharmacokinetic point-of-view in terms of the elimination half lives of both drugs.
    08 Jun 2010
    Change of the statistical design from non-inferiority to superiority due to the results of retrospecitive analyses on sequential therapies with sunitinib and sorafenib. Reduction of number of subjects from 540 to 346, increase of number of centers. Extension of Duration of enrolement. Some other changes according to an updated summary of product characteristics of Nexavar and Sutent.
    05 May 2011
    Adaption of the protocol according to the current SPC of Sutent® and Nexavar®
    19 Dec 2011
    Adaption of the protocol according to the current SPC of Sutent® and Nexavar®
    22 Mar 2012
    Adaption of the protocol according to the current SPC of Sutent® and Nexavar®
    12 Aug 2013
    Adaption of the protocol according to the current SPC of Sutent® and Nexavar®, calculation of analysis periods and new planned study end.

    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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