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    Clinical Trial Results:
    A Multinational, Randomized, Open-Label Phase III Study of Custirsen (TV-1011/OGX-011) In Combination With Docetaxel Versus Docetaxel As A Second-Line Treatment In Patients With Advanced or Metastatic (Stage IV) Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    2012-002447-14
    Trial protocol
    HU   ES   DE   IT   PL  
    Global end of trial date
    17 Nov 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    19 Feb 2017
    First version publication date
    19 Feb 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TV1011-LC-303
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01630733
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    OncoGenex Technologies Inc.
    Sponsor organisation address
    19820 North Creek Parkway, Suite 201, Bothell, Washington, United States, 98011
    Public contact
    Chief Medical Officer , OncoGenex Technologies Inc., 001 425-686-1500,
    Scientific contact
    Chief Medical Officer , OncoGenex Technologies Inc., 001 425-686-1500,
    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
    17 Nov 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Nov 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is to compare overall survival of subjects randomized to receiving custirsen in combination with docetaxel with subjects randomized to receive docetaxel alone.
    Protection of trial subjects
    Each subject was provided an informed consent form that was reviewed and approved by the site’s governing Institutional Review Board (IRB), Research Ethics Board (REB) or Ethics Committee (EC). The Principal Investigator (or designee) provided potential subjects with a verbal description of the study, including but not limited to, study purpose and study procedures, risks and benefits and answered all subject questions prior to signing the form.
    Background therapy
    Docetaxel 75 mg/m2 was administered as a 1 hr constant rate infusion on Day 1 of each 21-day treatment cycle
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Oct 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 27
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Hungary: 57
    Country: Number of subjects enrolled
    Taiwan: 8
    Country: Number of subjects enrolled
    Thailand: 34
    Country: Number of subjects enrolled
    Ukraine: 118
    Country: Number of subjects enrolled
    United States: 69
    Country: Number of subjects enrolled
    Israel: 8
    Country: Number of subjects enrolled
    Italy: 58
    Country: Number of subjects enrolled
    Korea, Republic of: 20
    Country: Number of subjects enrolled
    New Zealand: 5
    Country: Number of subjects enrolled
    Poland: 77
    Country: Number of subjects enrolled
    Russian Federation: 77
    Country: Number of subjects enrolled
    Spain: 63
    Worldwide total number of subjects
    664
    EEA total number of subjects
    298
    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)
    377
    From 65 to 84 years
    285
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Screening evaluations occurred in a period of up to 28 days (+3 days) from the first screening evaluation to randomization.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Docetaxel
    Arm description
    Docetaxel: 75 mg/m^2 intravenously (IV) over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Custirsen + Docetaxel
    Arm description
    Custirsen: Three loading doses of custirsen 640 mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle. Docetaxel: 75 mg/m^2 IV over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.
    Arm type
    Experimental

    Investigational medicinal product name
    Custirsen 20mg/ml concentrate for solution for infusion
    Investigational medicinal product code
    OGX-011/TV-1011
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Custirsen was added to 250 mL D5W or 0.9% normal saline solution. The dose was administered using either aperipheral or central indwelling catheter IV as an infusion over 2 hours.

    Number of subjects in period 1
    Docetaxel Custirsen + Docetaxel
    Started
    332
    332
    Started
    325
    332
    Entered Chemotherapy Period
    325
    320
    Entered Off Treatment Follow-up
    50 [1]
    49 [2]
    Entered Survival Follow-Up
    222 [3]
    234 [4]
    Completed
    229
    237
    Not completed
    103
    95
         Study Terminated by Sponsor
    85
    80
         Consent withdrawn by subject
    9
    10
         Not Specified
    3
    2
         Lost to follow-up
    6
    3
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones represent the flow of subjects through the study.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones represent the flow of subjects through the study.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones represent the flow of subjects through the study.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Milestones represent the flow of subjects through the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Docetaxel
    Reporting group description
    Docetaxel: 75 mg/m^2 intravenously (IV) over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Reporting group title
    Custirsen + Docetaxel
    Reporting group description
    Custirsen: Three loading doses of custirsen 640 mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle. Docetaxel: 75 mg/m^2 IV over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Reporting group values
    Docetaxel Custirsen + Docetaxel Total
    Number of subjects
    332 332 664
    Age categorical
    Units: Subjects
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    63.1 ± 8.4 62.2 ± 9.3 -
    Gender categorical
    Units: Subjects
        Female
    103 100 203
        Male
    229 232 461
    Sex: Female, Male
    Units: Subjects
        Female
    103 100 203
        Male
    229 232 461

    End points

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    End points reporting groups
    Reporting group title
    Docetaxel
    Reporting group description
    Docetaxel: 75 mg/m^2 intravenously (IV) over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Reporting group title
    Custirsen + Docetaxel
    Reporting group description
    Custirsen: Three loading doses of custirsen 640 mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle. Docetaxel: 75 mg/m^2 IV over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Primary: Overall Survival: All Randomized Population

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    End point title
    Overall Survival: All Randomized Population
    End point description
    Overall survival time is defined as the number of days from the date of randomization until the date of death from any cause. Participants who did not achieve the event (death) at the time of the analysis or who dropped out before completing the survival follow-up period will be censored at the date they were last known to be alive (i.e., right censored). Partial or missing dates of death or last contact were imputed.
    End point type
    Primary
    End point timeframe
    From randomization to death or last known date alive (up to 1269 days for Docetaxel arm and up to 1271 days for Docetaxel + Custirsen arm)
    End point values
    Docetaxel Custirsen + Docetaxel
    Number of subjects analysed
    332
    332
    Units: days
        median (confidence interval 95%)
    239 (197 to 276)
    275 (219 to 329)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Analyses control for stratification variables: Gender, Histology (Squamous, Non-Squamous), Best Overall Response to 1st-line platinum treatment, and Eastern Cooperative Oncology Group (ECOG) score.
    Comparison groups
    Docetaxel v Custirsen + Docetaxel
    Number of subjects included in analysis
    664
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    = 0.178
    Method
    one-sided Score test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.915
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.758
         upper limit
    1.105

    Primary: Overall Survival: Stratified by Histology - Squamous vs. Non-Squamous Tumor Histology

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    End point title
    Overall Survival: Stratified by Histology - Squamous vs. Non-Squamous Tumor Histology
    End point description
    Overall survival time is defined as the number of days from the date of randomization until the date of death from any cause. Participants who did not achieve the event (death) at the time of the analysis or who dropped out before completing the survival follow-up period will be censored at the date they were last known to be alive (i.e., right censored). Partial or missing dates of death or last contact were imputed. Non-squamous histology includes: adenocarcinoma, large-cell carcinoma, carcinoid tumor, and other.
    End point type
    Primary
    End point timeframe
    From randomization to death or last known date alive (up to 1331 days for Docetaxel arm and up to 1271 days for Docetaxel + Custirsen arm)
    End point values
    Docetaxel Custirsen + Docetaxel
    Number of subjects analysed
    332
    332
    Units: days
    median (confidence interval 95%)
        Squamous
    221 (162 to 267)
    232 (202 to 318)
        Non-squamous
    249 (198 to 357)
    281 (229 to 368)
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Squamous tumor histology. Analyses control for stratification variables: Gender, Histology (Squamous, Non-Squamous), Best Overall Response to 1st-line platinum treatment, and ECOG score.
    Comparison groups
    Docetaxel v Custirsen + Docetaxel
    Number of subjects included in analysis
    664
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.183
    Method
    one-sided Score test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.876
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.656
         upper limit
    1.169
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Non-squamous tumor histology. Analyses control for stratification variables: Gender, Histology (Squamous, Non-Squamous), Best Overall Response to 1st-line platinum treatment, and ECOG score.
    Comparison groups
    Docetaxel v Custirsen + Docetaxel
    Number of subjects included in analysis
    664
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.33
    Method
    one-sided Score test
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.946
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.737
         upper limit
    1.214

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose to last dose plus 30 days (31 to 941 days for docetaxel arm and 31 to 725 days for docetaxel + custirsen arm) until disease progression or death.
    Adverse event reporting additional description
    Safety Analysis Set: Participants who received at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    Custirsen + Docetaxel
    Reporting group description
    Custirsen: Three loading doses of custirsen 640 mg IV over 2 hours administered in 5 to 9 days prior to Day 1 of Cycle 1, then custirsen 640 mg IV weekly every 21-day cycle. Docetaxel: 75 mg/m^2 IV over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Reporting group title
    Docetaxel
    Reporting group description
    Docetaxel: 75 mg/m^2 IV over 1 hour on Day 1 of every 21-day cycle. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent, or protocol-specified parameters to stop.

    Serious adverse events
    Custirsen + Docetaxel Docetaxel
    Total subjects affected by serious adverse events
         subjects affected / exposed
    113 / 332 (34.04%)
    97 / 325 (29.85%)
         number of deaths (all causes)
    9
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    4 / 332 (1.20%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metastases to spine
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Asthenia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    4 / 332 (1.20%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    4 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    4 / 332 (1.20%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 1
    Generalised oedema
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 332 (2.11%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    6 / 7
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Adjustment disorder
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ilium fracture
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Influenza A virus test positive
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         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
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         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
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Bronchial obstruction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cough
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 332 (1.81%)
    13 / 325 (4.00%)
         occurrences causally related to treatment / all
    0 / 8
    2 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Epistaxis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 332 (0.90%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    4 / 332 (1.20%)
    5 / 325 (1.54%)
         occurrences causally related to treatment / all
    0 / 4
    1 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Pneumonitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    5 / 332 (1.51%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 332 (0.30%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Pulmonary hypertension
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulmonary oedema
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Respiratory distress
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    4 / 332 (1.20%)
    4 / 325 (1.23%)
         occurrences causally related to treatment / all
    1 / 4
    2 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    6 / 332 (1.81%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    6 / 7
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    13 / 332 (3.92%)
    16 / 325 (4.92%)
         occurrences causally related to treatment / all
    15 / 15
    16 / 16
         deaths causally related to treatment / all
    0 / 0
    2 / 2
    Leukopenia
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    16 / 332 (4.82%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    21 / 21
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Thrombotic thrombocytopenic purpura
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Altered state of consciousness
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Convulsion
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 332 (0.90%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 332 (0.60%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    12 / 332 (3.61%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    12 / 12
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal perforation
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 332 (0.60%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Skin and subcutaneous tissue disorders
    Cutaneous vasculitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (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
    Arthralgia
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 332 (0.60%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 332 (0.90%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hypercalcaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         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 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopneumonia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 332 (0.00%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection bacterial
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (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
    3 / 332 (0.90%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    2 / 332 (0.60%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumocystis jiroveci pneumonia
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis Escherichia coli
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    9 / 332 (2.71%)
    17 / 325 (5.23%)
         occurrences causally related to treatment / all
    8 / 11
    8 / 19
         deaths causally related to treatment / all
    3 / 3
    1 / 5
    Pyelonephritis
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    0 / 332 (0.00%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    3 / 332 (0.90%)
    1 / 325 (0.31%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 332 (0.60%)
    3 / 325 (0.92%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 3
         deaths causally related to treatment / all
    1 / 1
    0 / 1
    Septic shock
         subjects affected / exposed
    4 / 332 (1.20%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 332 (1.20%)
    2 / 325 (0.62%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 332 (0.30%)
    0 / 325 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    Custirsen + Docetaxel Docetaxel
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    312 / 332 (93.98%)
    296 / 325 (91.08%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 332 (5.42%)
    6 / 325 (1.85%)
         occurrences all number
    32
    7
    Aspartate aminotransferase increased
         subjects affected / exposed
    19 / 332 (5.72%)
    4 / 325 (1.23%)
         occurrences all number
    30
    4
    Blood creatinine increased
         subjects affected / exposed
    20 / 332 (6.02%)
    11 / 325 (3.38%)
         occurrences all number
    30
    13
    Weight decreased
         subjects affected / exposed
    31 / 332 (9.34%)
    29 / 325 (8.92%)
         occurrences all number
    36
    33
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    47 / 332 (14.16%)
    46 / 325 (14.15%)
         occurrences all number
    53
    50
    Dyspnoea
         subjects affected / exposed
    56 / 332 (16.87%)
    67 / 325 (20.62%)
         occurrences all number
    67
    83
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    87 / 332 (26.20%)
    66 / 325 (20.31%)
         occurrences all number
    148
    100
    Leukopenia
         subjects affected / exposed
    16 / 332 (4.82%)
    17 / 325 (5.23%)
         occurrences all number
    22
    24
    Neutropenia
         subjects affected / exposed
    58 / 332 (17.47%)
    39 / 325 (12.00%)
         occurrences all number
    103
    68
    Thrombocytopenia
         subjects affected / exposed
    22 / 332 (6.63%)
    3 / 325 (0.92%)
         occurrences all number
    34
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 332 (6.63%)
    17 / 325 (5.23%)
         occurrences all number
    25
    19
    Dysgeusia
         subjects affected / exposed
    19 / 332 (5.72%)
    19 / 325 (5.85%)
         occurrences all number
    20
    20
    Headache
         subjects affected / exposed
    29 / 332 (8.73%)
    27 / 325 (8.31%)
         occurrences all number
    39
    31
    Peripheral sensory neuropathy
         subjects affected / exposed
    22 / 332 (6.63%)
    17 / 325 (5.23%)
         occurrences all number
    33
    18
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    66 / 332 (19.88%)
    62 / 325 (19.08%)
         occurrences all number
    154
    110
    Chills
         subjects affected / exposed
    31 / 332 (9.34%)
    9 / 325 (2.77%)
         occurrences all number
    46
    10
    Fatigue
         subjects affected / exposed
    81 / 332 (24.40%)
    83 / 325 (25.54%)
         occurrences all number
    165
    152
    Non-cardiac chest pain
         subjects affected / exposed
    18 / 332 (5.42%)
    14 / 325 (4.31%)
         occurrences all number
    22
    16
    Oedema peripheral
         subjects affected / exposed
    30 / 332 (9.04%)
    31 / 325 (9.54%)
         occurrences all number
    40
    48
    Pyrexia
         subjects affected / exposed
    110 / 332 (33.13%)
    38 / 325 (11.69%)
         occurrences all number
    172
    53
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    15 / 332 (4.52%)
    19 / 325 (5.85%)
         occurrences all number
    17
    20
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    19 / 332 (5.72%)
    16 / 325 (4.92%)
         occurrences all number
    20
    20
    Constipation
         subjects affected / exposed
    39 / 332 (11.75%)
    33 / 325 (10.15%)
         occurrences all number
    50
    45
    Diarrhoea
         subjects affected / exposed
    85 / 332 (25.60%)
    74 / 325 (22.77%)
         occurrences all number
    136
    117
    Nausea
         subjects affected / exposed
    84 / 332 (25.30%)
    70 / 325 (21.54%)
         occurrences all number
    139
    98
    Stomatitis
         subjects affected / exposed
    27 / 332 (8.13%)
    22 / 325 (6.77%)
         occurrences all number
    37
    40
    Vomiting
         subjects affected / exposed
    47 / 332 (14.16%)
    33 / 325 (10.15%)
         occurrences all number
    72
    40
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    61 / 332 (18.37%)
    72 / 325 (22.15%)
         occurrences all number
    65
    84
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    24 / 332 (7.23%)
    16 / 325 (4.92%)
         occurrences all number
    34
    22
    Back pain
         subjects affected / exposed
    24 / 332 (7.23%)
    19 / 325 (5.85%)
         occurrences all number
    32
    25
    Bone pain
         subjects affected / exposed
    7 / 332 (2.11%)
    17 / 325 (5.23%)
         occurrences all number
    7
    17
    Muscular weakness
         subjects affected / exposed
    15 / 332 (4.52%)
    19 / 325 (5.85%)
         occurrences all number
    20
    24
    Myalgia
         subjects affected / exposed
    28 / 332 (8.43%)
    23 / 325 (7.08%)
         occurrences all number
    51
    34
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    83 / 332 (25.00%)
    71 / 325 (21.85%)
         occurrences all number
    116
    87
    Hypokalaemia
         subjects affected / exposed
    18 / 332 (5.42%)
    12 / 325 (3.69%)
         occurrences all number
    24
    13

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Aug 2012
    • Clarified exclusion criteria number 10 stating exclusion of patients with known hypersensitivity to taxanes. • Added clarification that worsening of bone pain requiring palliative radiation therapy will be considered clinical disease progression. • Corrected the permissible time window for hematology and serum biochemistry assesments on day 1 of each cycle to be consistent with other sections of the protocol. • Changed the dose modification relating to hematology toxicity to state that custirsen will not be held or modified. • Corrected the pharmacokinetic sampling procedure.
    12 Mar 2013
    • Added new exclusion criterion stating that patients with known and documented epidermal growth factor (EGFR) mutation who have not received an EGFR inhibitor must be excluded. • Revised pregnancy precautions for men of reproductive potential to use precautionary instruction as outlined in the docetaxel summary of product characteristics. • Revised diluents acceptable for custirsen formulation to include either 0.9% normal saline or 0.9% D5W. • Changed sample type for pregnancy testing (beta-human chorionic gonadotropin) for female subjects of childbearing potential from urine to serum. • Clarified terms for relationship of an adverse event to study drug by adding (not related) to No reasonable possibility and adding (related) to Reasonable possibility.
    16 Mar 2015
    • Changed sponsorship of study from Teva Pharmaceutical Industries, Ltd. to OncoGenex Technologies Inc. • Clarified 3 week delay in treatment timing for patient withdrawal. • Clarified that radiation therapy specifically for lung cancer could be reason for patient withdrawal. • Clarified Day 1 of each cycle is tied the day of docetaxel administration. • Clarified that a subject should have an “End of Treatment” assessment if more than 42 days between docetaxel administrations. • Clarified that either docetaxel or custirsen should be modified or held based on hematology toxicity for dose modification guidelines as outlined in protocol. • Changed SGOT (AST) Grade 1 and Grade 2 levels for dose modifications for hepatic toxicity (Grade 1 changed from <2.5x upper limit of normal [ULN] to <3.0xULN and Grade 2 from >2.5xULN to >3.0xULN). • Clarified that study period for serious adverse event reporting is from the subject’s signature on the informed consent form until the end of the treatment visit (28 days following last dose). • Changed parameters based on revision of the primary objective hypothesized HR from 0.8 to 0.75 as follows: 850 death events to 508 death events required, recruitment period of 4 years to 3.1 years and sample size target of 1100 to 700. • Added that OS analysis will include comparison by histology (squamous, non-squamous) between subjects receiving docetaxel with or without custirsen.
    13 Sep 2016
    • Decreased the number of subjects to be enrolled from 700 to approximately 660 and referenced the revised Statistical Analysis Plan (Version 3.1) which covered details related to patient enrollment and target of 447 death events for final analysis.

    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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