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    Clinical Trial Results:
    Randomised phase II trial of cediranib (AZD2171) vs. placebo in addition to cisplatin / gemcitabine chemotherapy for patients with advanced biliary tract cancers

    Summary
    EudraCT number
    		 2009-013408-30
    Trial protocol
    		 GB  
    Global end of trial date
    29 Sep 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jul 2016
    First version publication date
    29 Jul 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    UCL/09/0193
    Additional study identifiers
    ISRCTN number
    		 ISRCTN34043997
    US NCT number
    		 NCT00939848
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Funder Reference: C2930/A11428, MHRA CTA No.: 20363/0283/001-0001, Study Acronym: ABC-03
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Joint Research Office, Gower Street, London, United Kingdom, WC1E 6BT
    Public contact
    Public Contact, CR UK & UCL Cancer Trials Centre , ctc.sponsor@ucl.ac.uk
    Scientific contact
    Scientific Contact, CR UK & UCL Cancer Trials Centre , ctc.sponsor@ucl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate the efficacy and safety of cediranib in combination with cisplatin + gemcitabine (CisGem) chemotherapy compared to CisGem and placebo.
    Protection of trial subjects
    Hypertension was a known side effect of cediranib and a detailed plan for management of hypertension was included in the trial protocol. In general, patients were monitored closely for side effects and the protocol contained management plans to prevent or treat side effects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Apr 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
    United Kingdom: 124
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    55
    From 65 to 84 years
    69
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 124 patients were recruited into the ABC-03 trial (62 in each arm) between 20 April 2011 and 28 September 2012. Participants were recruited from 14 participating hospitals in the United Kingdom.

    Pre-assignment
    Screening details
    		 All eligibility criteria were based on routine tests and investigations.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    At randomisation patients were allocated a trial ID which was linked to their treatment allocation. The pateints trial ID was used to dispense the appropriate trial medication (cedrianib or placebo) using an interactive web based response system (IWRS). None of the treating clinician, pharmacist nor the pateint were aware of which treatment the patient was receiving. Cediranib and placebo bottles were labelled in a blinded manner.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 The control arm (Arm A)
    Arm description
    		 Patients on the control arm (Arm A) recieved cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 (CisGem) on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded placebo tablets taken once daily every day (continuous dosing).
    Arm type
    		 Placebo

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    cisplatin 25mg/m2 on days 1 and 8 of a 21 day cycle for 8 cycles

    Investigational medicinal product name
    gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    gemcitabine on days 1 and 8 of a 21 day cycle for 8 cycles

    Arm title
    		 The experimental arm (Arm B)
    Arm description
    		 Patients on the experimental arm (Arm B) received cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded cediranib 20 mg tablets taken once daily every day (continuous dosing).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cediranib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Blinded cediranib 20 mg tablets taken once daily every day (continuous dosing).

    Investigational medicinal product name
    cisplatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Sterile concentrate
    Routes of administration
    Intravenous use
    Dosage and administration details
    cisplatin 25mg/m2 on days 1 and 8 of a 21 day cycle for 8 cycles

    Investigational medicinal product name
    gemcitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    gemcitabine on days 1 and 8 of a 21 day cycle for 8 cycles

    Number of subjects in period 1
    		The control arm (Arm A) The experimental arm (Arm B)
    Started
    62
    62
    Completed
    29
    29
    Not completed
    33
    33
         Physician decision
    2
    2
         toxicity
    5
    16
         Did not start intervention (not fit for treatment)
    2
    -
         disease progression
    18
    9
         patient decision
    2
    1
         symptomatic deterioration
    4
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    The control arm (Arm A)
    Reporting group description
    		 Patients on the control arm (Arm A) recieved cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 (CisGem) on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded placebo tablets taken once daily every day (continuous dosing).

    Reporting group title
    The experimental arm (Arm B)
    Reporting group description
    		 Patients on the experimental arm (Arm B) received cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded cediranib 20 mg tablets taken once daily every day (continuous dosing).

    Reporting group values
    		 The control arm (Arm A) The experimental arm (Arm B) Total
    Number of subjects
    		 62 62 124
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 34 21 55
        From 65-84 years
    		 28 41 69
        85 years and over
    		 0 0 0
    Age continuous
    Eligible patients were aged ≥18 years with a histopathological/cytological diagnosis of non-resectable, recurrent or metastatic biliary tract carcinoma (intra- or extra-hepatic cholangiocarcinoma), gallbladder or ampullary carcinoma.
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 64.5 (59.7 to 73.1) 68 (60.4 to 73) -
    Gender categorical
    Units: Subjects
        Female
    		 34 28 62
        Male
    		 28 34 62
    Primary Tumour Site
    Units: Subjects
        Cholangiocarcinoma - Intrahepatic
    		 15 14 29
        Cholangiocarcinoma - Extrahepatic
    		 24 24 48
        Gallbladder
    		 19 20 39
        Ampulla
    		 4 4 8
    Histological grade
    Units: Subjects
        Well differentiated
    		 27 26 53
        Moderately differentiated
    		 21 20 41
        Poorly differentiated
    		 13 13 26
        Not specified
    		 1 3 4
    Prior therapy
    Units: Subjects
        Adjuvant chemotherapy
    		 1 2 3
        Other
    		 22 23 45
        None
    		 39 37 76
    ECOG performance status
    Units: Subjects
        ECOG 0
    		 28 27 55
        ECOG 1
    		 34 35 69
    Disease status
    Units: Subjects
        Locally advanced
    		 8 12 20
        metastatic
    		 54 50 104
    CA19-9 median (IQR) IU/mL
    Units: IU/mL
        median (inter-quartile range (Q1-Q3))
    		 53 (10 to 492) 298 (38 to 2258) -

    End points

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    End points reporting groups
    Reporting group title
    The control arm (Arm A)
    Reporting group description
    		 Patients on the control arm (Arm A) recieved cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 (CisGem) on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded placebo tablets taken once daily every day (continuous dosing).

    Reporting group title
    The experimental arm (Arm B)
    Reporting group description
    		 Patients on the experimental arm (Arm B) received cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded cediranib 20 mg tablets taken once daily every day (continuous dosing).

    Primary: Progression-free survival

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    End point title
    		 Progression-free survival
    End point description
    End point type
    Primary
    End point timeframe
    Overall Trial
    End point values
    		 The control arm (Arm A) The experimental arm (Arm B)
    Number of subjects analysed
    57
    59
    Units: Months
        median (confidence interval 95%)
    7.4 (5.7 to 8.5)
    8 (6.5 to 9.3)
    Statistical analysis title
    		 Progression-free survival
    Statistical analysis description
    The trial was designed to directly compare progression free survival between the two treatment groups, with 80% power and a two-sided alpha of 0·2, to detect a progression-free survival hazard ratio (HR) of 0·64. This required a sample size of 68 per group. The main analysis involved estimating the HR, 80% CI, and p value. If the HR was less than 1 and the p value was less than 0·2, the study would be deemed to have provided sufficient evidence to do a larger trial.
    Comparison groups
    The experimental arm (Arm B) v The control arm (Arm A)
    Number of subjects included in analysis
    116
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.2
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.64
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 0.51
         upper limit
    		 0.77

    Secondary: Overall survival

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    End point title
    		 Overall survival
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Trial
    End point values
    		 The control arm (Arm A) The experimental arm (Arm B)
    Number of subjects analysed
    50
    50
    Units: Months
        median (confidence interval 95%)
    11.9 (9.2 to 14.3)
    14.1 (10.2 to 16.4)
    No statistical analyses for this end point

    Secondary: Best overall response (RECIST v1.1)

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    End point title
    		 Best overall response (RECIST v1.1)
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Trial
    End point values
    		 The control arm (Arm A) The experimental arm (Arm B)
    Number of subjects analysed
    54
    59
    Units: Patients
        Complete Response (CR)
    0
    2
        Partial Response (PR)
    10
    24
        Stable Disease (SD)
    25
    20
        Response Rate (CR+PR)
    10
    26
        Disease Control Rate (CR+PR+SD)
    35
    46
        Progressive Disease (PD)
    15
    6
        Unknown
    4
    7
    No statistical analyses for this end point

    Secondary: Adverse Events

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    End point title
    		 Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Overall Trial
    End point values
    		 The control arm (Arm A) The experimental arm (Arm B)
    Number of subjects analysed
    62
    62
    Units: Patients
    62
    62
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall Trial
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    The control arm (Arm A)
    Reporting group description
    		 The control arm (Arm A) consisted of cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 (CisGem) on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded placebo tablets taken once daily every day (continuous dosing).

    Reporting group title
    The experimental arm (Arm B)
    Reporting group description
    		 The experimental arm (Arm B) consisted of cisplatin 25 mg/m2 plus gemcitabine 1000 mg/m2 on days 1 and 8 of a 21-day cycle for up to 8 cycles with blinded cediranib 20 mg tablets taken once daily every day (continuous dosing).

    Serious adverse events
    		 The control arm (Arm A) The experimental arm (Arm B)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 62 (61.29%)
    42 / 62 (67.74%)
         number of deaths (all causes)
    61
    61
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    5 / 62 (8.06%)
    5 / 62 (8.06%)
         occurrences causally related to treatment / all
    4 / 5
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    other, Cerebral Bleed
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    other, blocked biliary stent
         subjects affected / exposed
    2 / 62 (3.23%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    5 / 62 (8.06%)
    14 / 62 (22.58%)
         occurrences causally related to treatment / all
    6 / 8
    7 / 22
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnea
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 62 (1.61%)
    5 / 62 (8.06%)
         occurrences causally related to treatment / all
    1 / 1
    7 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 62 (1.61%)
    6 / 62 (9.68%)
         occurrences causally related to treatment / all
    1 / 1
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    White blood cell decreased
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fracture
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (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 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Chest pain - cardiac
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart failure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 62 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cognitive disturbance
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Syncope
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 62 (6.45%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 62 (1.61%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 62 (4.84%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 62 (3.23%)
    6 / 62 (9.68%)
         occurrences causally related to treatment / all
    1 / 2
    5 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Esophageal haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Nausea
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 62 (3.23%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    8 / 62 (12.90%)
    5 / 62 (8.06%)
         occurrences causally related to treatment / all
    4 / 8
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    other, Hemorrhage NOS
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         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
    Rash maculo-papular
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Other, degenerative disc changes
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (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
    Biliary tract infection
         subjects affected / exposed
    1 / 62 (1.61%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchial infection
         subjects affected / exposed
    3 / 62 (4.84%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    2 / 62 (3.23%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 62 (9.68%)
         occurrences causally related to treatment / all
    1 / 3
    6 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 62 (4.84%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    other, Infection and infestations source not known
         subjects affected / exposed
    4 / 62 (6.45%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    3 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 62 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 62 (1.61%)
    0 / 62 (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
    		 The control arm (Arm A) The experimental arm (Arm B)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    62 / 62 (100.00%)
    62 / 62 (100.00%)
    Vascular disorders
    Hot flashes
         subjects affected / exposed
    6 / 62 (9.68%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1
    Hypertension
         subjects affected / exposed
    30 / 62 (48.39%)
    42 / 62 (67.74%)
         occurrences all number
    30
    42
    Hypotension
         subjects affected / exposed
    5 / 62 (8.06%)
    2 / 62 (3.23%)
         occurrences all number
    5
    2
    Superficial thrombophlebitis
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    Thromboembolic Event
         subjects affected / exposed
    9 / 62 (14.52%)
    7 / 62 (11.29%)
         occurrences all number
    9
    7
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
         occurrences all number
    2
    5
    Edema limbs
         subjects affected / exposed
    17 / 62 (27.42%)
    22 / 62 (35.48%)
         occurrences all number
    17
    22
    Fatigue
         subjects affected / exposed
    47 / 62 (75.81%)
    52 / 62 (83.87%)
         occurrences all number
    47
    52
    Fever
         subjects affected / exposed
    17 / 62 (27.42%)
    24 / 62 (38.71%)
         occurrences all number
    17
    24
    Flu like symptoms
         subjects affected / exposed
    12 / 62 (19.35%)
    12 / 62 (19.35%)
         occurrences all number
    12
    12
    General disorders other - Night sweats
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 62 (9.68%)
    2 / 62 (3.23%)
         occurrences all number
    6
    2
    Pain
         subjects affected / exposed
    29 / 62 (46.77%)
    30 / 62 (48.39%)
         occurrences all number
    29
    30
    Pruritus
         subjects affected / exposed
    3 / 62 (4.84%)
    3 / 62 (4.84%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 62 (12.90%)
    13 / 62 (20.97%)
         occurrences all number
    8
    13
    Dyspnea
         subjects affected / exposed
    19 / 62 (30.65%)
    16 / 62 (25.81%)
         occurrences all number
    19
    16
    Epistaxis
         subjects affected / exposed
    6 / 62 (9.68%)
    17 / 62 (27.42%)
         occurrences all number
    6
    17
    Hiccups
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
         occurrences all number
    2
    3
    Sore Throat
         subjects affected / exposed
    6 / 62 (9.68%)
    11 / 62 (17.74%)
         occurrences all number
    6
    11
    Psychiatric disorders
    Depression
         subjects affected / exposed
    6 / 62 (9.68%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1
    Insomnia
         subjects affected / exposed
    12 / 62 (19.35%)
    11 / 62 (17.74%)
         occurrences all number
    12
    11
    Anxiety
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Investigations
    Platelet count decreased
         subjects affected / exposed
    32 / 62 (51.61%)
    44 / 62 (70.97%)
         occurrences all number
    32
    44
    White blood cell count decreased
         subjects affected / exposed
    39 / 62 (62.90%)
    43 / 62 (69.35%)
         occurrences all number
    39
    43
    Neutrophil count decreased
         subjects affected / exposed
    43 / 62 (69.35%)
    48 / 62 (77.42%)
         occurrences all number
    43
    48
    Creatinine increased
         subjects affected / exposed
    10 / 62 (16.13%)
    17 / 62 (27.42%)
         occurrences all number
    10
    17
    GGT increased
         subjects affected / exposed
    54 / 62 (87.10%)
    61 / 62 (98.39%)
         occurrences all number
    54
    61
    Alanine aminotransferase increased
         subjects affected / exposed
    43 / 62 (69.35%)
    50 / 62 (80.65%)
         occurrences all number
    43
    50
    Alkaline phosphatase increased
         subjects affected / exposed
    47 / 62 (75.81%)
    47 / 62 (75.81%)
         occurrences all number
    47
    47
    Aspartate aminotransferase increased
         subjects affected / exposed
    37 / 62 (59.68%)
    43 / 62 (69.35%)
         occurrences all number
    37
    43
    Blood bilirubin increased
         subjects affected / exposed
    13 / 62 (20.97%)
    12 / 62 (19.35%)
         occurrences all number
    13
    12
    Weight loss
         subjects affected / exposed
    4 / 62 (6.45%)
    12 / 62 (19.35%)
         occurrences all number
    4
    12
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
         occurrences all number
    2
    3
    Nervous system disorders
    Cognitive disturbance
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Dizziness
         subjects affected / exposed
    8 / 62 (12.90%)
    6 / 62 (9.68%)
         occurrences all number
    8
    6
    Dysgeusia
         subjects affected / exposed
    19 / 62 (30.65%)
    20 / 62 (32.26%)
         occurrences all number
    19
    20
    Lethargy
         subjects affected / exposed
    42 / 62 (67.74%)
    43 / 62 (69.35%)
         occurrences all number
    42
    43
    Peripheral sensory neuropathy
         subjects affected / exposed
    16 / 62 (25.81%)
    16 / 62 (25.81%)
         occurrences all number
    16
    16
    Presyncope
         subjects affected / exposed
    4 / 62 (6.45%)
    3 / 62 (4.84%)
         occurrences all number
    4
    3
    Seizure
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    57 / 62 (91.94%)
    59 / 62 (95.16%)
         occurrences all number
    57
    59
    Febrile neutropenia
         subjects affected / exposed
    1 / 62 (1.61%)
    4 / 62 (6.45%)
         occurrences all number
    1
    4
    Ear and labyrinth disorders
    Hearing Impaired
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Tinnitus
         subjects affected / exposed
    9 / 62 (14.52%)
    4 / 62 (6.45%)
         occurrences all number
    9
    4
    Eye disorders
    Blurred vision
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
         occurrences all number
    2
    3
    Eye pain
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 62 (3.23%)
    5 / 62 (8.06%)
         occurrences all number
    2
    5
    Abdominal pain
         subjects affected / exposed
    32 / 62 (51.61%)
    32 / 62 (51.61%)
         occurrences all number
    32
    32
    Ascites
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Bloating
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    Constipation
         subjects affected / exposed
    42 / 62 (67.74%)
    42 / 62 (67.74%)
         occurrences all number
    42
    42
    Diarrhoea
         subjects affected / exposed
    24 / 62 (38.71%)
    45 / 62 (72.58%)
         occurrences all number
    24
    45
    Dry mouth
         subjects affected / exposed
    8 / 62 (12.90%)
    15 / 62 (24.19%)
         occurrences all number
    8
    15
    Dyspepsia
         subjects affected / exposed
    7 / 62 (11.29%)
    13 / 62 (20.97%)
         occurrences all number
    7
    13
    Flatulence
         subjects affected / exposed
    6 / 62 (9.68%)
    7 / 62 (11.29%)
         occurrences all number
    6
    7
    Gastroesophageal relux disease
         subjects affected / exposed
    17 / 62 (27.42%)
    10 / 62 (16.13%)
         occurrences all number
    17
    10
    Mucositis oral
         subjects affected / exposed
    13 / 62 (20.97%)
    25 / 62 (40.32%)
         occurrences all number
    13
    25
    Nausea
         subjects affected / exposed
    43 / 62 (69.35%)
    43 / 62 (69.35%)
         occurrences all number
    43
    43
    Toothache
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    30 / 62 (48.39%)
    30 / 62 (48.39%)
         occurrences all number
    30
    30
    Hepatobiliary disorders
    Hepatobiliary disorder other - biliary obstruction
         subjects affected / exposed
    4 / 62 (6.45%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 62 (29.03%)
    10 / 62 (16.13%)
         occurrences all number
    18
    10
    Dry skin
         subjects affected / exposed
    4 / 62 (6.45%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 62 (1.61%)
    3 / 62 (4.84%)
         occurrences all number
    1
    3
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    3 / 62 (4.84%)
    5 / 62 (8.06%)
         occurrences all number
    3
    5
    Papulopustular rash
         subjects affected / exposed
    3 / 62 (4.84%)
    7 / 62 (11.29%)
         occurrences all number
    3
    7
    Rash maculo-papular
         subjects affected / exposed
    6 / 62 (9.68%)
    12 / 62 (19.35%)
         occurrences all number
    6
    12
    Skin ulceration
         subjects affected / exposed
    0 / 62 (0.00%)
    3 / 62 (4.84%)
         occurrences all number
    0
    3
    Renal and urinary disorders
    Urinary frequency
         subjects affected / exposed
    3 / 62 (4.84%)
    2 / 62 (3.23%)
         occurrences all number
    3
    2
    Urinary tract pain
         subjects affected / exposed
    0 / 62 (0.00%)
    4 / 62 (6.45%)
         occurrences all number
    0
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 62 (8.06%)
    4 / 62 (6.45%)
         occurrences all number
    5
    4
    Back pain
         subjects affected / exposed
    11 / 62 (17.74%)
    15 / 62 (24.19%)
         occurrences all number
    11
    15
    Generalised muscle weakness
         subjects affected / exposed
    6 / 62 (9.68%)
    13 / 62 (20.97%)
         occurrences all number
    6
    13
    Myalgia
         subjects affected / exposed
    11 / 62 (17.74%)
    7 / 62 (11.29%)
         occurrences all number
    11
    7
    Neck pain
         subjects affected / exposed
    3 / 62 (4.84%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    Pain in extremity
         subjects affected / exposed
    6 / 62 (9.68%)
    8 / 62 (12.90%)
         occurrences all number
    6
    8
    Infections and infestations
    Biliary tract infection
         subjects affected / exposed
    3 / 62 (4.84%)
    8 / 62 (12.90%)
         occurrences all number
    3
    8
    Infection
         subjects affected / exposed
    7 / 62 (11.29%)
    3 / 62 (4.84%)
         occurrences all number
    7
    3
    Lung infection
         subjects affected / exposed
    11 / 62 (17.74%)
    4 / 62 (6.45%)
         occurrences all number
    11
    4
    Mucosal infection
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 62 (9.68%)
         occurrences all number
    3
    6
    Sepsis
         subjects affected / exposed
    3 / 62 (4.84%)
    6 / 62 (9.68%)
         occurrences all number
    3
    6
    Skin infection
         subjects affected / exposed
    3 / 62 (4.84%)
    1 / 62 (1.61%)
         occurrences all number
    3
    1
    Upper respiratory infection
         subjects affected / exposed
    9 / 62 (14.52%)
    15 / 62 (24.19%)
         occurrences all number
    9
    15
    Urinary tract infection
         subjects affected / exposed
    7 / 62 (11.29%)
    9 / 62 (14.52%)
         occurrences all number
    7
    9
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    22 / 62 (35.48%)
    27 / 62 (43.55%)
         occurrences all number
    22
    27
    Hypoalbuminaemia
         subjects affected / exposed
    23 / 62 (37.10%)
    31 / 62 (50.00%)
         occurrences all number
    23
    31
    Hypomagnesaemia
         subjects affected / exposed
    21 / 62 (33.87%)
    30 / 62 (48.39%)
         occurrences all number
    21
    30
    Hypophosphataemia
         subjects affected / exposed
    19 / 62 (30.65%)
    25 / 62 (40.32%)
         occurrences all number
    19
    25
    Hyponatraemia
         subjects affected / exposed
    32 / 62 (51.61%)
    36 / 62 (58.06%)
         occurrences all number
    32
    36
    Hypokalaemia
         subjects affected / exposed
    18 / 62 (29.03%)
    21 / 62 (33.87%)
         occurrences all number
    18
    21
    Anorexia
         subjects affected / exposed
    27 / 62 (43.55%)
    43 / 62 (69.35%)
         occurrences all number
    27
    43
    Dehydration
         subjects affected / exposed
    2 / 62 (3.23%)
    3 / 62 (4.84%)
         occurrences all number
    2
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/2617920
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