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    Clinical Trial Results:
    Evaluation of the efficacy of high throughput genome analysis as a therapeutic decision tool for patients with metastatic non small cell lung cancer.

    Summary
    EudraCT number
    2013-001653-27
    Trial protocol
    FR  
    Global end of trial date
    31 Dec 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    12 Jun 2025
    First version publication date
    12 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UC_0105-1305_/_IFCT_1301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02117167
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UNICANCER
    Sponsor organisation address
    101 rue de Tolbiac, Paris, France, 75015
    Public contact
    Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr
    Scientific contact
    Nourredine AIT RAHMOUNE, UNICANCER, +33 0171936704, n.ait-rahmoune@unicancer.fr
    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
    12 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Safir 02 Lung was an open-label multicentric randomized phase II trial, using high throughput genome analysis as a therapeutic decision tool, aimed at comparing a targeted treatment administered according to identified molecular anomalies of the tumor with a standard maintenance as per guidelines (targeted substudy 1: Arm A1 and B1) as well as immunotherapy versus maintenance therapy in patients without actionable genomic alterations or non eligible to substudy 1 (immune substudy 2: Arm A2 and B2). The main objective was to evaluate whether treatment with targeted agents guided by high throughput molecular analyses (CGH array, next generation sequencing) improves overall progression-free survival as compared to standard maintenance therapy in patients with metastatic NSCLC ( (primary objective of substudy 1).
    Protection of trial subjects
    The clinical trial was conducted in accordance with: - the principles of ethics as stated in the last version in use of the Declaration of Helsinki, - the Good Clinical Practices (GCP) defined by the International Conference on Harmonization (ICH–E6, 17/07/96), - the European directive 2001/20/CE on the conduct of clinical trials, - Huriet’s law (n° 88-1138) of December 20th, 1988, relative to the protection of persons, participating in biomedical research and modified by the Public Health Law n°2004-806 of August 9th, 2004, - the law on ‘informatics and freedom’ (Informatique et Libertés n° 78-17) of January 6th,1978 modified by the law n° 2004-801 of August 6th, 2004 relative to the protection of persons with regard to the computerized processing of personal data, - the relevant principles of Décision du 24 novembre 2006 fixant les règles de bonnes pratiques cliniques pour les recherches biomédicales portant sur des médicaments à usage humain - Amended Law n° 2004-800 du 6 août 2004, relative to bioethics, - Regulation (EU) 2016/679 on the protection of natural persons with regard to the processing of personal data and on the free movement of such data (General Data Protection Regulation)
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Apr 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 358
    Worldwide total number of subjects
    358
    EEA total number of subjects
    358
    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)
    242
    From 65 to 84 years
    116
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    999 patients screened: 394 patients were eligible for substudy 1, among which 175 patients were randomized, N=116 patients were randomized in arm A1 and N=59 patients in arm B1. 365 patients were eligible for substudy 2, among which 183 patie

    Pre-assignment
    Screening details
    Patients were considered as pre-eligible for randomisation in the substudy 1 when both following mandatory conditions were met : stable or responding disease was observed after 4 cycles of chemotherapy and targetable alteration was identified by the Molecular Tumor Board (MTB) Otherwise patients be oriented to the immunotherapy substudy 2

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Arm A1 : Planned targeted therapy
    Arm description
    Arm A1 / targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis. In arm A1, N=18 patients were treated with AZD2014, N=8 with AZD4547, N=9 with AZD5363, N=6 with AZD8931, N=4 with olaparib, N=1 with savotinib, N=65 with selumitinib, and N=5 with vandetanib.
    Arm type
    Experimental

    Investigational medicinal product name
    Vistusertib
    Investigational medicinal product code
    AZD2014
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 mg bd, continuous dosing.

    Investigational medicinal product name
    AZD4547
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    80 mg bd, 2 weeks on/1 week off

    Investigational medicinal product name
    Capivasertib
    Investigational medicinal product code
    AZD5363
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    480 mg bd, 4 days on/3 days off

    Investigational medicinal product name
    AZD8931
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40 mg bd, continuous dosing

    Investigational medicinal product name
    Olaparib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg bd continuous dosing

    Investigational medicinal product name
    Savolitinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg od continuous dosing (400 mg od for patient with body weight less than 50 kg)

    Investigational medicinal product name
    Selumetinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    75 mg bd, continuous dosing

    Investigational medicinal product name
    Vandetanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg od, continuous dosing

    Arm title
    Arm B1: Standard maintenance therapy
    Arm description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In arm B1: 1 patient received erlotinib, 4 patients received Gemcitabin, and 54 patients received pemetrexed. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.
    Arm type
    Active comparator

    Investigational medicinal product name
    Erlotinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg, 100 mg and 150 mg erlotinib (as erlotinib hydrochloride) are used in this trial.

    Investigational medicinal product name
    Gemcitabin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard chemotherapies were prescribed as per usual practice and according to the product Summary of Product Characteristics (SmPC).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, every 3 weeks

    Arm title
    Arm A2: MEDI4736
    Arm description
    Planned immunotherapy; durvalumab
    Arm type
    Experimental

    Investigational medicinal product name
    Durvalumab
    Investigational medicinal product code
    MEDI4736
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10 mg/kg, every 2 weeks.

    Arm title
    Arm B2: Standard maintenance therapy
    Arm description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.
    Arm type
    Active comparator

    Investigational medicinal product name
    Gemcitabin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Standard chemotherapies were prescribed as per usual practice and according to the product Summary of Product Characteristics (SmPC).

    Investigational medicinal product name
    Pemetrexed
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    500 mg/m2, every 3 weeks

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Treatment is left to the investigator’s decision as per local practice.

    Number of subjects in period 1
    Arm A1 : Planned targeted therapy Arm B1: Standard maintenance therapy Arm A2: MEDI4736 Arm B2: Standard maintenance therapy
    Started
    116
    59
    121
    62
    Completed
    1
    1
    10
    0
    Not completed
    115
    58
    111
    62
         Clinical progression
    2
    3
    1
    3
         Physician decision
    1
    1
    4
    4
         Consent withdrawn by subject
    2
    1
    1
    4
         Adverse event, non-fatal
    15
    8
    12
    7
         Death
    1
    1
    1
    3
         Other
    1
    -
    1
    -
         Progressive disease
    90
    42
    84
    40
         Sponsor decision
    3
    2
    1
    1
         Alive/End Of Protocol (Completed)
    -
    -
    6
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A1 : Planned targeted therapy
    Reporting group description
    Arm A1 / targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis. In arm A1, N=18 patients were treated with AZD2014, N=8 with AZD4547, N=9 with AZD5363, N=6 with AZD8931, N=4 with olaparib, N=1 with savotinib, N=65 with selumitinib, and N=5 with vandetanib.

    Reporting group title
    Arm B1: Standard maintenance therapy
    Reporting group description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In arm B1: 1 patient received erlotinib, 4 patients received Gemcitabin, and 54 patients received pemetrexed. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

    Reporting group title
    Arm A2: MEDI4736
    Reporting group description
    Planned immunotherapy; durvalumab

    Reporting group title
    Arm B2: Standard maintenance therapy
    Reporting group description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

    Reporting group values
    Arm A1 : Planned targeted therapy Arm B1: Standard maintenance therapy Arm A2: MEDI4736 Arm B2: Standard maintenance therapy Total
    Number of subjects
    116 59 121 62 358
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    88 41 78 35 242
        From 65-84 years
    27 18 43 27 115
        85 years and over
    1 0 0 0 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    60 (55 to 64) 59 (52 to 66) 62 (53 to 67) 62 (52 to 68) -
    Gender categorical
    Units: Subjects
        Female
    46 25 48 21 140
        Male
    70 34 73 41 218
    ECOG
    Units: Subjects
        ECOG 0
    45 32 48 19 144
        ECOG 1
    71 27 73 43 214
    Histological type
    Units: Subjects
        Non Small Cell Lung Cancer
    116 59 119 62 356
        Small Cell Lung Cancer
    0 0 2 0 2
    Histological subtype
    Units: Subjects
        Adenocarcinoma
    102 51 107 55 315
        Large Cell Carcinoma
    0 1 5 1 7
        Squamous Cell Carcinoma
    14 6 8 5 33
        Other
    0 1 1 1 3
    Metastatic disease
    Units: Subjects
        No
    4 3 6 3 16
        Yes
    112 56 115 59 342
    Number of metastatic sites at screening
    Units: Number
        arithmetic mean (standard deviation)
    2.9 ( 1.3 ) 3.0 ( 1.6 ) 2.8 ( 1.41 ) 2.6 ( 1.1 ) -
    The median time between initial diagnosis and randomization
    Units: Months
        median (inter-quartile range (Q1-Q3))
    4 (4 to 5) 4 (4 to 5) 4.3 (4 to 5) 4.6 (4 to 5) -

    End points

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    End points reporting groups
    Reporting group title
    Arm A1 : Planned targeted therapy
    Reporting group description
    Arm A1 / targeted arm: targeted maintenance from a list of targeted drugs guided by the genomic analysis. In arm A1, N=18 patients were treated with AZD2014, N=8 with AZD4547, N=9 with AZD5363, N=6 with AZD8931, N=4 with olaparib, N=1 with savotinib, N=65 with selumitinib, and N=5 with vandetanib.

    Reporting group title
    Arm B1: Standard maintenance therapy
    Reporting group description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In arm B1: 1 patient received erlotinib, 4 patients received Gemcitabin, and 54 patients received pemetrexed. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

    Reporting group title
    Arm A2: MEDI4736
    Reporting group description
    Planned immunotherapy; durvalumab

    Reporting group title
    Arm B2: Standard maintenance therapy
    Reporting group description
    Standard maintenance as per guidelines : with pemetrexed in non-squamous NSCLC only. In squamous NSCLC, treatment is left to the investigator’s decision as per local practice and shall be one of the 2 most common attitudes in France 1- Follow up with no active maintenance therapy 2- Gemcitabine In the Arm B2: 5 patients received Gemcitabin, 54 patients received Pemetrexed, 1 patient received Vinorelbine, and 2 patients did not receive treatment. Treatement duration: Treatment will be continued until disease progression, unacceptable toxicity, intercurrent conditions that preclude continuation of treatment.

    Primary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    Progression-free survival in the targeted drug arm compared to standard maintenance therapy arm. PFS was defined as the time from randomization to the first documented progression of disease or death, whatever the cause. Patients still alive at the time of analysis without documented progression (including lost of follow-up) were censored at the last known alive date (primary endpoint of substudy 1).
    End point type
    Primary
    End point timeframe
    from randomization to disease progression or death from any cause, whichever comes first, up to 16 months.
    End point values
    Arm A1 : Planned targeted therapy Arm B1: Standard maintenance therapy Arm A2: MEDI4736 Arm B2: Standard maintenance therapy
    Number of subjects analysed
    116
    59
    121
    62
    Units: Months
        number (confidence interval 95%)
    2.7 (1.6 to 2.9)
    2.7 (1.6 to 4.1)
    3.0 (2.3 to 4.4)
    3.0 (2.0 to 5.1)
    Statistical analysis title
    PFS analysis (substudy 1)
    Statistical analysis description
    The Cox regression analysis was then adjusted for the factors used as stratification variables in the randomization. There was no difference between arm A1 and arm B1 according to treatment, histological subtype, disease status at randomization, smoking status, and molecular alteration category.
    Comparison groups
    Arm A1 : Planned targeted therapy v Arm B1: Standard maintenance therapy
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.8691
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.7
         upper limit
    1.36
    Statistical analysis title
    PFS analysis (substudy 2)
    Statistical analysis description
    The Cox regression analysis was then adjusted for the factors used as stratification variables in the randomization. The results showed a difference base on histological subtypes (squamous vs non-squamous; p=8.5e-05) but no difference was observed between arm A2 and arm B2 according to treatment, disease status at randomization, and smoking status.
    Comparison groups
    Arm A2: MEDI4736 v Arm B2: Standard maintenance therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.379
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.86
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.62
         upper limit
    1.2

    Secondary: Overall survival (OS) in both arms

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    End point title
    Overall survival (OS) in both arms
    End point description
    OS in each substudy. OS was defined as the time from randomization to death due to any cause. Patients still alive at the time of analysis (including lost of follow-up) were censored at the last known alive date.
    End point type
    Secondary
    End point timeframe
    from randomization to death (any cause), up to 16 months.
    End point values
    Arm A1 : Planned targeted therapy Arm B1: Standard maintenance therapy Arm A2: MEDI4736 Arm B2: Standard maintenance therapy
    Number of subjects analysed
    116
    59
    121
    62
    Units: Months
        median (confidence interval 95%)
    14.3 (11.0 to 18.3)
    14.1 (8.0 to 30.9)
    17.0 (12.1 to 19.5)
    14.9 (10.5 to 22.0)
    Statistical analysis title
    OS analysis (Substudy 1)
    Statistical analysis description
    There was no difference in OS based on treatments, histological subtypes, smoking status, and molecular alterations. There was a difference according to disease status at randomization (p=0.0325).
    Comparison groups
    Arm A1 : Planned targeted therapy v Arm B1: Standard maintenance therapy
    Number of subjects included in analysis
    175
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.8719
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.69
         upper limit
    1.55
    Statistical analysis title
    OS analysis (Substudy 2)
    Statistical analysis description
    There were no overall survival differences based on treatments, disease status at randomization, and smoking status. There was a difference according to histological subtypes (squamous vs non-squamous; p=0.007).
    Comparison groups
    Arm A2: MEDI4736 v Arm B2: Standard maintenance therapy
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.728
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.61
         upper limit
    1.4

    Secondary: ORR

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    End point title
    ORR
    End point description
    To compare overall response rates (ORR) and changes in tumor size in each substudy.
    End point type
    Secondary
    End point timeframe
    Tumor response is assessed every 21 days from treatment initiation until first progression or death from any cause, whichever comes first, up to 16 months
    End point values
    Arm A1 : Planned targeted therapy Arm B1: Standard maintenance therapy Arm A2: MEDI4736 Arm B2: Standard maintenance therapy
    Number of subjects analysed
    116
    59
    121
    62
    Units: percent
    number (not applicable)
        CR/PR
    5.3
    10.5
    14.3
    3.6
        PD/SD
    94.7
    89.5
    85.7
    96.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Toxicities will be assessed during the whole treatment period (4 months expected in average) followed by a 1-year post-treatment follow-up period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Arm A1
    Reporting group description
    -

    Reporting group title
    Arm B1
    Reporting group description
    -

    Reporting group title
    Arm A2
    Reporting group description
    -

    Reporting group title
    Arm B2
    Reporting group description
    -

    Serious adverse events
    Arm A1 Arm B1 Arm A2 Arm B2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    21 / 175 (12.00%)
    14 / 59 (23.73%)
    19 / 121 (15.70%)
    13 / 62 (20.97%)
         number of deaths (all causes)
    78
    37
    72
    35
         number of deaths resulting from adverse events
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Superficial basal cell carcinoma
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Intracardiac thrombus
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischemic stroke
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial disease
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thromboembolic event
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Aplasia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Catheter site extravasation
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fever
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flu-like symptoms
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Hyperthermia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden death, cause unknown
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
    Thoracic pain
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest tightness
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hemoptysis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pneumonitis
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Pneumopathy
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Investigations
    Liver function test increased
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fracture of scapula
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myopericarditis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial tamponade
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Confusional state
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stroke
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia aggravated
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aplasia bone marrow
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile aplasia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile bone marrow aplasia
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    Eye disorders
    Central retinal vein occlusion
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sigmoiditis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute calculous cholecystitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Toxicodermia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Macroscopic hematuria
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Costal pain
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Rheumatoid arthritis flare up
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemophilus pneumonia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Perineal abscess
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumococcal pneumonia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatremia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorexia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Arm A1 Arm B1 Arm A2 Arm B2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    113 / 175 (64.57%)
    53 / 59 (89.83%)
    112 / 121 (92.56%)
    55 / 62 (88.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Atypical Fibroxanthoma
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Metastases To Meninges
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metastatic Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thyroid Neoplasm
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vascular disorders
    Capillary Fragility
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Deep Vein Thrombosis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hot Flush
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hypertension
         subjects affected / exposed
    12 / 175 (6.86%)
    2 / 59 (3.39%)
    4 / 121 (3.31%)
    0 / 62 (0.00%)
         occurrences all number
    21
    3
    6
    0
    Phlebitis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Thrombosis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Collateral Circulation
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Embolism
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Haematoma
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Intermittent Claudication
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Lymphoedema
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Superior Vena Cava Syndrome
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Vascular Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    2
    Venous Insufficiency
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Surgical and medical procedures
    Nutritional
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tooth Extraction
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Prophylaxis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    40 / 175 (22.86%)
    17 / 59 (28.81%)
    45 / 121 (37.19%)
    33 / 62 (53.23%)
         occurrences all number
    126
    58
    191
    73
    Chest Pain
         subjects affected / exposed
    12 / 175 (6.86%)
    8 / 59 (13.56%)
    22 / 121 (18.18%)
    9 / 62 (14.52%)
         occurrences all number
    25
    12
    61
    19
    Chills
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    6
    0
    1
    1
    Crepitations
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Face Oedema
         subjects affected / exposed
    9 / 175 (5.14%)
    2 / 59 (3.39%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    13
    8
    1
    0
    Fatigue
         subjects affected / exposed
    20 / 175 (11.43%)
    12 / 59 (20.34%)
    16 / 121 (13.22%)
    15 / 62 (24.19%)
         occurrences all number
    43
    33
    57
    39
    Feeling Cold
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    General Physical Health deterioration
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    1 / 121 (0.83%)
    3 / 62 (4.84%)
         occurrences all number
    0
    2
    1
    3
    Generalised Oedema
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperthermia
         subjects affected / exposed
    1 / 175 (0.57%)
    2 / 59 (3.39%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    1
    3
    1
    0
    Impaired Healing
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza Like Illness
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    5 / 121 (4.13%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    7
    1
    Malaise
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Mucosal Inflammation
         subjects affected / exposed
    16 / 175 (9.14%)
    1 / 59 (1.69%)
    3 / 121 (2.48%)
    1 / 62 (1.61%)
         occurrences all number
    21
    2
    3
    1
    Mucosal Toxicity
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    31 / 175 (17.71%)
    12 / 59 (20.34%)
    6 / 121 (4.96%)
    12 / 62 (19.35%)
         occurrences all number
    126
    26
    17
    22
    Oedema Peripheral
         subjects affected / exposed
    17 / 175 (9.71%)
    7 / 59 (11.86%)
    4 / 121 (3.31%)
    5 / 62 (8.06%)
         occurrences all number
    41
    16
    13
    19
    Pain
         subjects affected / exposed
    15 / 175 (8.57%)
    6 / 59 (10.17%)
    17 / 121 (14.05%)
    9 / 62 (14.52%)
         occurrences all number
    23
    32
    37
    10
    Peripheral Swelling
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    12 / 175 (6.86%)
    3 / 59 (5.08%)
    14 / 121 (11.57%)
    3 / 62 (4.84%)
         occurrences all number
    16
    3
    16
    4
    Sudden Death
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Xerosis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Chest Discomfort
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Facial pain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    2
    0
    0
    1
    Sarcoidosis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    7
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Erectile Dysfunction
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Balanoposthitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Cough
         subjects affected / exposed
    24 / 175 (13.71%)
    7 / 59 (11.86%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    40
    11
    0
    0
    Dysphonia
         subjects affected / exposed
    5 / 175 (2.86%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    32 / 175 (18.29%)
    12 / 59 (20.34%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    59
    19
    0
    0
    Epistaxis
         subjects affected / exposed
    6 / 175 (3.43%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Haemoptysis
         subjects affected / exposed
    3 / 175 (1.71%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Hypoxia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lung Disorder
         subjects affected / exposed
    3 / 175 (1.71%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Nasal Dryness
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pleuritic Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pneumonitis
         subjects affected / exposed
    5 / 175 (2.86%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Productive Cough
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Pulmonary Embolism
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Pulmonary Haemorrhage
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary Pneumatocele
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Rhinitis Allergic
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    12
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    4 / 121 (3.31%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    7
    1
    Confusional State
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Delirium
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    2
    4
    Hallucination
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    6 / 175 (3.43%)
    2 / 59 (3.39%)
    4 / 121 (3.31%)
    3 / 62 (4.84%)
         occurrences all number
    11
    12
    10
    8
    Irritability
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Libido Decreased
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Sleep Disorder
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Logorrhoea
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nightmare
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    15
    0
    Investigations
    Alanine Aminotransferase increased
         subjects affected / exposed
    5 / 175 (2.86%)
    8 / 59 (13.56%)
    2 / 121 (1.65%)
    3 / 62 (4.84%)
         occurrences all number
    17
    8
    9
    4
    Aspartate Aminotransferase
         subjects affected / exposed
    6 / 175 (3.43%)
    6 / 59 (10.17%)
    4 / 121 (3.31%)
    3 / 62 (4.84%)
         occurrences all number
    22
    6
    6
    5
    Blood Alkaline Phosphatase
         subjects affected / exposed
    2 / 175 (1.14%)
    2 / 59 (3.39%)
    0 / 121 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    3
    6
    0
    2
    Blood Cholesterol
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Blood Creatine
         subjects affected / exposed
    5 / 175 (2.86%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    11
    0
    4
    0
    Blood Creatinine Increased
         subjects affected / exposed
    6 / 175 (3.43%)
    2 / 59 (3.39%)
    10 / 121 (8.26%)
    2 / 62 (3.23%)
         occurrences all number
    11
    3
    16
    9
    Blood Lactate
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    4
    1
    3
    1
    Blood Phosphorus
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Blood Pressure Increased
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    6
    0
    10
    9
    Blood Urea Increased
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Creatinine Renal Clearance
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Electrocardiogram Qt
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Intestinal Transit Time
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Lipase Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    6 / 121 (4.96%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    24
    0
    Platelet Count Decreased
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    1
    1
    1
    Platelet Count Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    0
    1
    Protein Total Decreased
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Transaminases Increased
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Troponin
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Weight Decreased
         subjects affected / exposed
    3 / 175 (1.71%)
    3 / 59 (5.08%)
    5 / 121 (4.13%)
    3 / 62 (4.84%)
         occurrences all number
    3
    3
    6
    3
    Weight Increased
         subjects affected / exposed
    4 / 175 (2.29%)
    1 / 59 (1.69%)
    5 / 121 (4.13%)
    1 / 62 (1.61%)
         occurrences all number
    5
    2
    10
    1
    Amino Acid Level Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Amylase Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    10 / 121 (8.26%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    34
    0
    Blood Thyroid Stimulating Hormone
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Breath Sounds Abnormal
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    8
    0
    Cardiac Murmur
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Eosinophil Count Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Gamma-Glutamyltransferase
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    6 / 121 (4.96%)
    6 / 62 (9.68%)
         occurrences all number
    0
    0
    18
    10
    Haemoglobin Decreased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    High Density Lipoprotein Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Thyroxine Increased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vitamin D Decreased
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Injury, poisoning and procedural complications
    Frostbite
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye Burns
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Fracture
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ligament Sprain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Limb Injury
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Scapula Fracture
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Skin Injury
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Congenital, familial and genetic disorders
    Aplasia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Ichthyosis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Atrial Fibrillation
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bradycardia
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Extrasystoles
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pericardial Effusion
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    3
    0
    Tachycardia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Atrioventricular Block First Degree
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac Arrest
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myocardial Infarction
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Myocarditis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    4
    0
    0
    1
    Ataxia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Balance Disorder
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    0
    2
    Carpal Tunnel Syndrome
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    2 / 62 (3.23%)
         occurrences all number
    2
    1
    2
    2
    Dysaesthesia
         subjects affected / exposed
    1 / 175 (0.57%)
    2 / 59 (3.39%)
    0 / 121 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    1
    2
    0
    3
    Dysarthria
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysgeusia
         subjects affected / exposed
    7 / 175 (4.00%)
    2 / 59 (3.39%)
    1 / 121 (0.83%)
    3 / 62 (4.84%)
         occurrences all number
    33
    3
    1
    4
    Dyskinesia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Facial Paralysis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    10 / 175 (5.71%)
    0 / 59 (0.00%)
    16 / 121 (13.22%)
    4 / 62 (6.45%)
         occurrences all number
    17
    0
    59
    4
    Ischaemic Stroke
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Language Disorder
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Nervous System Disorder
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Neuralgia
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    14
    2
    0
    Neuropathy Peripheral
         subjects affected / exposed
    6 / 175 (3.43%)
    5 / 59 (8.47%)
    7 / 121 (5.79%)
    2 / 62 (3.23%)
         occurrences all number
    19
    24
    27
    2
    Paraesthesia
         subjects affected / exposed
    8 / 175 (4.57%)
    7 / 59 (11.86%)
    9 / 121 (7.44%)
    5 / 62 (8.06%)
         occurrences all number
    31
    17
    16
    21
    Peripheral Sensory
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Restless Legs Syndrome
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Sciatica
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    3 / 121 (2.48%)
    1 / 62 (1.61%)
         occurrences all number
    4
    2
    5
    1
    Tremor
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    2 / 62 (3.23%)
         occurrences all number
    2
    0
    1
    2
    Allodynia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Aphonia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Convulsion
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Dropped Head Syndrome
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    4
    2
    Olfactory Nerve Disorder
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    1
    Viith Nerve Paralysis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 175 (11.43%)
    20 / 59 (33.90%)
    18 / 121 (14.88%)
    16 / 62 (25.81%)
         occurrences all number
    52
    57
    48
    45
    Bicytopenia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Bone Marrow Failure
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eosinophilia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    9
    0
    0
    0
    Febrile Neutropenia
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    0
    1
    Leukopenia
         subjects affected / exposed
    1 / 175 (0.57%)
    3 / 59 (5.08%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    3
    0
    0
    Lymphopenia
         subjects affected / exposed
    0 / 175 (0.00%)
    2 / 59 (3.39%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    5
    0
    Neutropenia
         subjects affected / exposed
    1 / 175 (0.57%)
    8 / 59 (13.56%)
    2 / 121 (1.65%)
    3 / 62 (4.84%)
         occurrences all number
    2
    15
    6
    3
    Thrombocytopenia
         subjects affected / exposed
    1 / 175 (0.57%)
    6 / 59 (10.17%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    1
    8
    2
    0
    Thrombocytosis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    22
    0
    4
    1
    Ear Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Hypoacusis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Tinnitus
         subjects affected / exposed
    7 / 175 (4.00%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    2 / 62 (3.23%)
         occurrences all number
    46
    2
    2
    8
    Vertigo
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    6 / 121 (4.96%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    12
    0
    Eye disorders
    Chorioretinopathy
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Conjunctival Haemorrhage
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dry Eye
         subjects affected / exposed
    5 / 175 (2.86%)
    3 / 59 (5.08%)
    1 / 121 (0.83%)
    2 / 62 (3.23%)
         occurrences all number
    11
    9
    1
    2
    Eye Disorder
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Eye Swelling
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    0
    1
    Eyelid Oedema
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    6
    0
    0
    2
    Lacrimation Increased
         subjects affected / exposed
    3 / 175 (1.71%)
    3 / 59 (5.08%)
    0 / 121 (0.00%)
    10 / 62 (16.13%)
         occurrences all number
    11
    6
    0
    42
    Ocular Hypertension
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Periorbital Oedema
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    2 / 62 (3.23%)
         occurrences all number
    2
    0
    0
    9
    Photopsia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Retinal Detachment
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    10
    0
    0
    0
    Retinal Vein Occlusion
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Retinopathy
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Serous Retinal
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vsion Blurred
         subjects affected / exposed
    6 / 175 (3.43%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    10
    0
    3
    0
    Visual Acuity Reduced
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Visual Impairment
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    2
    1
    3
    0
    Xerophthalmia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blindness
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    2
    Diplopia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    9
    0
    Eye Irritation
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye Oedema
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    5
    Eyelid Skin Dryness
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Vitreous Floaters
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Abdominal Pain
         subjects affected / exposed
    11 / 175 (6.29%)
    3 / 59 (5.08%)
    8 / 121 (6.61%)
    3 / 62 (4.84%)
         occurrences all number
    17
    3
    17
    3
    Abdominal Pain Upper
         subjects affected / exposed
    9 / 175 (5.14%)
    5 / 59 (8.47%)
    5 / 121 (4.13%)
    4 / 62 (6.45%)
         occurrences all number
    24
    18
    7
    8
    Anal Haemorrhage
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    17 / 175 (9.71%)
    8 / 59 (13.56%)
    16 / 121 (13.22%)
    9 / 62 (14.52%)
         occurrences all number
    30
    12
    37
    18
    Diarrhoea
         subjects affected / exposed
    35 / 175 (20.00%)
    7 / 59 (11.86%)
    20 / 121 (16.53%)
    8 / 62 (12.90%)
         occurrences all number
    95
    8
    45
    13
    Dry Mouth
         subjects affected / exposed
    7 / 175 (4.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    11
    0
    2
    1
    Dyspepsia
         subjects affected / exposed
    6 / 175 (3.43%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    2 / 175 (1.14%)
    2 / 59 (3.39%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    5
    2
    5
    0
    Functional
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal Disorder
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrointestinal Motility
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Gastrooesophageal Reflux
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    8
    0
    4
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Mouth Ulceration
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Nausea
         subjects affected / exposed
    30 / 175 (17.14%)
    17 / 59 (28.81%)
    14 / 121 (11.57%)
    17 / 62 (27.42%)
         occurrences all number
    55
    31
    31
    33
    Noninfective Gingivitis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Odynophagia
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    5
    0
    0
    1
    Reflux Gastritis
         subjects affected / exposed
    3 / 175 (1.71%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    16
    1
    0
    0
    Salivary Hypersecretion
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    4 / 175 (2.29%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    0
    0
    Vomiting
         subjects affected / exposed
    19 / 175 (10.86%)
    6 / 59 (10.17%)
    5 / 121 (4.13%)
    9 / 62 (14.52%)
         occurrences all number
    28
    10
    8
    19
    Aerophagia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Anal Fissure
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    3
    Colitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Inguinal Hernia
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Subileus
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Tongue Oedema
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    1
    3
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    4 / 121 (3.31%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    7
    0
    Hepatocellular Injury
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    3 / 121 (2.48%)
    3 / 62 (4.84%)
         occurrences all number
    11
    1
    4
    8
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 175 (0.00%)
    3 / 59 (5.08%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Hepatomegaly
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    5 / 175 (2.86%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    14
    0
    0
    0
    Alopecia
         subjects affected / exposed
    7 / 175 (4.00%)
    2 / 59 (3.39%)
    4 / 121 (3.31%)
    1 / 62 (1.61%)
         occurrences all number
    18
    2
    4
    9
    Dermatitis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dermatitis Acneiform
         subjects affected / exposed
    13 / 175 (7.43%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    31
    0
    1
    0
    Dry Skin
         subjects affected / exposed
    25 / 175 (14.29%)
    3 / 59 (5.08%)
    13 / 121 (10.74%)
    3 / 62 (4.84%)
         occurrences all number
    71
    4
    34
    6
    Eczema
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    4
    1
    Erythema
         subjects affected / exposed
    12 / 175 (6.86%)
    1 / 59 (1.69%)
    4 / 121 (3.31%)
    2 / 62 (3.23%)
         occurrences all number
    45
    1
    6
    2
    Hypertrichosis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Ichthyosis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Lividity
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Nail Discolouration
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nail Disorder
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    10
    0
    6
    0
    Nail Ridging
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nail Toxicity
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    1
    0
    Night Sweats
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    5 / 121 (4.13%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    9
    0
    Onychoclasis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Onycholysis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Palmar-Plantar
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    6
    0
    0
    0
    Photosensitivity Reaction
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pruritus
         subjects affected / exposed
    14 / 175 (8.00%)
    1 / 59 (1.69%)
    18 / 121 (14.88%)
    1 / 62 (1.61%)
         occurrences all number
    19
    1
    66
    1
    Rash
         subjects affected / exposed
    48 / 175 (27.43%)
    3 / 59 (5.08%)
    10 / 121 (8.26%)
    7 / 62 (11.29%)
         occurrences all number
    167
    5
    44
    9
    Rash Follicular
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    18
    0
    0
    0
    Rash Macular
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Rash Maculo-Papular
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    7
    0
    1
    0
    Rash Pruritic
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin Fissures
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Skin Lesion
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    5
    0
    1
    0
    Skin Toxicity
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Stasis Dermatitis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Actinic Keratosis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Cutaneous Sarcoidosis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    8
    0
    Intertrigo
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Macule
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    2
    Pigmentation Disorder
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash Erythematous
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Rash Papular
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin Exfoliation
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin Induration
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Skin Mass
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Vitiligo
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    11
    0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Dysuria
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haematuria
         subjects affected / exposed
    4 / 175 (2.29%)
    2 / 59 (3.39%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    8
    2
    1
    1
    Proteinuria
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    0
    1
    Renal Failure
         subjects affected / exposed
    5 / 175 (2.86%)
    3 / 59 (5.08%)
    2 / 121 (1.65%)
    4 / 62 (6.45%)
         occurrences all number
    8
    4
    2
    8
    Renal Impairment
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Renal Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Ureteral Disorder
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary Incontinence
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pollakiuria
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Urinary Retention
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    8 / 121 (6.61%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    19
    0
    Hyperthyroidism
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    9 / 121 (7.44%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    24
    1
    Thyroid Disorder
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    9
    0
    Thyroiditis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    5
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 175 (6.29%)
    3 / 59 (5.08%)
    18 / 121 (14.88%)
    5 / 62 (8.06%)
         occurrences all number
    26
    5
    113
    5
    Back Pain
         subjects affected / exposed
    13 / 175 (7.43%)
    3 / 59 (5.08%)
    15 / 121 (12.40%)
    7 / 62 (11.29%)
         occurrences all number
    23
    4
    51
    15
    Bone Pain
         subjects affected / exposed
    2 / 175 (1.14%)
    2 / 59 (3.39%)
    9 / 121 (7.44%)
    6 / 62 (9.68%)
         occurrences all number
    2
    3
    15
    7
    Flank Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    5
    0
    0
    Hypercreatinaemia
         subjects affected / exposed
    0 / 175 (0.00%)
    3 / 59 (5.08%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    19
    0
    Joint Stiffness
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Joint Swelling
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Muscle Spasms
         subjects affected / exposed
    5 / 175 (2.86%)
    0 / 59 (0.00%)
    4 / 121 (3.31%)
    0 / 62 (0.00%)
         occurrences all number
    12
    0
    13
    0
    Muscular Weakness
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Musculoskeletal Chest Pain
         subjects affected / exposed
    2 / 175 (1.14%)
    2 / 59 (3.39%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    4
    2
    2
    1
    Musculoskeletal Pain
         subjects affected / exposed
    3 / 175 (1.71%)
    3 / 59 (5.08%)
    13 / 121 (10.74%)
    5 / 62 (8.06%)
         occurrences all number
    4
    4
    44
    5
    Myalgia
         subjects affected / exposed
    10 / 175 (5.71%)
    1 / 59 (1.69%)
    8 / 121 (6.61%)
    3 / 62 (4.84%)
         occurrences all number
    22
    1
    16
    5
    Neck Pain
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    7 / 121 (5.79%)
    2 / 62 (3.23%)
         occurrences all number
    0
    1
    31
    2
    Pain In Extremity
         subjects affected / exposed
    7 / 175 (4.00%)
    3 / 59 (5.08%)
    6 / 121 (4.96%)
    2 / 62 (3.23%)
         occurrences all number
    17
    5
    10
    2
    Periarthritis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Rheumatoid Arthritis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Spinal Pain
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    4 / 121 (3.31%)
    0 / 62 (0.00%)
         occurrences all number
    1
    2
    16
    0
    Musculoskeletal Stiffness
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Myositis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nuchal Rigidity
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Osteoarthritis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    6
    0
    Tendonitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    3
    Torticollis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Bronchitis
         subjects affected / exposed
    7 / 175 (4.00%)
    6 / 59 (10.17%)
    10 / 121 (8.26%)
    4 / 62 (6.45%)
         occurrences all number
    9
    8
    15
    4
    Candida Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Cellulitis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Conjunctivitis
         subjects affected / exposed
    4 / 175 (2.29%)
    4 / 59 (6.78%)
    7 / 121 (5.79%)
    6 / 62 (9.68%)
         occurrences all number
    4
    7
    17
    13
    Device Related Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Diverticulitis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Ear Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Eye Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Folliculitis
         subjects affected / exposed
    12 / 175 (6.86%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    47
    2
    2
    0
    Fungal Infection
         subjects affected / exposed
    4 / 175 (2.29%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    1 / 62 (1.61%)
         occurrences all number
    6
    1
    3
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gingival Abscess
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Herpes Zoster
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Hordeolum
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Influenza
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Lung Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Nail Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Onychomycosis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral Fungal Infection
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Oral Herpes
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Paronychia
         subjects affected / exposed
    9 / 175 (5.14%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    29
    0
    1
    0
    Periodontitis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pharyngitis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    4
    0
    0
    1
    Pneumonia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    1
    0
    3
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash Pustular
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Respiratory Tract Infection
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    2
    0
    0
    1
    Rhinitis
         subjects affected / exposed
    6 / 175 (3.43%)
    3 / 59 (5.08%)
    7 / 121 (5.79%)
    2 / 62 (3.23%)
         occurrences all number
    8
    4
    7
    2
    Sinusitis
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Skin Infection
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Tooth Abscess
         subjects affected / exposed
    2 / 175 (1.14%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    1 / 62 (1.61%)
         occurrences all number
    4
    0
    4
    1
    Vulvovaginal Candidiasis
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Vulvovaginal Mycotic
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abscess
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laryngitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    1
    1
    Periumbilical Abscess
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Sepsis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Spinal Cord Infection
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    0
    0
    1
    Tracheitis
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Viral Infection
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 175 (0.57%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Cell Death
         subjects affected / exposed
    4 / 175 (2.29%)
    1 / 59 (1.69%)
    4 / 121 (3.31%)
    3 / 62 (4.84%)
         occurrences all number
    6
    2
    10
    5
    Decreased Appetite
         subjects affected / exposed
    21 / 175 (12.00%)
    7 / 59 (11.86%)
    20 / 121 (16.53%)
    14 / 62 (22.58%)
         occurrences all number
    40
    12
    33
    18
    Dehydration
         subjects affected / exposed
    0 / 175 (0.00%)
    1 / 59 (1.69%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    0
    1
    0
    1
    Hypercalcaemia
         subjects affected / exposed
    2 / 175 (1.14%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    4
    0
    Hypercholesterolaemia
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Hypercreatinaemia
         subjects affected / exposed
    0 / 175 (0.00%)
    3 / 59 (5.08%)
    6 / 121 (4.96%)
    0 / 62 (0.00%)
         occurrences all number
    0
    3
    21
    0
    Hyperglycaemia
         subjects affected / exposed
    6 / 175 (3.43%)
    1 / 59 (1.69%)
    2 / 121 (1.65%)
    0 / 62 (0.00%)
         occurrences all number
    10
    1
    4
    0
    Hyperkalaemia
         subjects affected / exposed
    3 / 175 (1.71%)
    1 / 59 (1.69%)
    4 / 121 (3.31%)
    1 / 62 (1.61%)
         occurrences all number
    3
    2
    6
    2
    Hypermagnesaemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hyperphosphataemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 175 (2.29%)
    1 / 59 (1.69%)
    1 / 121 (0.83%)
    1 / 62 (1.61%)
         occurrences all number
    11
    1
    1
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    3 / 121 (2.48%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    14
    0
    Hypomagnesaemia
         subjects affected / exposed
    6 / 175 (3.43%)
    0 / 59 (0.00%)
    4 / 121 (3.31%)
    1 / 62 (1.61%)
         occurrences all number
    10
    0
    5
    2
    Hyponatraemia
         subjects affected / exposed
    3 / 175 (1.71%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    3
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hypoproteinaemia
         subjects affected / exposed
    1 / 175 (0.57%)
    0 / 59 (0.00%)
    0 / 121 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Malnutrition
         subjects affected / exposed
    0 / 175 (0.00%)
    0 / 59 (0.00%)
    1 / 121 (0.83%)
    0 / 62 (0.00%)
         occurrences all number
    0
    0
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Feb 2014
    - Modification of the investigators list.
    25 Mar 2014
    - Modification of the coordinating investigator’s contact details - Rephrasing of the primary objective - Addition of a secondary objective - Modifications of inclusion and non-inclusion criteria (precision on IC N°9, modification of NIC N°1 of the selection process, and modification of IC N°2, ICN°6, NIC N°3 and NIC N°6 of the randomization process). - Clarification on the population considered for the analysis of the primary endpoint - Precision on the duration of the cycle in figure 1 of the diagram of the study - Clarification on cross-over between study arms A and B - Modification of the stratification factors - Clarification on non-randomisation reasons and treatment accountancy - Modifications of administration and dose reduction recommendations in the event of toxicity - Modifications of concomitant treatments, in the follow-up and exams. - Addition of explanatory diagram (general organization of the tumor sample circuit / period between the end of the induction treatment and randomization) - Planification of an interim analysis after the randomisation of 60 patients in the SAFIR02 program - Modifications of toxicities regarding eyes and skin - Clarification on SAEs criteria - Clarification on the moment of Steering Committee and IDMC meet - Modifications on biopsy collection - Correction of typographic errors
    24 Jul 2014
    - Modification of the investigators list.
    07 Jan 2015
    - Modifications of IC and NIC (modification of ICN°3 and NIC N°11 of the selection process) - Modification of Figure 1 - Update of the protocol (Tables 5 et 13, section 11.1.3) and investigator’s brochures - Modification of section 7.7.2.4 (concomitant treatment administration) - Suppresssion of Section 10 (inclustion criteria previously listed) - Change of the CRB contact details - Modification of the stratification factors - Addition of an “other” category in Appendix 6 (Order of preference for treatment) - Clarification on Appendix 9 (Guidance on management of hepatotoxicity)
    10 Jul 2015
    - Modification of the investigators list
    09 Sep 2015
    - Modification of the study design with the addition of the substudy 2 to assess efficacy and toxicity of the antiPD-L1 MEDI4736 (Durvalumab). - Modification of IC and NIC (screening phase: IC N°7 and addition NIC N°3; Substudy 1: NIC N°6; NIC N°10; NIC N°12; NIC N°13). - Updates of the targeted therapies information. - Update of toxicity profiles of targeted therapies and toxicity management guidelines.
    16 Nov 2015
    - Modification of toxicity management of MEDI4736.
    24 Mar 2016
    - Modification study design and patients’ diaries (Targeted therapy / Immunotherapy / Standard Chimiotherapy)
    19 Apr 2016
    - Modification of the investigators list
    09 Sep 2016
    - Increase of the number of patients included during screening phase. - Modification molecular analysis method with use of Formalin-Fixed Paraffin-Embedded tissue and plasma to generate tumoral genomic profile. - Modification of maintenance treatment with withdrawal of Erlotinib in epidermal cancers - Introduction of MEDI4736 pseudo-progression management guidelines.
    16 Nov 2016
    - Modification of the investigators list
    16 Jan 2017
    - Modification of the investigators list
    22 Mar 2017
    - Modification of the investigators list
    19 Sep 2018
    - Replacement of Dr Claire LETHROSNE by Dr Laetitia RAJPAR as a principal investigator at the hospital Louis Pasteur at Chartres. - Modification of the investigators list
    25 Mar 2019
    - Ending of AZD8931 manufacture - Futility analyses - Addition of targeted therapies (Olaparib, Savolitinib, Cobimetinib, and Vemurafenib) - Reduction of the number of tumoral assessment following 6 months treatment - Update of the Durvalumab investigator’s brochure - Update of the Selumetinib investigator’s brochure - Update of the AZD2014 investigator’s brochure - Update of the AZD5363 investigator’s brochure - Addition of a place of release of treatment batches - Addition of the possibility to use cytoblocks - Extension of durvalumab administrations until progression - Change of coordinator
    04 Jun 2019
    - Recruitment stopped - Addition of a storage site, releases and deliveries of experimental products - Update of the Olaparib investigator’s brochure - Update of the Savolitinib investigator’s brochure - Update of the AZD5363 investigator’s brochure - Update of the Durvalumab investigator’s brochure - General Data Protection Regulation integration - Modification of the investigators list
    01 May 2020
    - Update of the Olaparib investigator’s brochure - Update of the Durvalumab investigator’s brochure

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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