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    Clinical Trial Results:
    A double-blind, randomized, placebo-controlled Phase III study to assess the efficacy of recMAGE-A3 + AS15 Antigen-Specific Cancer Immunotherapeutic as adjuvant therapy in patients with resectable MAGE-A3-positive Non-Small Cell Lung Cancer

    Summary
    EudraCT number
    		 2007-001283-73
    Trial protocol
    		 BE   DE   IE   FI   ES   SI   FR   SE   GR   IT   LV   AT   NL   HU   CZ   EE   GB  
    Global end of trial date
    23 Sep 2014

    Results information
    Results version number
    		 v2(current)
    This version publication date
    13 Dec 2020
    First version publication date
    03 Mar 2016
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Results have been amended to account for consistency with other registries.

    Trial information

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    Trial identification
    Sponsor protocol code
    109493
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00480025
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium, B-1330
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 044 2089-904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this Phase III study is to demonstrate the clinical efficacy (in terms of disease-free survival) of recMAGE-A3 + AS15 versus placebo in NSCLC after complete surgical resection. three co-primary objectives are considered: •Objective A: Efficacy in the overall population; •Objective B: Efficacy in the population of patients who did not receive adjuvant chemotherapy (no-CT population). •Objective C: Efficacy in the population of patients presenting the potentially favourable gene signature.
    Protection of trial subjects
    Patients were observed closely for at least 30 minutes following treatment, with appropriate medical treatment readily available in case of a rare anaphylactic reaction. MAGE-A3 ASCI/placebo were administered by qualified and trained personnel, only to eligible subjects with no contraindications to any components of these products. During treatment, the following was checked to assess need to postpone treatment: acute disease at time of administration; any systemic grade ≥ 2 Common Terminology Criteria Adverse Event related or possibly related to treatment; fever, defined as an oral, axillary or tympanic temperature =< 38°C; need for influenza vaccine, immunoglobulins and/or any blood products; any medical reason exposing the patient to unacceptable risk. Patients were required to discontinue treatment in case of evidence of disease relapse/occurrence of second primary lung cancer; treatment with either investigational or non-registered product other than MAGE-A3 ASCI study product or other anticancer treatments; anaphylactic reaction following treatment administration; any intolerable adverse event; clinical signs or symptoms indicative of any autoimmune disorder, except vitiligo; appearance of any confirmed or suspected immunosuppressive or immunodeficient condition, or any condition requiring use of any immunosuppressive agent or systemic corticosteroids prescribed for chronic use; inability of the patient to complete study evaluations due to unforeseen circumstances; other conditions indicating the patient’s best interest to be withdrawn from treatment. In addition, between the end of the 120-weeks treatment phase, the following follow-up (FU) of patients was also planned: 1) an active FU for survival, recurrence, serious adverse events related to treatment & SAEs related to study participation and concurrent GSK medication of up to 5 years from the 1st treatment, and 2) annual contacts up to 10 years after 1st treatment.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 Oct 2007
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 8 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 10
    Country: Number of subjects enrolled
    Australia: 25
    Country: Number of subjects enrolled
    Brazil: 21
    Country: Number of subjects enrolled
    Canada: 37
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    Norway: 22
    Country: Number of subjects enrolled
    Poland: 166
    Country: Number of subjects enrolled
    Spain: 86
    Country: Number of subjects enrolled
    Sweden: 12
    Country: Number of subjects enrolled
    United Kingdom: 83
    Country: Number of subjects enrolled
    Austria: 26
    Country: Number of subjects enrolled
    Belgium: 35
    Country: Number of subjects enrolled
    Czech Republic: 50
    Country: Number of subjects enrolled
    Estonia: 57
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 107
    Country: Number of subjects enrolled
    Germany: 268
    Country: Number of subjects enrolled
    Greece: 97
    Country: Number of subjects enrolled
    Hungary: 57
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Italy: 113
    Country: Number of subjects enrolled
    China: 159
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Japan: 210
    Country: Number of subjects enrolled
    Korea, Republic of: 108
    Country: Number of subjects enrolled
    Russian Federation: 55
    Country: Number of subjects enrolled
    Singapore: 1
    Country: Number of subjects enrolled
    Switzerland: 11
    Country: Number of subjects enrolled
    Taiwan: 31
    Country: Number of subjects enrolled
    Thailand: 20
    Country: Number of subjects enrolled
    Ukraine: 22
    Country: Number of subjects enrolled
    United States: 343
    Worldwide total number of subjects
    2312
    EEA total number of subjects
    1220
    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)
    1251
    From 65 to 84 years
    1055
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 2315 patients were screened towards participation in the study. For 3 of these subjects informed consent forms issues were reported, and thus only 2312 subjects were considered for analyses/results Out of these 2312 subjects, 2278 were enrolled in the study.

    Pre-assignment
    Screening details
    		 Out of the 2278 enrolled patients, only 2272 patients received at least one dose of study treatment (1515 received MAGE-A3 ASCI and 757 received placebo).

    Pre-assignment period milestones
    Number of subjects started
    		 2312
    Number of subjects completed
    		 2272

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Not treated: 40
    Period 1
    Period 1 title
    Entire Study Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Because the final establishment of the gene expression signature classifier by testing the samples on the training set was to only start after a positive interim analysis or after the final analysis of DFS in the overall/no-CT population, Disease Free Survival (DFS) in the GS+ population was to be analyzed at a later time point. Therefore, the Sponsor, investigators and patients should remain blinded to the treatment assignment until analysis of DFS in the GS+ population.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MAGE-A3 Total Group
    Arm description
    		 Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    recMAGE-A3 recombinant protein formulated in AS15 adjuvant
    Investigational medicinal product code
    recMAGE-A3 + AS15
    Other name
    MAGE-A3 ASCI, MAGE-A3 ASCI product, GSK1572932A
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Up to 13 doses via intramuscular injections in the deltoid or lateral region of the thigh preferably alternating on right and left side.

    Arm title
    		 Placebo Total Group
    Arm description
    		 Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Sucrose reconstituted with an oil-in-water emulsion
    Pharmaceutical forms
    Powder and suspension for suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Up to 13 doses via intramuscular injections in the deltoid or lateral region of the thigh preferably alternating on right and left side.

    Number of subjects in period 1 [1]
    		MAGE-A3 Total Group Placebo Total Group
    Started
    1515
    757
    Completed
    763
    388
    Not completed
    752
    369
         Adverse event, non-fatal
    44
    12
         Disease Progression / Recurrence
    449
    224
         SAE including intercurrent illness
    76
    42
         Unspecified
    70
    29
         Protocol deviation
    12
    7
         Patients remaining ongoing at Data Lock Point
    101
    55
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of the 2312 enrolled patients, not all started treatment, only 2272 patients started the trial.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MAGE-A3 Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Reporting group title
    Placebo Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Reporting group values
    		 MAGE-A3 Total Group Placebo Total Group Total
    Number of subjects
    		 1515 757 2272
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.1 ± 8.96 63.4 ± 9.15 -
    Gender categorical
    Units: Subjects
        Female
    		 370 179 549
        Male
    		 1145 578 1723
    Subject analysis sets

    Subject analysis set title
    MAGE-A3 CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had received adjuvant chemotherapy prior to randomization (CT Population).

    Subject analysis set title
    Placebo CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had received adjuvant chemotherapy prior to randomization (CT Population).

    Subject analysis set title
    MAGE-A3 No-CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had not received adjuvant chemotherapy prior to randomization (No-CT Population).

    Subject analysis set title
    Placebo No-CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had not received adjuvant chemotherapy prior to randomization (No-CT Population).

    Subject analysis sets values
    		 MAGE-A3 CT Group Placebo CT Group MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects
    784
    392
    731
    365
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    61.1 ± 8.27
    61.1 ± 8.65
    65.3 ± 9.16
    65.8 ± 9.07
    Gender categorical
    Units: Subjects
        Female
    185
    97
    185
    82
        Male
    599
    295
    546
    283

    End points

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    End points reporting groups
    Reporting group title
    MAGE-A3 Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Reporting group title
    Placebo Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Subject analysis set title
    MAGE-A3 CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had received adjuvant chemotherapy prior to randomization (CT Population).

    Subject analysis set title
    Placebo CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had received adjuvant chemotherapy prior to randomization (CT Population).

    Subject analysis set title
    MAGE-A3 No-CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had not received adjuvant chemotherapy prior to randomization (No-CT Population).

    Subject analysis set title
    Placebo No-CT Group
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks. Patients in this sub-group consisted solely of patients who had not received adjuvant chemotherapy prior to randomization (No-CT Population).

    Primary: Person year rate (PYAR) as regards disease-free survival (DFS) in the overall population

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    End point title
    		 Person year rate (PYAR) as regards disease-free survival (DFS) in the overall population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: events/person-years
    number (not applicable)
        DFS PYAR – Overall Population
    0.17
    0.168
    Statistical analysis title
    		 DFS Comparing MAGE-A3 vs placebo – All Patients
    Statistical analysis description
    Analysis compared DFS PYAR between groups for period from 1st treatment dose to DLP. A Cox model was used to evaluate treatment efficacy (TE). TE was calculated as PYAR in MAGE-A3 Total Group (PYAR1) divided by PYAR in Placebo Total Group (PYAR2), and weighed for adjustment factors. This comparison in all patients (overall population) also included taking into account stratification by previous CT vs. No-CT treatment and weighing using randomization-minimization factors (RMF) as regressors.
    Comparison groups
    MAGE-A3 Total Group v Placebo Total Group
    Number of subjects included in analysis
    2272
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.7379 [2]
    Method
    		 Regression, Cox
    Parameter type
    		 TE
    Point estimate
    1.024
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.891
         upper limit
    		 1.177
    Notes
    [1] - RMF taken into account included: 1) Number of chemotherapy cycles received (1, 2 vs. 3, 4), if any; 2) Pathological stage of the disease (IB vs. II vs. IIIA); 3) Type of lymph-node sampling (minimal lymph-node sampling vs. systematic radical mediastinal lymphadenectomy); 4) ECOG performance status randomization (0, 1 vs. 2); 5) Smoking status ( 100 cigarettes a lifetime vs. > 100 cigarettes and current smoker vs. > 100 cigarettes and past smoker).
    [2] - 2-sided p-value of Likelihood Ratio test from RMF-adjusted Cox regression, Efron method used to handle ties. Overall population objective reached if p-value < 2%/4% in absence/presence of statistically significant effect in the No-CT population.

    Primary: Person year rate (PYAR) as regards disease-free survival (DFS) in the No-CT population

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    End point title
    		 Person year rate (PYAR) as regards disease-free survival (DFS) in the No-CT population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects analysed
    731
    365
    Units: events/person-years
    number (not applicable)
        DFS PYAR – No-CT Population
    0.169
    0.178
    Statistical analysis title
    		 DFS Comparing MAGE-A3 vs placebo – No-CT Patients
    Statistical analysis description
    Analysis compared DFS PYAR between groups for the period from 1st treatment dose to DLP. A Cox model was used to evaluate treatment efficacy (TE). TE was calculated as PYAR in MAGE-A3 No-CT Group (PYAR1) divided by PYAR in Placebo No-CT Group (PYAR2) and weighed for adjustment factors. This comparison in all patients (overall population) also included taking into account weighing using randomization-minimization factors (RMF) as regressors.
    Comparison groups
    MAGE-A3 No-CT Group v Placebo No-CT Group
    Number of subjects included in analysis
    1096
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.7572 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 TE
    Point estimate
    0.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.797
         upper limit
    		 1.179
    Notes
    [3] - RMF included: 1) Number of chemotherapy cycles received (1, 2 vs. 3, 4), if any; 2) Pathological stage of the disease (IB vs. II vs. IIIA); 3) Type of lymph-node sampling (minimal lymph-node sampling vs. systematic radical mediastinal lymphadenectomy); 4) ECOG performance status randomization (0, 1 vs. 2); 5) Smoking status ( 100 cigarettes a lifetime vs. > 100 cigarettes and current smoker vs. > 100 cigarettes and past smoker).
    [4] - 2-sided p-value of Likelihood Ratio test from RMF-adjusted Cox regression, Efron method used to handle ties. No-CT population objective reached if p-value < 2.56%/4% in absence/presence of statistically significant effect in the No-CT population.

    Secondary: Person year rate (PYAR) as regards disease-free survival (DFS) in the CT population

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    End point title
    		 Person year rate (PYAR) as regards disease-free survival (DFS) in the CT population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 CT Group Placebo CT Group
    Number of subjects analysed
    784
    392
    Units: events/person-years
    number (not applicable)
        DFS PYAR – CT Population
    0.172
    0.158
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards overall-survival (OS) in the overall population

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    End point title
    		 Person year rate (PYAR) as regards overall-survival (OS) in the overall population
    End point description
    OS was defined as the time interval from randomization to the date of death, irrespective of the cause of death. Patients still alive were censored at the last visit they were known to be alive. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: events/person-years
    number (not applicable)
        OS PYAR – Overall Population
    0.082
    0.081
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards overall-survival (OS) in the No-CT population

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    End point title
    		 Person year rate (PYAR) as regards overall-survival (OS) in the No-CT population
    End point description
    OS was defined as the time interval from randomization to the date of death, irrespective of the cause of death. Patients still alive were censored at the last visit they were known to be alive. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects analysed
    731
    365
    Units: events/person-years
    number (not applicable)
        OS PYAR – No-CT Population
    0.084
    0.086
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards overall-survival (OS) in the CT population

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    End point title
    		 Person year rate (PYAR) as regards overall-survival (OS) in the CT population
    End point description
    OS was defined as the time interval from randomization to the date of death, irrespective of the cause of death. Patients still alive were censored at the last visit they were known to be alive. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 CT Group Placebo CT Group
    Number of subjects analysed
    784
    392
    Units: events/person-years
    number (not applicable)
        OS PYAR – CT Population
    0.08
    0.076
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the Overall population

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    End point title
    		 Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the Overall population
    End point description
    LCSS was defined as the time interval from randomization to the date of death due to lung cancer. Deaths due to other or unknown causes were censored at the date of death. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: events/person-years
    number (not applicable)
        LCSS PYAR – Overall Population
    0.064
    0.061
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the No-CT population

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    End point title
    		 Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the No-CT population
    End point description
    LCSS was defined as the time interval from randomization to the date of death due to lung cancer. Deaths due to other or unknown causes were censored at the date of death. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects analysed
    731
    365
    Units: events/person-years
    number (not applicable)
        LCSS PYAR – No-CT Population
    0.064
    0.06
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the CT population

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    End point title
    		 Person year rate (PYAR) as regards lung-cancer specific survival (LCSS) in the CT population
    End point description
    LCSS was defined as the time interval from randomization to the date of death due to lung cancer. Deaths due to other or unknown causes were censored at the date of death. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median OS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 CT Group Placebo CT Group
    Number of subjects analysed
    784
    392
    Units: events/person-years
    number (not applicable)
        LCSS PYAR – CT Population
    0.063
    0.063
    No statistical analyses for this end point

    Secondary: Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the overall population

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    End point title
    		 Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the overall population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. Median DFS KMEs in % were obtained non-parametrically by Kaplan-Meier method and confidence intervals (CIs) calculated using the Greenwood formula for standard error computation.
    End point type
    Secondary
    End point timeframe
    KME assessed at 2, 3, 4 and 5-year (Y) post Dose 1 of treatment. Follow-up period was from administration of 1st dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: percent probability
    median (confidence interval 95%)
        DFS KME at 2Y – Overall Population
    65.57 (63.08 to 67.95)
    65.5 (61.94 to 68.81)
        DFS KME at 3Y – Overall Population
    59.97 (57.3 to 62.53)
    60.42 (56.62 to 64)
        DFS KME at 4Y – Overall Population
    56.72 (53.8 to 59.54)
    57.19 (53.07 to 61.1)
        DFS KME at 5Y – Overall Population
    51.73 (47.66 to 55.64)
    49.56 (42.87 to 55.88)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the No-CT population

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    End point title
    		 Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the No-CT population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. Median DFS KMEs in % were obtained non-parametrically by Kaplan-Meier method and confidence intervals (CIs) calculated using the Greenwood formula for standard error computation.
    End point type
    Secondary
    End point timeframe
    KME assessed at 2, 3, 4 and 5-year (Y) post Dose 1 of treatment Follow-up period was from administration of 1st dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects analysed
    731
    365
    Units: percent probability
    median (confidence interval 95%)
        DFS KME at 2Y – No-CT Population
    66.03 (62.39 to 69.4)
    63.96 (58.72 to 68.72)
        DFS KME at 3Y – No-CT Population
    59.6 (55.7 to 63.27)
    57.62 (52.02 to 62.81)
        DFS KME at 4Y – No-CT Population
    55.4 (51.06 to 59.52)
    54.85 (48.98 to 60.33)
        DFS KME at 5Y – No-CT Population
    49.72 (43.44 to 55.67)
    44.59 (34.64 to 54.05)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the CT population

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    End point title
    		 Kaplan-Meier estimate (KME) of 2, 3, 4 and 5-year as regards disease-free survival (DFS) in the CT population
    End point description
    DFS = time interval from randomization to 1st evidence of recurrence/death, if occurring before. All recurrence types were included, including local, regional & distant metastasis & 2nd primary lung cancer (i.e. local recurrence, defined as a tumor within same lung or at bronchial stump; regional recurrence, involving a clinically or radiologically manifest disease in mediastinum or supraclavicular nodes; & distant recurrence [any tumor arising in contralateral lung or outside hemithorax]). Deaths occurring without prior documentation of recurrence were considered as event & not censored. If no event occurred by time of analysis, time to event was censored at last assessment date of patient. New 1ry cancers outside lungs were not considered as event. Median DFS KMEs in % were obtained non-parametrically by Kaplan-Meier method and confidence intervals (CIs) calculated using the Greenwood formula for standard error computation.
    End point type
    Secondary
    End point timeframe
    KME assessed at 2, 3, 4 and 5-year (Y) post Dose 1 of treatment. Follow-up period was from administration of 1st dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 CT Group Placebo CT Group
    Number of subjects analysed
    784
    392
    Units: percent probability
    median (confidence interval 95%)
        DFS KME at 2Y – CT Population
    65.17 (61.67 to 68.43)
    66.94 (61.98 to 71.41)
        DFS KME at 3Y – CT Population
    60.39 (56.68 to 63.89)
    63.09 (57.84 to 67.87)
        DFS KME at 4Y – CT Population
    58.17 (54.22 to 61.9)
    59.3 (53.33 to 64.76)
        DFS KME at 5Y – CT Population
    53.64 (48.28 to 58.7)
    54.8 (46.44 to 62.39)
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the overall population

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    End point title
    		 Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the overall population
    End point description
    DFSS was defined as the interval from randomization to the date of disease recurrence or death due to lung cancer. Patients who had died due to another cause than lung cancer were censored on their date of death and patients alive at the time of analysis were censored on the date of last assessment. Patients with no assessment post-randomization were censored on the date of randomization. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: events/person-years
    number (not applicable)
        DFSS PYAR – Overall Population
    0.159
    0.154
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the No-CT population

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    End point title
    		 Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the No-CT population
    End point description
    DFSS was defined as the interval from randomization to the date of disease recurrence or death due to lung cancer. Patients who had died due to another cause than lung cancer were censored on their date of death and patients alive at the time of analysis were censored on the date of last assessment. Patients with no assessment post-randomization were censored on the date of randomization. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 No-CT Group Placebo No-CT Group
    Number of subjects analysed
    731
    365
    Units: events/person-years
    number (not applicable)
        DFSS PYAR – No-CT Population
    0.155
    0.159
    No statistical analyses for this end point

    Secondary: Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the CT population

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    End point title
    		 Person year rate (PYAR) as regards disease-free specific survival (DFSS) in the CT population
    End point description
    DFSS was defined as the interval from randomization to the date of disease recurrence or death due to lung cancer. Patients who had died due to another cause than lung cancer were censored on their date of death and patients alive at the time of analysis were censored on the date of last assessment. Patients with no assessment post-randomization were censored on the date of randomization. PYAR = n (=number of subjects reported with at least 1 event) divided by T (=sum of follow-up period [in years] censored at 1st occurrence of event in group). Median DFS estimates were obtained non-parametrically by Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from administration of first dose of MAGE-A3 ASCI study product/placebo solution to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 CT Group Placebo CT Group
    Number of subjects analysed
    784
    392
    Units: events/person-years
    number (not applicable)
        DFSS PYAR – CT Population
    0.162
    0.149
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for anti-Melanoma AntiGEn (MAGE)-A3 antibodies (Anti-MAGE-A3 S+)

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    End point title
    		 Number of subjects seropositive for anti-Melanoma AntiGEn (MAGE)-A3 antibodies (Anti-MAGE-A3 S+)
    End point description
    A seropositive subject for anti-MAGE-A3 antibodies was a subject with anti-MAGE-A3 antibodies >= the seropositivity cut-off of 27 Enzyme-linked immunosorbent assay (ELISA) units per millilitre (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    Pre-treatment (PRE), at Weeks (W) 6 and 12, at Months (M) 9, 12, 18 and 30 and at one year after treatment concluding time point, i.e. at follow-up visit 2 at W120 added of one year (At 12M post W120)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1184
    614
    Units: Subjects
        Anti-MAGE-A3 S+, PRE (N=1184;614)
    105
    53
        Anti-MAGE-A3 S+, W6 (N=945;548)
    929
    43
        Anti-MAGE-A3 S+, W12 (N=925;491)
    921
    42
        Anti-MAGE-A3 S+, M9 (N=633;352)
    631
    30
        Anti-MAGE-A3 S+, M12 (N=538;279)
    536
    19
        Anti-MAGE-A3 S+, M18 (N=420;229)
    419
    15
        Anti-MAGE-A3 S+, M30 (N=384;222)
    383
    17
        Anti-MAGE-A3 S+, at 12M post W120 (N=76;47)
    75
    5
    No statistical analyses for this end point

    Secondary: Number of humoral responders as regards anti-Melanoma AntiGEn (MAGE)-A3 antibodies (Anti-MAGE-A3 HR)

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    End point title
    		 Number of humoral responders as regards anti-Melanoma AntiGEn (MAGE)-A3 antibodies (Anti-MAGE-A3 HR)
    End point description
    A seropositive/seronegative subject for anti-MAGE-A3 antibodies was a subject with anti-MAGE-A3 antibodies >=/< the seropositivity cut-off of 27 Enzyme-linked immunosorbent assay (ELISA) units per millilitre (EL.U/mL). A humoral responder as regards anti-MAGE-A3 antibodies was defined as 1) for initially seronegative patients, a patient with post-administration Anti-MAGE-A3 antibody concentration >= 27 EL.U/mL; 2) for initially seropositive patients: post-treatment administration antibody concentration >= 2 fold the pre-treatment antibody concentration.
    End point type
    Secondary
    End point timeframe
    At Weeks (W) 6 and 12, at Months (M) 9, 12, 18 and 30 and at one year after treatment concluding time point, i.e. at follow-up visit 2 at W120 added of one year (at 12M post W120)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    942
    548
    Units: Subjects
        Anti-MAGE-A3 HR, W6 (N=942;548)
    922
    10
        Anti-MAGE-A3 HR, W12 (N=920;491)
    916
    15
        Anti-MAGE-A3 HR, M9 (N=630;352)
    627
    13
        Anti-MAGE-A3 HR, M12 (N=537;279)
    534
    6
        Anti-MAGE-A3 HR, M18 (N=420;229)
    417
    7
        Anti-MAGE-A3 HR, M30 (N=382;222)
    380
    8
        Anti-MAGE-A3 HR, at 12M post W120 (N=76;47)
    75
    3
    No statistical analyses for this end point

    Secondary: Number of subjects seropositive for anti-protein D (PD) antibodies (Anti-PD S+)

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    End point title
    		 Number of subjects seropositive for anti-protein D (PD) antibodies (Anti-PD S+)
    End point description
    A seropositive subject for anti-PD antibodies was a subject with anti-PD antibodies >= the seropositivity cut-off of 100 Enzyme-linked immunosorbent assay (ELISA) units per millilitre (EL.U/mL).
    End point type
    Secondary
    End point timeframe
    Pre-treatment (PRE), at Weeks (W) 6 and 12, at Months (M) 9, 12, 18 and 30 and at one year after treatment concluding time point, i.e. at follow-up visit 2 at W120 added of one year (at 12M post W120)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1096
    554
    Units: Subjects
        Anti-PD S+, PRE (N=1096;554)
    381
    210
        Anti-PD S+, W6 (N=967;493)
    958
    195
        Anti-PD S+, W12 (N=864;436)
    860
    176
        Anti-PD S+, M9 (N=582;311)
    580
    133
        Anti-PD S+, M12 (N=485;243)
    483
    101
        Anti-PD S+, M18 (N=376;197)
    375
    77
        Anti-PD S+, M30 (N=358;189)
    357
    75
        Anti-PD S+, at 12M post W120 (N=78;46)
    77
    17
    No statistical analyses for this end point

    Secondary: Number of humoral responders as regards anti-protein D (PD) antibodies (Anti-PD HR)

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    End point title
    		 Number of humoral responders as regards anti-protein D (PD) antibodies (Anti-PD HR)
    End point description
    A seropositive/seronegative subject for anti-PD antibodies was a subject with anti-PD antibodies ≥/< the seropositivity cut-off of 100 Enzyme-linked immunosorbent assay (ELISA) units per millilitre (EL.U/mL). A humoral responder as regards anti-PD antibodies was defined as 1) for initially seronegative patients, a patient with post-administration anti-PD antibody concentration ≥ 100 EL.U/mL; 2) for initially seropositive patients: post-administration antibody concentration ≥ 2 fold the pre-vaccination antibody concentration.
    End point type
    Secondary
    End point timeframe
    At Weeks (W) 6 and 12, at Months (M) 9, 12, 18 and 30 and at one year after treatment concluding time point, i.e. at follow-up visit 2 at W120 added of one year (at 12M post W120)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    962
    490
    Units: Subjects
        Anti-PD HR, W6 (N=962;490)
    945
    27
        Anti-PD HR, W12 (N=859;432)
    853
    35
        Anti-PD HR, M9 (N=579;307)
    575
    26
        Anti-PD HR, M12 (N=482;240)
    479
    19
        Anti-PD HR, M18 (N=374;194)
    370
    21
        Anti-PD HR, M30 (N=354;186)
    352
    17
        Anti-PD HR, at 12M post W120 (N=78;46)
    77
    4
    No statistical analyses for this end point

    Secondary: Health-related quality of life (HQL) scores

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    End point title
    		 Health-related quality of life (HQL) scores
    End point description
    HQL was assessed using the EQ-5D generic health state classification and valuation system. The number and percentage of patients with each score within each dimension of the EQ-5D questionnaire (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) were tabulated at each assessment for each group. Each of these scores can take 3 levels: no problem (level 1), moderate problem (level 2) or extreme problem (level 3). Resulting descriptive mean and standard deviation (SD) for the EQ-5D Utility Value (EQ-5D UV) were tabulated.Valid EQ-5D data were defined as questionnaires assessed 1) on day of and before treatment administration; or 2) on day after treatment administration for W0, W6, W12; or 3)during follow-up visits or at time of recurrence. The EQ-5D total score ranges from -0.016 (worst health state) to 1.000 (best health state).
    End point type
    Secondary
    End point timeframe
    At Week (W) 0 on day of treatment (DoT) (W0 DoT), W0 on day post treatment (DpT) (W0 DpT), W6 DoT, W6 DpT, W12 DoT, W12 DpT, Month (M) 6, M9, M12, M24, 6M post W120, at recurrence, and at 12M post W120
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    226
    103
    Units: Score on a scale
    arithmetic mean (standard deviation)
        EQ-5D UV, At W0 DoT (N=226;103)
    0.83 ± 0.152
    0.823 ± 0.189
        EQ-5D UV, At W0 DpT (N=206;93)
    0.788 ± 0.182
    0.838 ± 0.177
        EQ-5D UV, At W6 DoT (N=215;99)
    0.837 ± 0.182
    0.825 ± 0.191
        EQ-5D UV, At W6 DpT (N=188;94)
    0.798 ± 0.205
    0.835 ± 0.176
        EQ-5D UV, At W12 DoT (N=201;97)
    0.848 ± 0.158
    0.811 ± 0.236
        EQ-5D UV, At W12 DpT (N=186;87)
    0.841 ± 0.152
    0.831 ± 0.211
        EQ-5D UV, At M6 (N=176;84)
    0.847 ± 0.182
    0.825 ± 0.236
        EQ-5D UV, At M9 (N=173;81)
    0.84 ± 0.197
    0.81 ± 0.219
        EQ-5D UV, At M12 (N=146;69)
    0.857 ± 0.166
    0.824 ± 0.214
        EQ-5D UV, At M24 (N=102;50)
    0.855 ± 0.179
    0.865 ± 0.145
        EQ-5D UV, At 6M post W120 (N=7;3)
    0.723 ± 0.298
    0.679 ± 0.073
        EQ-5D UV, At recurrence (N=41;14)
    0.662 ± 0.343
    0.785 ± 0.159
        EQ-5D UV, At 12M post W120 (N=16;5)
    0.753 ± 0.199
    0.777 ± 0.395
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal alanine aminotransferase (ALT) values by maximum grade

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    End point title
    		 Number of patients with abnormal alanine aminotransferase (ALT) values by maximum grade
    End point description
    The status of each patient as regards ALT laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1 and G2. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        ALT - SCR UNK; DLP G0
    1
    0
        ALT - SCR UNK; DLP G1
    1
    1
        ALT - SCR UNK; DLP G2
    0
    0
        ALT - SCR UNK; DLP G3
    0
    0
        ALT - SCR UNK; DLP G4
    0
    0
        ALT - SCR UNK; DLP UNK
    3
    1
        ALT - SCR G0; DLP G0
    1133
    588
        ALT - SCR G0; DLP G1
    162
    77
        ALT - SCR G0; DLP G2
    17
    8
        ALT - SCR G0; DLP G3
    7
    7
        ALT - SCR G0; DLP G4
    1
    1
        ALT - SCR G0; DLP UNK
    113
    37
        ALT - SCR G1; DLP G0
    34
    14
        ALT - SCR G1; DLP G1
    32
    17
        ALT - SCR G1; DLP G2
    4
    3
        ALT - SCR G1; DLP G3
    1
    2
        ALT - SCR G1; DLP G4
    0
    0
        ALT - SCR G1; DLP UNK
    4
    1
        ALT - SCR G2; DLP G0
    0
    0
        ALT - SCR G2; DLP G1
    1
    0
        ALT - SCR G2; DLP G2
    1
    0
        ALT - SCR G2; DLP G3
    0
    0
        ALT - SCR G2; DLP G4
    0
    0
        ALT - SCR G2; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal alanine aspartate aminotransferase (AST) values by maximum grade

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    End point title
    		 Number of patients with abnormal alanine aspartate aminotransferase (AST) values by maximum grade
    End point description
    The status of each patient as regards AST laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1 and G2. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        AST - SCR UNK; DLP G0
    12
    4
        AST - SCR UNK; DLP G1
    5
    2
        AST - SCR UNK; DLP G2
    0
    0
        AST - SCR UNK; DLP G3
    0
    0
        AST - SCR UNK; DLP G4
    0
    0
        AST - SCR UNK; DLP UNK
    5
    2
        AST - SCR G0; DLP G0
    1170
    579
        AST - SCR G0; DLP G1
    136
    84
        AST - SCR G0; DLP G2
    6
    4
        AST - SCR G0; DLP G3
    8
    5
        AST - SCR G0; DLP G4
    2
    1
        AST - SCR G0; DLP UNK
    111
    37
        AST - SCR G1; DLP G0
    26
    19
        AST - SCR G1; DLP G1
    25
    16
        AST - SCR G1; DLP G2
    5
    2
        AST - SCR G1; DLP G3
    0
    1
        AST - SCR G1; DLP G4
    0
    0
        AST - SCR G1; DLP UNK
    2
    1
        AST - SCR G2; DLP G0
    0
    0
        AST - SCR G2; DLP G1
    0
    0
        AST - SCR G2; DLP G2
    0
    0
        AST - SCR G2; DLP G3
    1
    0
        AST - SCR G2; DLP G4
    0
    0
        AST - SCR G2; DLP UNK
    1
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal alkaline phosphatase (ALKP) values by maximum grade

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    End point title
    		 Number of patients with abnormal alkaline phosphatase (ALKP) values by maximum grade
    End point description
    The status of each patient as regards ALKP laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1 and G2. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        ALKP - SCR UNK; DLP G0
    21
    3
        ALKP - SCR UNK; DLP G1
    0
    0
        ALKP - SCR UNK; DLP G2
    0
    0
        ALKP - SCR UNK; DLP G3
    1
    0
        ALKP - SCR UNK; DLP G4
    0
    0
        ALKP - SCR UNK; DLP UNK
    5
    3
        ALKP - SCR G0; DLP G0
    1121
    569
        ALKP - SCR G0; DLP G1
    99
    63
        ALKP - SCR G0; DLP G2
    3
    2
        ALKP - SCR G0; DLP G3
    1
    0
        ALKP - SCR G0; DLP G4
    0
    0
        ALKP - SCR G0; DLP UNK
    107
    39
        ALKP - SCR G1; DLP G0
    63
    35
        ALKP - SCR G1; DLP G1
    79
    38
        ALKP - SCR G1; DLP G2
    1
    0
        ALKP - SCR G1; DLP G3
    1
    0
        ALKP - SCR G1; DLP G4
    0
    0
        ALKP - SCR G1; DLP UNK
    11
    4
        ALKP - SCR G2; DLP G0
    0
    0
        ALKP - SCR G2; DLP G1
    2
    1
        ALKP - SCR G2; DLP G2
    0
    0
        ALKP - SCR G2; DLP G3
    0
    0
        ALKP - SCR G2; DLP G4
    0
    0
        ALKP - SCR G2; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal bilirubin (BIL) values by maximum grade

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    End point title
    		 Number of patients with abnormal bilirubin (BIL) values by maximum grade
    End point description
    The status of each patient as regards BIL laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0) and G1. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        BIL - SCR UNK; DLP G0
    9
    2
        BIL - SCR UNK; DLP G1
    1
    0
        BIL - SCR UNK; DLP G2
    0
    0
        BIL - SCR UNK; DLP G3
    0
    0
        BIL - SCR UNK; DLP G4
    0
    0
        BIL - SCR UNK; DLP UNK
    4
    2
        BIL - SCR G0; DLP G0
    1275
    661
        BIL - SCR G0; DLP G1
    74
    28
        BIL - SCR G0; DLP G2
    11
    9
        BIL - SCR G0; DLP G3
    1
    2
        BIL - SCR G0; DLP G4
    1
    0
        BIL - SCR G0; DLP UNK
    114
    37
        BIL - SCR G1; DLP G0
    10
    5
        BIL - SCR G1; DLP G1
    8
    9
        BIL - SCR G1; DLP G2
    5
    1
        BIL - SCR G1; DLP G3
    1
    0
        BIL - SCR G1; DLP G4
    0
    0
        BIL - SCR G1; DLP UNK
    1
    1
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal creatinine (CREA) values by maximum grade

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    End point title
    		 Number of patients with abnormal creatinine (CREA) values by maximum grade
    End point description
    The status of each patient as regards CREA laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1 and G2. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        CREA - SCR UNK; DLP G0
    2
    0
        CREA - SCR UNK; DLP G1
    0
    0
        CREA - SCR UNK; DLP G2
    0
    0
        CREA - SCR UNK; DLP G3
    0
    0
        CREA - SCR UNK; DLP G4
    2
    0
        CREA - SCR UNK; DLP UNK
    1139
    577
        CREA - SCR G0; DLP G0
    126
    74
        CREA - SCR G0; DLP G1
    9
    3
        CREA - SCR G0; DLP G2
    3
    1
        CREA - SCR G0; DLP G3
    1
    0
        CREA - SCR G0; DLP G4
    103
    32
        CREA - SCR G0; DLP UNK
    27
    14
        CREA - SCR G1; DLP G0
    72
    44
        CREA - SCR G1; DLP G1
    11
    6
        CREA - SCR G1; DLP G2
    0
    0
        CREA - SCR G1; DLP G3
    1
    0
        CREA - SCR G1; DLP G4
    6
    4
        CREA - SCR G1; DLP UNK
    0
    0
        CREA - SCR G2; DLP G0
    7
    2
        CREA - SCR G2; DLP G1
    6
    0
        CREA - SCR G2; DLP G2
    0
    0
        CREA - SCR G2; DLP G3
    0
    0
        CREA - SCR G2; DLP G4
    0
    0
        CREA - SCR G2; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal haemoglobin (HGB) values by maximum grade

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    End point title
    		 Number of patients with abnormal haemoglobin (HGB) values by maximum grade
    End point description
    The status of each patient as regards HGB laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1, G2 and G3. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        HGB - SCR UNK; DLP G0
    3
    0
        HGB - SCR UNK; DLP G1
    1
    0
        HGB - SCR UNK; DLP G2
    0
    0
        HGB - SCR UNK; DLP G3
    0
    0
        HGB - SCR UNK; DLP G4
    0
    0
        HGB - SCR UNK; DLP UNK
    3
    0
        HGB - SCR G0; DLP G0
    534
    274
        HGB - SCR G0; DLP G1
    70
    26
        HGB - SCR G0; DLP G2
    9
    5
        HGB - SCR G0; DLP G3
    1
    1
        HGB - SCR G0; DLP G4
    0
    2
        HGB - SCR G0; DLP UNK
    50
    19
        HGB - SCR G1; DLP G0
    342
    187
        HGB - SCR G1; DLP G1
    310
    142
        HGB - SCR G1; DLP G2
    17
    14
        HGB - SCR G1; DLP G3
    6
    3
        HGB - SCR G1; DLP G4
    2
    0
        HGB - SCR G1; DLP UNK
    49
    15
        HGB - SCR G2; DLP G0
    29
    30
        HGB - SCR G2; DLP G1
    63
    31
        HGB - SCR G2; DLP G3
    12
    3
        HGB - SCR G2; DLP G4
    1
    3
        HGB - SCR G2; DLP UNK
    1
    0
        HGB - SCR G3; DLP G0
    6
    0
        HGB - SCR G3; DLP G1
    2
    1
        HGB - SCR G3; DLP G2
    3
    1
        HGB - SCR G3; DLP G3
    1
    0
        HGB - SCR G3; DLP G4
    0
    0
        HGB - SCR G3; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal leukocytes (LEU) values by maximum grade

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    End point title
    		 Number of patients with abnormal leukocytes (LEU) values by maximum grade
    End point description
    The status of each patient as regards LEU laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1, G2 and G3. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        LEU - SCR UNK; DLP G0
    1
    0
        LEU - SCR UNK; DLP G1
    0
    0
        LEU - SCR UNK; DLP G2
    0
    0
        LEU - SCR UNK; DLP G3
    0
    0
        LEU - SCR UNK; DLP G4
    0
    0
        LEU - SCR UNK; DLP UNK
    1
    0
        LEU - SCR G0; DLP G0
    1259
    652
        LEU - SCR G0; DLP G1
    45
    29
        LEU - SCR G0; DLP G2
    4
    2
        LEU - SCR G0; DLP G3
    2
    0
        LEU - SCR G0; DLP G4
    6
    2
        LEU - SCR G0; DLP UNK
    98
    32
        LEU - SCR G1; DLP G0
    54
    24
        LEU - SCR G1; DLP G1
    21
    5
        LEU - SCR G1; DLP G2
    2
    1
        LEU - SCR G1; DLP G3
    0
    0
        LEU - SCR G1; DLP G4
    0
    1
        LEU - SCR G1; DLP UNK
    4
    0
        LEU - SCR G2; DLP G0
    13
    6
        LEU - SCR G2; DLP G1
    3
    2
        LEU - SCR G2; DLP G2
    2
    0
        LEU - SCR G2; DLP G3
    0
    0
        LEU - SCR G2; DLP G4
    0
    0
        LEU - SCR G2; DLP UNK
    0
    0
        LEU - SCR G3; DLP G0
    0
    1
        LEU - SCR G3; DLP G1
    0
    0
        LEU - SCR G3; DLP G2
    0
    0
        LEU - SCR G3; DLP G3
    0
    0
        LEU - SCR G3; DLP G4
    0
    0
        LEU - SCR G3; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal lymphocytes (LYM) values by maximum grade

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    End point title
    		 Number of patients with abnormal lymphocytes (LYM) values by maximum grade
    End point description
    The status of each patient as regards LYM laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1, G2 and G3. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        LYM - SCR UNK; DLP G0
    12
    3
        LYM - SCR UNK; DLP G1
    3
    1
        LYM - SCR UNK; DLP G2
    0
    0
        LYM - SCR UNK; DLP G3
    0
    0
        LYM - SCR UNK; DLP G4
    0
    0
        LYM - SCR UNK; DLP UNK
    4
    2
        LYM - SCR G0; DLP G0
    999
    518
        LYM - SCR G0; DLP G1
    160
    89
        LYM - SCR G0; DLP G2
    40
    16
        LYM - SCR G0; DLP G3
    5
    0
        LYM - SCR G0; DLP G4
    0
    0
        LYM - SCR G0; DLP UNK
    96
    35
        LYM - SCR G1; DLP G0
    47
    27
        LYM - SCR G1; DLP G1
    86
    42
        LYM - SCR G1; DLP G2
    15
    4
        LYM - SCR G1; DLP G3
    1
    4
        LYM - SCR G1; DLP G4
    2
    0
        LYM - SCR G1; DLP UNK
    20
    5
        LYM - SCR G2; DLP G0
    3
    1
        LYM - SCR G2; DLP G1
    7
    2
        LYM - SCR G2; DLP G2
    4
    3
        LYM - SCR G2; DLP G3
    2
    1
        LYM - SCR G2; DLP G4
    0
    0
        LYM - SCR G2; DLP UNK
    0
    1
        LYM - SCR G3; DLP G0
    4
    1
        LYM - SCR G3; DLP G1
    1
    2
        LYM - SCR G3; DLP G2
    3
    0
        LYM - SCR G3; DLP G3
    1
    0
        LYM - SCR G3; DLP G4
    0
    0
        LYM - SCR G3; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal neutrophils (NEU) values by maximum grade

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    End point title
    		 Number of patients with abnormal neutrophils (NEU) values by maximum grade
    End point description
    The status of each patient as regards NEU laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1, G2, G3 and G4. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        NEU - SCR UNK; DLP G0
    12
    3
        NEU - SCR UNK; DLP G1
    0
    0
        NEU - SCR UNK; DLP G2
    0
    0
        NEU - SCR UNK; DLP G3
    0
    0
        NEU - SCR UNK; DLP G4
    0
    0
        NEU - SCR UNK; DLP UNK
    1
    2
        NEU - SCR G0; DLP G0
    1200
    625
        NEU - SCR G0; DLP G1
    47
    28
        NEU - SCR G0; DLP G2
    1
    3
        NEU - SCR G0; DLP G3
    2
    1
        NEU - SCR G0; DLP G4
    3
    1
        NEU - SCR G0; DLP UNK
    111
    37
        NEU - SCR G1; DLP G0
    56
    23
        NEU - SCR G1; DLP G1
    31
    10
        NEU - SCR G1; DLP G2
    3
    1
        NEU - SCR G1; DLP G3
    0
    0
        NEU - SCR G1; DLP G4
    0
    0
        NEU - SCR G1; DLP UNK
    3
    2
        NEU - SCR G2; DLP G0
    32
    16
        NEU - SCR G2; DLP G1
    5
    1
        NEU - SCR G2; DLP G2
    2
    2
        NEU - SCR G2; DLP G3
    0
    0
        NEU - SCR G2; DLP G4
    0
    0
        NEU - SCR G2; DLP UNK
    1
    1
        NEU - SCR G3; DLP G0
    3
    1
        NEU - SCR G3; DLP G1
    0
    0
        NEU - SCR G3; DLP G2
    0
    0
        NEU - SCR G3; DLP G3
    0
    0
        NEU - SCR G3; DLP G4
    0
    0
        NEU - SCR G3; DLP UNK
    0
    0
        NEU - SCR G4; DLP G0
    1
    0
        NEU - SCR G4; DLP G1
    0
    0
        NEU - SCR G4; DLP G2
    1
    0
        NEU - SCR G4; DLP G3
    0
    0
        NEU - SCR G4; DLP G4
    0
    0
        NEU - SCR G4; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with abnormal platelets (PLA) values by maximum grade

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    End point title
    		 Number of patients with abnormal platelets (PLA) values by maximum grade
    End point description
    The status of each patient as regards PLA laboratory values at baseline (SCR) up to DLP was collected and graded according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. The post-treatment values were presented by worst grade versus baseline grade. SCR CTC grade statuses reported were unknown (UNK), Grade 0 (G0), G1 and G3. CTC grade statuses reported at DLP were G0, G1, G2, G3, G4, and UNK.
    End point type
    Secondary
    End point timeframe
    Period of follow-up was from screening (SCR) to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        PLA - SCR UNK; DLP G0
    1
    1
        PLA - SCR UNK; DLP G1
    0
    0
        PLA - SCR UNK; DLP G2
    0
    0
        PLA - SCR UNK; DLP G3
    0
    0
        PLA - SCR UNK; DLP G4
    0
    0
        PLA - SCR UNK; DLP UNK
    1
    0
        PLA - SCR G0; DLP G0
    1275
    648
        PLA - SCR G0; DLP G1
    78
    38
        PLA - SCR G0; DLP G2
    6
    2
        PLA - SCR G0; DLP G3
    1
    0
        PLA - SCR G0; DLP G4
    7
    2
        PLA - SCR G0; DLP UNK
    98
    35
        PLA - SCR G1; DLP G0
    22
    16
        PLA - SCR G1; DLP G1
    17
    10
        PLA - SCR G1; DLP G2
    2
    4
        PLA - SCR G1; DLP G3
    1
    0
        PLA - SCR G1; DLP G4
    0
    0
        PLA - SCR G1; DLP UNK
    5
    0
        PLA - SCR G3; DLP G0
    1
    1
        PLA - SCR G3; DLP G1
    0
    0
        PLA - SCR G3; DLP G2
    0
    0
        PLA - SCR G3; DLP G3
    0
    0
        PLA - SCR G3; DLP G4
    0
    0
        PLA - SCR G3; DLP UNK
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with any adverse events (AEs) and with AEs by maximum grade reported – Up to data lock point (DLP)

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    End point title
    		 Number of patients with any adverse events (AEs) and with AEs by maximum grade reported – Up to data lock point (DLP)
    End point description
    An AE was any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs reported are here below tabulated irrespective of grade, as well as graded by maximum grade reported according to the Common Terminology Criteria (CTC) Adverse event terminology, version 3.0. Maximum grade reported and tabulated were Grade 1 (G1), G2, G3, G4 and G5. Any here below is defined as irrespective of CTC grade reported.
    End point type
    Secondary
    End point timeframe
    Within the 31-day follow-up period post treatment administration, up to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        Patients with any AEs
    1369
    556
        Patients with G1 AEs
    563
    225
        Patients with G2 AEs
    560
    209
        Patients with G3 AEs
    184
    88
        Patients with G4 AEs
    49
    26
        Patients with G5 AEs
    13
    8
    No statistical analyses for this end point

    Secondary: Number of patients with serious adverse events (SAEs) – Up to data lock point (DLP)

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    End point title
    		 Number of patients with serious adverse events (SAEs) – Up to data lock point (DLP)
    End point description
    A SAE is any untoward medical occurrence that resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability/incapacity, was a congenital anomaly/birth defect in the offspring of a study subject, or was a Grade 4 AE according to CTC for Adverse Events, Version 3.0. Events part of natural course of lung cancer (i.e., disease progression, recurrence) were captured towards clinical efficacy assessment (CEA) and were not reported as SAEs. Death due to a progressive disease was similarly recorded towards CEA, but not as an SAE. However, if progression of lung cancer disease was greater than normally be expected, or if investigators considered that there was a causal relationship between treatment or protocol design/procedures and disease progression/ recurrence, then it was reported as SAE. Any new cancer (non-related to lung cancer) was reported as SAE.
    End point type
    Secondary
    End point timeframe
    From screening (SCR) up to data lock point (DLP) on 23 January 2014 (up to 5 years per patient)
    End point values
    		 MAGE-A3 Total Group Placebo Total Group
    Number of subjects analysed
    1515
    757
    Units: Subjects
        Patient(s) with SAE(s)
    330
    164
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From screening (Day 0) up to data lock point (DLP) on 23 January 2014, for up to 5 years per patient.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    MAGE-A3 Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of MAGE-A3 ASCI, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Reporting group title
    Placebo Total Group
    Reporting group description
    		 Patients received up to 13 doses (D) of placebo, 5 Ds every 3 weeks followed by 8 Ds every 12 weeks.

    Serious adverse events
    		 MAGE-A3 Total Group Placebo Total Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    330 / 1515 (21.78%)
    164 / 757 (21.66%)
         number of deaths (all causes)
    30
    17
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    4 / 1515 (0.26%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma pancreas
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Basal cell carcinoma
         subjects affected / exposed
    8 / 1515 (0.53%)
    4 / 757 (0.53%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign oesophageal neoplasm
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder cancer
         subjects affected / exposed
    2 / 1515 (0.13%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bladder transitional cell carcinoma
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder transitional cell carcinoma stage II
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bowen’s disease
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1515 (0.07%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brenner tumour
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemangioma
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colon cancer
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dermatofibrosarcoma protuberans
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diffuse large b-cell lymphoma
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric cancer
         subjects affected / exposed
    2 / 1515 (0.13%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal stromal tumour
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal squamous cell carcinoma
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lentigo maligna
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukaemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant peritoneal neoplasm
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oesophageal adenocarcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oropharyngeal cancer
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ovarian cancer metastatic
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian fibroma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic carcinoma metastatic
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    8 / 1515 (0.53%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer recurrent
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal adenocarcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cancer
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seborrhoeic keratosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of pharynx
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tracheal cancer
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    5 / 1515 (0.33%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    4 / 1515 (0.26%)
    4 / 757 (0.53%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bleeding varicose vein
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurogenic shock
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 1515 (0.13%)
    5 / 757 (0.66%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery thrombosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         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
    Asthenia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 1515 (0.20%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    2 / 1515 (0.13%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 3
    Euthanasia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Impaired healing
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mass
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         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 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorder
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Acquired hydrocele
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical dysplasia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ovarian cyst
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    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 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute respiratory failure
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Alveolitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Apnoea
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopleural fistula
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchostenosis
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    6 / 1515 (0.40%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiccups
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic pulmonary fibrosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal oedema
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infiltration
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    4 / 1515 (0.26%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    7 / 1515 (0.46%)
    4 / 757 (0.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pulmonary granuloma
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 1515 (0.00%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    17 / 1515 (1.12%)
    4 / 757 (0.53%)
         occurrences causally related to treatment / all
    0 / 18
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Alcohol withdrawal syndrome
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood uric acid increased
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 1515 (0.07%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Alcohol poisoning
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    6 / 1515 (0.40%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (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 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site pain
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative thoracic procedure complication
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural complication
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural haemorrhage
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural intestinal perforation
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skull fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Splenic rupture
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Traumatic intracranial haemorrhage
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 1515 (0.13%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adams-stokes syndrome
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    3 / 1515 (0.20%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 1515 (0.26%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Atrial flutter
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    5 / 1515 (0.33%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 1515 (0.07%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiac fibrillation
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac flutter
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congestive cardiomyopathy
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    4 / 1515 (0.26%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prinzmetal angina
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Silent myocardial infarction
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         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
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stress cardiomyopathy
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    2 / 1515 (0.13%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia alzheimer’s type
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial aneurysm
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 1515 (0.26%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    2 / 1515 (0.13%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 1515 (0.46%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia macrocytic
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersplenism
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Idiopathic thrombocytopenic purpura
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenitis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Age-related macular degeneration
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Macular fibrosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal artery occlusion
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         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 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis microscopic
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis ulcerative
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diaphragmatic hernia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis intestinal haemorrhagic
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal stenosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         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 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 1515 (0.07%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    5 / 1515 (0.33%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    7 / 1515 (0.46%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia, obstructive
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal polyp
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic necrosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatitis chronic
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritoneal adhesions
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis chronic
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    3 / 1515 (0.20%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    4 / 1515 (0.26%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Portal vein thrombosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytoclastic vasculitis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash pruritic
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Glomerulonephritis rapidly progressive
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    5 / 1515 (0.33%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ureteric dilatation
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary bladder polyp
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (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
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (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
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibromyalgia
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    4 / 1515 (0.26%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    3 / 1515 (0.20%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic sclerosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute hepatitis b
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Carbuncle
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis streptococcal
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Citrobacter infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea infectious
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diverticulitis
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    0 / 1515 (0.00%)
    2 / 757 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis b
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    3 / 1515 (0.20%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    5 / 1515 (0.33%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection viral
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (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
    4 / 1515 (0.26%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    26 / 1515 (1.72%)
    15 / 757 (1.98%)
         occurrences causally related to treatment / all
    0 / 27
    1 / 16
         deaths causally related to treatment / all
    0 / 5
    1 / 4
    Pneumonia bacterial
         subjects affected / exposed
    4 / 1515 (0.26%)
    4 / 757 (0.53%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia pseudomonas aeruginosa
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Post procedural infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Q fever
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rickettsiosis
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 1515 (0.33%)
    3 / 757 (0.40%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 1515 (0.07%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 1515 (0.26%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vestibular neuronitis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral pericarditis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 1515 (0.13%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 1515 (0.13%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insulin-requiring type 2 diabetes mellitus
         subjects affected / exposed
    0 / 1515 (0.00%)
    1 / 757 (0.13%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic alkalosis
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    1 / 1515 (0.07%)
    0 / 757 (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
    		 MAGE-A3 Total Group Placebo Total Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1225 / 1515 (80.86%)
    300 / 757 (39.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    129 / 1515 (8.51%)
    40 / 757 (5.28%)
         occurrences all number
    241
    50
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    92 / 1515 (6.07%)
    26 / 757 (3.43%)
         occurrences all number
    199
    55
    Chills
         subjects affected / exposed
    118 / 1515 (7.79%)
    7 / 757 (0.92%)
         occurrences all number
    249
    16
    Fatigue
    alternative assessment type: Systematic
         subjects affected / exposed
    243 / 1515 (16.04%)
    50 / 757 (6.61%)
         occurrences all number
    579
    85
    Influenza like illness
         subjects affected / exposed
    198 / 1515 (13.07%)
    23 / 757 (3.04%)
         occurrences all number
    682
    39
    Injection site erythema
         subjects affected / exposed
    104 / 1515 (6.86%)
    3 / 757 (0.40%)
         occurrences all number
    344
    3
    Injection site pain
         subjects affected / exposed
    476 / 1515 (31.42%)
    35 / 757 (4.62%)
         occurrences all number
    1880
    73
    Injection site reaction
         subjects affected / exposed
    273 / 1515 (18.02%)
    14 / 757 (1.85%)
         occurrences all number
    1368
    17
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    237 / 1515 (15.64%)
    14 / 757 (1.85%)
         occurrences all number
    578
    26
    Pyrexia
         subjects affected / exposed
    529 / 1515 (34.92%)
    38 / 757 (5.02%)
         occurrences all number
    1732
    49
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    76 / 1515 (5.02%)
    31 / 757 (4.10%)
         occurrences all number
    110
    42
    Nausea
         subjects affected / exposed
    108 / 1515 (7.13%)
    36 / 757 (4.76%)
         occurrences all number
    177
    45
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    131 / 1515 (8.65%)
    71 / 757 (9.38%)
         occurrences all number
    155
    80
    Dyspnoea
         subjects affected / exposed
    83 / 1515 (5.48%)
    47 / 757 (6.21%)
         occurrences all number
    91
    52
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    120 / 1515 (7.92%)
    6 / 757 (0.79%)
         occurrences all number
    258
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    105 / 1515 (6.93%)
    31 / 757 (4.10%)
         occurrences all number
    161
    35
    Myalgia
         subjects affected / exposed
    183 / 1515 (12.08%)
    20 / 757 (2.64%)
         occurrences all number
    588
    23
    Pain in extremity
         subjects affected / exposed
    125 / 1515 (8.25%)
    24 / 757 (3.17%)
         occurrences all number
    251
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    79 / 1515 (5.21%)
    28 / 757 (3.70%)
         occurrences all number
    112
    30

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Nov 2010
    Amendment 1 included the following changes: 1) Evaluation of efficacy of study treatment in GS+ vs GS- population was upgraded to secondary objective of the trial; 2) Analysis of impact of study treatment on patients’ health-related Quality of Life or utility was added as new secondary objective along with corresponding endpoints; 3) New, optional translational research was added including pharmacogenetic testing, DNA demethylation analysis & antigen spreading; 4) Recording of autoimmune diseases as AEs of specific interest was included in protocol & a list of types of diseases/disorders with potential autoimmune causality to be considered established; 5) Hematology & biochemistry safety laboratory tests were added for Week 12 visit; 6) Allowed concomitant medication was changed: a) systemic corticosteroids was prohibited only when prescribed for chronic treatment (more than 7 consecutive days [D]), b) immunoglobulins &/or any blood products administration was allowed provided a minimum of 7D between immunoglobulins &/or blood products & study treatment administration; 7) Study treatment postponement was allowed to permit influenza vaccination in framework of imposed influenza vaccination programs to allow a minimum of 7D between influenza vaccine & study treatment administration; 8) Clarifications were added to protocol (e.g. allowed time intervals for scans, randomization & surgery, clarifications on acceptance of scans, etc.) without changing study procedures; 9) Country specific appendices were included for countries also participating in PRAME-AS15-NSC-001 (ADJ) (GSK ID: 113174) study to allow simultaneous screening for both studies, i.e. both MAGE-A3 & PRAME expression could be tested on the tumor samples. 10) Japan was added as participating country & an appendix with Japan specific requirements was added. 11) Certain information was updated, e.g. contact numbers for emergency code breaking & SAE reporting, description of the ECOG performance status.
    18 Oct 2011
    Amendment 2 included the following changes: 1) After trial initiation, a GS at the tumor site associated with a clinical response to MAGE-A3 ASCI was identified in 2 trials in melanoma and lung cancer. This opens the possibility to identify patients likely to benefit from MAGE-A3 ASCI. To clinically validate these GS biomarkers, DFS analysis in patients presenting the GS was added as co-primary (1ry) objective; 2) At the time of the initially planned 1st interim analysis (IA) there would not have been enough events reported in GS+ population to conclude on relevance of GS selection approach. Clinical validation of GS could only be performed on data set available at time of 2nd IA or final analysis (FA). It was decided to remove 1st efficacy IA; 3) In addition, secondary (2ry) endpoints to evaluate OS & lung-cancer-related survival in GS+ and GS- patients were added; 4) Other 2ry objectives were clarified in accordance with addition of above co-1ry objective; 5) Alpha levels assigned to objectives A and B were adapted to take into account correlation between test statistics for no-CT and overall; 6) A weighted Bonferroni-Holm strategy using the closure principle was put in place in case of efficacy claims at the FA; 7) The Wald test was replaced by Likelihood Ratio test as primary test in Cox models, due to that a slight increase in 1-sided type I error is expected when using an unbalanced design together with Wald test; 8) It was clarified that at time of the analyses, 2-sided p-values will be reported & design considerations adapted using 2-sided significance levels; 9) To validate predictive value of GS, an interaction test between MAGE-A3 ASCI vs placebo & GS status was planned; 10) A new criterion for study treatment postponement to allow recovery of possibly related CTC grade ≥ 2 AEs was added; 11) IDMC responsibilities were modified to accommodate that an independent statistician (vs the sponsor) was to provide the FA for review by the IDMC.
    06 Jun 2012
    Protocol Amendment 3 included the following changes: 1) At the European Medicines Agency’s (EMA) request, GSK Biologicals updated its procedure for emergency unblinding during the conduct of a clinical study; 2) According to the revised procedure, the responsibility and the decision to break the treatment code in emergency situations resided solely with the investigator and consequently, the investigator would have full authority to break the treatment code. Wording in the protocol was adapted accordingly; 3) To ensure the availability of images that could be valuable to the accurate assessment of a patient’s disease status, instructions that GSK could collect for review any imaging performed within the scope of this trial and not only images that are related to the identification of recurrences were included; 4) Clarification that at the concluding examination following a recurrence, any tumor assessment performed at the visit showing recurrence did not have to be repeated; 5) Some corrections were made, i.e. footnote cross references, clinical cut off for anti-MAGE-A3 antibodies enzyme-linked immunosorbent assay (ELISA), the power to detect a differential effect in the GS+ population for validation of the gene profile.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Apr 2014
    The study was terminated early on 1 April 2014 following assessment of the lack of efficacy of the MAGE-A3 ASCI study product by the IDMC for the study, as the first two co-primary objectives (DFS in the overall population and DFS in the No-CT population) were not reached. The third co-primary objective, i.e. DFS in the test set of the GS+ population, could not be assessed as no GS classifier could be identified in the training set. The final analysis presented in this summary was performed on all the data collected up to the data lock point (DLP) of 23 January 2014. No follow-up analysis was performed including additional data collected until the end of the study as these were very limited data. Safety data were recorded after the data lock point of the Final Analysis. These safety data are not reported in the safety section of this summary and are as follows for the period spreading from DLP to study end (23 September 2014): 1) For this entire period of assessment, SAEs were additionally reported by 7 and 3 patients in the MAGE-A3 and Placebo groups, respectively, none of these SAEs having a fatal outcome and one of them reported in the MAGE-A3 Group (MedDRA preferred term: mediastinitis) being assessed by the investigators as related to MAGE-A3 ASCI study product; and 2) during the 31-day periods following each treatment administration, at least one AE was reported by 38 and 15 patients in MAGE-A3 and Placebo groups, respectively. Overall these additional safety data did not alter the rates of AEs as displayed in this summary.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Objective C to demonstrate clinical efficacy in terms of DFS of the MAGE-A3 product versus placebo in NSCLC after complete surgical resection in the GS+ population could not be evaluated as no GS classifier could be identified in the training set.
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