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    Clinical Trial Results:
    A Phase II, multi-center, open-label, five-arm study to evaluate the efficacy and safety of oral ceritinib treatment for patients with ALK-positive non-small cell lung cancer (NSCLC) metastatic to the brain and/or to leptomeninges Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    		 2014-000578-20
    Trial protocol
    		 ES   FR   GB   DE   NL   BE   IT  
    Global end of trial date
    06 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Feb 2020
    First version publication date
    22 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLDK378A2205
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02336451
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Study Director, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Study Director, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the antitumor activity of ceritinib in patients with ALK-positive NSCLC metastatic to the brain and/or to leptomeninges based on Investigator assessment per Response evaluation criteria in solid tumors (*RECIST 1.1)
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    Brazil: 3
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Italy: 41
    Country: Number of subjects enrolled
    Korea, Republic of: 19
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    New Zealand: 7
    Country: Number of subjects enrolled
    Russian Federation: 9
    Country: Number of subjects enrolled
    Singapore: 2
    Country: Number of subjects enrolled
    Spain: 16
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United States: 7
    Worldwide total number of subjects
    156
    EEA total number of subjects
    86
    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)
    129
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 156 patients were enrolled and treated with ceritinib. The FAS (N=156) included all patients who received at least one dose of ceritinib with 42, 40, 12, 44 and 18 patients in arms 1 to 5 respectively. The Safety set was identical to full analysis set in this study.

    Pre-assignment
    Screening details
    		 Approximately 160 patients were planned to be enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm 1 (PrALKi=Y, PrBRad=Y)
    Arm description
    		 Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Ceritinib (LDK378) was administered orally once daily at a dose of 750 mg (5 x 150 mg capsules) on a continuous dosing schedule in fasted conditions. No reference therapy was administered in this study.

    Arm title
    		 Arm 2 (PrALKi=Y, PrBRad=N)
    Arm description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Ceritinib (LDK378) was administered orally once daily at a dose of 750 mg (5 x 150 mg capsules) on a continuous dosing schedule in fasted conditions. No reference therapy was administered in this study.

    Arm title
    		 Arm 3 (PrALKi=N, PrBRad=Y)
    Arm description
    		 Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Ceritinib (LDK378) was administered orally once daily at a dose of 750 mg (5 x 150 mg capsules) on a continuous dosing schedule in fasted conditions. No reference therapy was administered in this study.

    Arm title
    		 Arm 4 (PrALKi=N, PrBRad=N)
    Arm description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Ceritinib (LDK378) was administered orally once daily at a dose of 750 mg (5 x 150 mg capsules) on a continuous dosing schedule in fasted conditions. No reference therapy was administered in this study.

    Arm title
    		 Arm 5 (LepDis)
    Arm description
    		 Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ceritinib
    Investigational medicinal product code
    LDK378
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Ceritinib (LDK378) was administered orally once daily at a dose of 750 mg (5 x 150 mg capsules) on a continuous dosing schedule in fasted conditions. No reference therapy was administered in this study.

    Number of subjects in period 1
    		Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Started
    42
    40
    12
    44
    18
    Completed
    0
    0
    0
    0
    0
    Not completed
    42
    40
    12
    44
    18
         Adverse event, serious fatal
    6
    2
    3
    6
    6
         Physician decision
    9
    6
    7
    16
    3
         Adverse event, non-fatal
    1
    2
    -
    6
    4
         Patient/guardian decision
    2
    4
    -
    2
    1
         Progressive disease
    23
    26
    2
    14
    4
         Protocol deviation
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1 (PrALKi=Y, PrBRad=Y)
    Reporting group description
    		 Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 2 (PrALKi=Y, PrBRad=N)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 3 (PrALKi=N, PrBRad=Y)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 4 (PrALKi=N, PrBRad=N)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 5 (LepDis)
    Reporting group description
    		 Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.

    Reporting group values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis) Total
    Number of subjects
    		 42 40 12 44 18 156
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 38 31 10 36 14 129
        From 65-84 years
    		 4 9 2 8 4 27
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48.6 ± 11.37 54.5 ± 12.32 50.0 ± 9.67 51.8 ± 11.21 49.9 ± 11.38 -
    Sex: Female, Male
    Units:
        Female
    		 21 19 6 27 9 82
        Male
    		 21 21 6 17 9 74
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
    		 18 11 7 8 3 47
        Black
    		 0 0 0 1 0 1
        Caucasian
    		 24 27 4 32 15 102
        Other
    		 0 2 1 2 0 5
        Unknown
    		 0 0 0 1 0 1
    Subject analysis sets

    Subject analysis set title
    Ceritinib 750mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants all received a dose of 750 mg orally in fasted state

    Subject analysis sets values
    		 Ceritinib 750mg
    Number of subjects
    145
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    129
        From 65-84 years
    27
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    ±
    Sex: Female, Male
    Units:
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        Asian
        Black
        Caucasian
        Other
        Unknown

    End points

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    End points reporting groups
    Reporting group title
    Arm 1 (PrALKi=Y, PrBRad=Y)
    Reporting group description
    		 Participants with metastases in the brain without evidence of leptomeningeal carcinomatosis (LC), previously treated with radiation to the brain and with prior exposure to an Anaplastic lymphoma kinase inhibitor (ALK-I). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 2 (PrALKi=Y, PrBRad=N)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain but with prior exposure to an ALK-I. Previous treatment with ALK-I other than crizotinib was not allowed in this arm 2 as of protocol amendment 3 and had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 3 (PrALKi=N, PrBRad=Y)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously treated with radiation to the brain but with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 4 (PrALKi=N, PrBRad=N)
    Reporting group description
    		 Participants with metastases in the brain without evidence of LC, previously untreated with radiation to the brain and with no prior exposure to an ALK-I. Participants in this arm had to present with active brain lesion defined as a lesion free of any local treatment (like stereotactic radiosurgery or whole brain radiation).

    Reporting group title
    Arm 5 (LepDis)
    Reporting group description
    		 Participants had LC with or without evidence of active lesion at the baseline Gadolinium-enhanced brain magnetic resonance imaging (MRI). Previous treatment with ALK-I other than crizotinib was not allowed in this arm as of protocol amendment 3.

    Subject analysis set title
    Ceritinib 750mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants all received a dose of 750 mg orally in fasted state

    Primary: Overall response rate (ORR) per Investigator assessment

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    End point title
    		 Overall response rate (ORR) per Investigator assessment [1]
    End point description
    Overall response rate (ORR) is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by the investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a nontarget lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Primary
    End point timeframe
    43 months
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint.
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    35.7 (21.6 to 52.0)
    30.0 (16.6 to 46.5)
    50.0 (21.1 to 78.9)
    59.1 (43.2 to 73.7)
    16.7 (3.6 to 41.4)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR) per Investigator assessment

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    End point title
    		 Disease Control Rate (DCR) per Investigator assessment
    End point description
    DCR: percentage of parts. with best overall response of CR, PR or stable disease (SD) in the whole body, as assessed per RECIST 1.1 by investigator. CR: Disappearance of all nonnodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    66.7 (50.5 to 80.4)
    82.5 (67.2 to 92.7)
    66.7 (34.9 to 90.1)
    70.5 (54.8 to 83.2)
    66.7 (41.0 to 86.7)
    No statistical analyses for this end point

    Secondary: Overall Intracranial Response Rate (OIRR) per modified RECIST 1.1 per Investigator assessment

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    End point title
    		 Overall Intracranial Response Rate (OIRR) per modified RECIST 1.1 per Investigator assessment
    End point description
    OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    28
    29
    7
    33
    8
    Units: Percentage of participants
        number (confidence interval 95%)
    39.3 (21.5 to 59.4)
    27.6 (12.7 to 47.2)
    28.6 (3.7 to 71.0)
    51.5 (33.5 to 69.2)
    12.5 (0.3 to 52.7)
    No statistical analyses for this end point

    Secondary: Overall Intracranial Response Rate (OIRR) per modified RECIST 1.1 per Blinded Independent Review Committee (BIRC) assessment

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    End point title
    		 Overall Intracranial Response Rate (OIRR) per modified RECIST 1.1 per Blinded Independent Review Committee (BIRC) assessment
    End point description
    OIRR was calculated based on response assessments in the brain for patients having measurable brain metastases at baseline. OIRR was defined as the percentage of participants with a best overall confirmed response of CR or PR in the brain as assessed per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or decreased by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    30
    29
    6
    34
    10
    Units: Percentage of participants
        number (confidence interval 95%)
    33.3 (17.3 to 52.8)
    24.1 (10.3 to 43.5)
    33.3 (4.3 to 77.7)
    58.8 (40.7 to 75.4)
    20.0 (2.5 to 55.6)
    No statistical analyses for this end point

    Secondary: Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per Investigator assessment at Weeks 8 & 16

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    End point title
    		 Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per Investigator assessment at Weeks 8 & 16
    End point description
    IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    Week 8 and Week 16
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        IDCR at Week 8
    71.4 (55.4 to 84.3)
    75.0 (58.8 to 87.3)
    58.3 (27.7 to 84.8)
    68.2 (52.4 to 81.4)
    66.7 (41.0 to 86.7)
        IDCR at Week 16
    59.5 (43.3 to 74.4)
    62.5 (45.8 to 77.3)
    58.3 (27.7 to 84.8)
    65.9 (50.1 to 79.5)
    50.0 (26.0 to 74.0)
    No statistical analyses for this end point

    Secondary: Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per Investigator assessment - Overall

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    End point title
    		 Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per Investigator assessment - Overall
    End point description
    IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by the Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    71.4 (55.4 to 84.3)
    85.0 (70.2 to 94.3)
    75.0 (42.8 to 94.5)
    75.0 (59.7 to 86.8)
    66.7 (41.0 to 86.7)
    No statistical analyses for this end point

    Secondary: Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per BIRC assessment at Weeks 8 & 16

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    End point title
    		 Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per BIRC assessment at Weeks 8 & 16
    End point description
    IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    Week 8 and Week 16
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        IDCR at 8 weeks
    76.2 (60.5 to 87.9)
    80.0 (64.4 to 90.9)
    58.3 (27.7 to 84.8)
    68.2 (52.4 to 81.4)
    66.7 (41.0 to 86.7)
        IDCR at 16 weeks
    69.0 (52.9 to 82.4)
    62.5 (45.8 to 77.3)
    58.3 (27.7 to 84.8)
    68.2 (52.4 to 81.4)
    38.9 (17.3 to 64.3)
    No statistical analyses for this end point

    Secondary: Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per BIRC assessment - Overall

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    End point title
    		 Intracranial Disease Control Rate (IDCR) per modified RECIST 1.1 per BIRC assessment - Overall
    End point description
    IDCR overall: percentage of participants with a best overall response of CR, PR, SD or non-CR/non-PD in the brain, as assessed per modified RECIST 1.1 by Investigator. This was applied to the brain only. CR: Disappearance of all non-nodal target & non-target lesions. All lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    73.8 (58.0 to 86.1)
    85.0 (70.2 to 94.3)
    66.7 (34.9 to 90.1)
    75.0 (59.7 to 86.8)
    66.7 (41.0 to 86.7)
    No statistical analyses for this end point

    Secondary: Time to intracranial tumor response (TTIR) per modified RECIST 1.1 per Investigator assessment

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    End point title
    		 Time to intracranial tumor response (TTIR) per modified RECIST 1.1 per Investigator assessment
    End point description
    TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    11
    8
    2
    17
    1
    Units: months
        median (full range (min-max))
    1.87 (1.7 to 7.5)
    1.84 (1.6 to 9.1)
    3.56 (1.8 to 5.3)
    1.77 (1.3 to 7.4)
    1.80 (1.8 to 1.8)
    No statistical analyses for this end point

    Secondary: Time to intracranial tumor response (TTIR) per modified RECIST 1.1 per BIRC assessment

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    End point title
    		 Time to intracranial tumor response (TTIR) per modified RECIST 1.1 per BIRC assessment
    End point description
    TTIR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the brain as assessed per modified RECIST 1.1 criteria for patients with measurable brain metastases at baseline. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    10
    7
    2
    20
    2
    Units: months
        median (full range (min-max))
    1.91 (1.7 to 5.6)
    1.68 (1.6 to 7.2)
    6.31 (3.5 to 9.1)
    1.81 (1.3 to 9.2)
    1.22 (0.7 to 1.8)
    No statistical analyses for this end point

    Secondary: Duration of intracranial response (DOIR) by modified RECIST 1.1 per Investigator assessment

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    End point title
    		 Duration of intracranial response (DOIR) by modified RECIST 1.1 per Investigator assessment
    End point description
    Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. This was applied to the brain only. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    11
    8
    2
    17
    1
    Units: months
        median (confidence interval 95%)
    9.2 (3.7 to 999)
    10.1 (3.8 to 17.3)
    999 (999 to 999)
    7.5 (5.6 to 11.2)
    5.5 (0 to 999)
    No statistical analyses for this end point

    Secondary: Duration of intracranial response (DOIR) by modified RECIST 1.1 per BIRC assessment

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    End point title
    		 Duration of intracranial response (DOIR) by modified RECIST 1.1 per BIRC assessment
    End point description
    Defined as the time from the first documented response (PR or CR) in the brain to the date of the first documented disease progression in the brain or death due to any cause, amongst participants with measurable brain metastases at baseline and a confirmed response (PR or CR) in the brain as per modified RECIST 1.1. CR: Disappearance of all nonnodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    10
    7
    2
    20
    2
    Units: months
        median (confidence interval 95%)
    11.0 (3.8 to 999)
    4.6 (3.5 to 20.3)
    99 (18.4 to 999)
    9.2 (5.7 to 11.3)
    3.4 (2.0 to 4.7)
    No statistical analyses for this end point

    Secondary: Overall Extracranial Response Rate (OERR) per RECIST 1.1 per Investigator & BIRC assessment

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    End point title
    		 Overall Extracranial Response Rate (OERR) per RECIST 1.1 per Investigator & BIRC assessment
    End point description
    OERR was defined as the percentage of participants with a best overall confirmed response of CR or PR outside of the brain, as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        OERR per Investigator assessment
    31.0 (17.6 to 47.1)
    42.5 (27.0 to 59.1)
    41.7 (15.2 to 72.3)
    61.4 (45.5 to 75.6)
    22.2 (6.4 to 47.6)
        OERR per BIRC assessment
    26.2 (13.9 to 42.0)
    25.0 (12.7 to 41.2)
    50.0 (21.1 to 78.9)
    61.4 (45.5 to 75.6)
    16.7 (3.6 to 41.4)
    No statistical analyses for this end point

    Secondary: Extracranial Disease Control Rate (EDCR) per RECIST 1.1 per Investigator & BIRC assessment - Overall

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    End point title
    		 Extracranial Disease Control Rate (EDCR) per RECIST 1.1 per Investigator & BIRC assessment - Overall
    End point description
    EDCR overall was defined as the percentage of participants with a best overall response of CR, PR or SD outside of the brain as assessed per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        EDCR per Investigator assessment
    69.0 (52.9 to 82.4)
    92.5 (79.6 to 98.4)
    66.7 (34.9 to 90.1)
    72.7 (57.2 to 85.0)
    72.2 (46.5 to 90.3)
        EDCR per BIRC assessment
    64.3 (48.0 to 78.4)
    80.0 (64.4 to 90.9)
    66.7 (34.9 to 90.1)
    68.2 (52.4 to 81.4)
    72.2 (46.5 to 90.3)
    No statistical analyses for this end point

    Secondary: Extracranial Disease Control Rate (EDCR) per RECIST 1.1 per Investigator & BIRC assessment at weeks 8 & 16

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    End point title
    		 Extracranial Disease Control Rate (EDCR) per RECIST 1.1 per Investigator & BIRC assessment at weeks 8 & 16
    End point description
    EDCR at weeks 8 & 16: defined as percentage of parts. with CR, PR or SD outside of the brain at Wk 8 & 16 extracranial tumor evaluations respectively, per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    Week 8 and Week 16
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
    number (confidence interval 95%)
        EDCR per Investigator @ Week 8
    69.0 (52.9 to 82.4)
    82.5 (67.2 to 92.7)
    58.3 (27.7 to 84.8)
    63.6 (47.8 to 77.6)
    72.2 (46.5 to 90.3)
        EDCR per Investigator @ Week 16
    57.1 (41.0 to 72.3)
    82.5 (67.2 to 92.7)
    66.7 (34.9 to 90.1)
    65.9 (50.1 to 79.5)
    50.0 (26.0 to 74.0)
        EDCR per BIRC @ Week 8
    66.7 (50.5 to 80.4)
    72.5 (56.1 to 85.4)
    58.3 (27.7 to 84.8)
    61.4 (45.5 to 75.6)
    72.2 (46.5 to 90.3)
        EDCR per BIRC @ Week 16
    54.8 (38.7 to 70.2)
    70.0 (53.5 to 83.4)
    66.7 (34.9 to 90.1)
    68.2 (52.4 to 81.4)
    44.4 (21.5 to 69.2)
    No statistical analyses for this end point

    Secondary: Time to extracranial tumor response (TTER) per RECIST 1.1 per Investigator assessment

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    End point title
    		 Time to extracranial tumor response (TTER) per RECIST 1.1 per Investigator assessment
    End point description
    TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    13
    17
    5
    27
    4
    Units: months
        median (full range (min-max))
    1.87 (1.7 to 18.2)
    1.87 (1.6 to 9.3)
    1.81 (1.2 to 12.7)
    1.77 (1.3 to 5.7)
    2.73 (1.8 to 3.6)
    No statistical analyses for this end point

    Secondary: Time to extracranial tumor response (TTER) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Time to extracranial tumor response (TTER) per RECIST 1.1 per BIRC assessment
    End point description
    TTER was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) outside of the brain as assessed per RECIST 1.1 criteria. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    10
    6
    4
    27
    4
    Units: months
        median (full range (min-max))
    1.81 (1.7 to 12.9)
    1.86 (1.6 to 22.9)
    2.66 (1.7 to 5.5)
    1.77 (1.3 to 22.0)
    1.81 (1.8 to 1.9)
    No statistical analyses for this end point

    Secondary: Duration of extracranial response (DOER) per RECIST 1.1 per Investigator assessment

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    End point title
    		 Duration of extracranial response (DOER) per RECIST 1.1 per Investigator assessment
    End point description
    DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    13
    17
    5
    27
    4
    Units: months
        median (confidence interval 95%)
    18.4 (5.6 to 999)
    19.3 (5.7 to 999)
    999 (999 to 999)
    99 (24.4 to 999)
    4.6 (1.9 to 999)
    No statistical analyses for this end point

    Secondary: Duration of extracranial response (DOER) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Duration of extracranial response (DOER) per RECIST 1.1 per BIRC assessment
    End point description
    DOER was defined as the time from the first documented response (PR or CR) outside of the brain to the date of the first documented disease progression outside of the brain or death due to any cause, amongst patients with a confirmed response (PR or CR) outside of the brain per RECIST 1.1. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    11
    10
    6
    27
    3
    Units: months
        median (confidence interval 95%)
    999 (5.5 to 999)
    6.0 (3.7 to 27.7)
    999 (16.5 to 999)
    999 (11.5 to 999)
    5.5 (3.8 to 999)
    No statistical analyses for this end point

    Secondary: Overall response rate (ORR) (whole body) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Overall response rate (ORR) (whole body) per RECIST 1.1 per BIRC assessment
    End point description
    Overall response rate ORR is defined as the percentage of participants with a best overall confirmed response of complete response (CR) or partial response (PR) in the whole body as assessed per RECIST 1.1 by BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    23.8 (12.1 to 39.5)
    15.0 (5.7 to 29.8)
    33.3 (9.9 to 65.1)
    61.4 (45.5 to 75.6)
    11.1 (1.4 to 34.7)
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) (whole body) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Disease control rate (DCR) (whole body) per RECIST 1.1 per BIRC assessment
    End point description
    DCR: defined as percentage of participants with a best overall response of CR, PR or stable disease (SD) in the whole body, per RECIST 1.1 by BIRC. CR: Disappearance of all nonnodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), & no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed and non-target lesions are not in progression or in complete response. SD: Neither sufficient shrinkage in the target lesion to qualify for PR or CR nor an increase in lesions which would qualify for PD & non-target lesions are not in unequivocal progression.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: Percentage of participants
        number (confidence interval 95%)
    61.9 (45.6 to 76.4)
    80.0 (64.4 to 90.9)
    66.7 (34.9 to 90.1)
    68.2 (52.4 to 81.4)
    72.2 (46.5 to 90.3)
    No statistical analyses for this end point

    Secondary: Time to tumor response (TTR) (whole body) per RECIST 1.1 per Investigator assessment

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    End point title
    		 Time to tumor response (TTR) (whole body) per RECIST 1.1 per Investigator assessment
    End point description
    TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed per RECIST 1.1 criteria per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be nonpathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    15
    12
    6
    26
    3
    Units: months
        median (full range (min-max))
    1.87 (1.7 to 9.3)
    2.00 (1.7 to 9.3)
    1.82 (1.2 to 30.1)
    1.81 (1.3 to 3.7)
    1.91 (1.8 to 3.6)
    No statistical analyses for this end point

    Secondary: Time to tumor response (TTR) (whole body) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Time to tumor response (TTR) (whole body) per RECIST 1.1 per BIRC assessment
    End point description
    TTR was defined as the time from the date of the first dose of ceritinib to the date of the first documented response (CR or PR) in the whole body as assessed by RECIST 1.1 criteria per BIRC assessment. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be nonpathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    10
    6
    4
    27
    2
    Units: months
        median (full range (min-max))
    2.00 (1.7 to 12.9)
    1.76 (1.6 to 1.9)
    1.82 (1.7 to 26.5)
    1.81 (1.3 to 22.0)
    1.86 (1.8 to 1.9)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) (whole body) per RECIST 1.1 per Investigator assessment

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    End point title
    		 Duration of response (DOR) (whole body) per RECIST 1.1 per Investigator assessment
    End point description
    DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per Investigator. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    15
    12
    6
    26
    3
    Units: months
        median (confidence interval 95%)
    10.8 (4.1 to 999)
    12.8 (3.7 to 17.3)
    99 (11.7 to 999)
    9.2 (7.3 to 23.9)
    5.5 (3.7 to 9.9)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR) (whole body) per RECIST 1.1 per BIRC assessment

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    End point title
    		 Duration of response (DOR) (whole body) per RECIST 1.1 per BIRC assessment
    End point description
    DOR was defined as the time from the first documented response (PR or CR) to the date of the first documented disease progression or death due to any cause, amongst patients with a confirmed response (PR or CR) in the whole body per RECIST 1.1 per BIRC. CR: Disappearance of all non-nodal target and non-target lesions. In addition, all lymph nodes assigned a target or a non-target lesions must be non-pathological in size (< 10 mm short axis), and no new lesion is identified. PR: When all target lesions have disappeared or there is a decrease by at least 30% in the sum of diameter of all target lesions (taking as reference the baseline sum of diameters) is observed & non-target lesions are not in progression or in complete response.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    10
    6
    4
    27
    2
    Units: months
        median (confidence interval 95%)
    11.0 (2.0 to 999)
    10.6 (3.7 to 20.3)
    999 (16.5 to 999)
    9.2 (5.7 to 14.3)
    5.7 (5.5 to 6.0)
    No statistical analyses for this end point

    Secondary: Progression free survival (PFS) (whole body) per RECIST 1.1 per Investigator & BIRC assessment

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    End point title
    		 Progression free survival (PFS) (whole body) per RECIST 1.1 per Investigator & BIRC assessment
    End point description
    PFS was defined as the time from the date of the first dose of ceritinib to the date of the first radiologically documented disease progression in the whole body per RECIST 1.1 or death due to any cause. A patient who had not progressed or died at the date of the analysis was censored at the time of the last adequate tumor evaluation on or before the cut-off date.
    End point type
    Secondary
    End point timeframe
    43 months
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: months
    median (confidence interval 95%)
        PFS per Investigator assessment (n=32,35,6,33,14)
    7.2 (3.3 to 10.9)
    5.6 (3.6 to 9.2)
    999 (1.0 to 999)
    7.9 (5.5 to 9.4)
    5.2 (1.6 to 7.2)
        PFS per BIRC assessment (n=34,36,8,33,14)
    5.0 (3.3 to 9.1)
    5.5 (3.6 to 7.3)
    15.5 (1.0 to 999)
    7.7 (5.5 to 9.7)
    3.6 (1.6 to 5.4)
    No statistical analyses for this end point

    Secondary: Overal survival (OS)

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    End point title
    		 Overal survival (OS)
    End point description
    OS was defined as time from the date of first dose of ceritinib to the date of death due to any cause. The OS time for patients who were alive at the end of the study or were lost to follow-up was censored at the date of last contact.
    End point type
    Secondary
    End point timeframe
    24 weeks
    End point values
    		 Arm 1 (PrALKi=Y, PrBRad=Y) Arm 2 (PrALKi=Y, PrBRad=N) Arm 3 (PrALKi=N, PrBRad=Y) Arm 4 (PrALKi=N, PrBRad=N) Arm 5 (LepDis)
    Number of subjects analysed
    42
    40
    12
    44
    18
    Units: months
        median (confidence interval 95%)
    24.0 (12.6 to 999)
    999 (16.2 to 999)
    999 (1.0 to 999)
    999 (26.5 to 999)
    7.2 (1.6 to 16.9)
    No statistical analyses for this end point

    Secondary: Pharmacokinetics (PK) of ceritinib in study population: Cmax/trough & Cmin/trough

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    End point title
    		 Pharmacokinetics (PK) of ceritinib in study population: Cmax/trough & Cmin/trough
    End point description
    Cmax is the maximum (peak) concentration of drug in plasma. Cmin is the minimum (trough) concentration of drug in plasma. Sparse blood samples for ceritinib PK evaluation in plasma were collected on C1D1 up to C6D1 from all patients who received at least one dose of investigational study treatment.
    End point type
    Secondary
    End point timeframe
    Cmax: Cycle 2 Day 1 (C2D1); Cmin: C1D1, C1D8, C1D15, C2D1, C3D1, C4D1, C5D1, C6D1 - all 0hr (pre dose)
    End point values
    		 Ceritinib 750mg
    Number of subjects analysed
    130
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cmin C1D1: 0hr. (pre dose) (n=130)
    0 ± 0.0
        Cmin C1D8: 0hr. (pre dose) (n=107)
    658 ± 59.2
        Cmin C1D15: 0hr. (pre dose) (n=106)
    846 ± 52.9
        Cmin C2D1: 0hr. (pre dose) (n=84)
    1000 ± 50.0
        Cmax C2D1: 4 - 10 hrs. (post dose) (n = 73)
    1100 ± 47.8
        Cmin C3D1: 0hr. (pre dose) (n=61)
    982 ± 59.1
        Cmin C4D1: 0hr. (pre dose) (n=46)
    978 ± 75.4
        Cmin C5D1: 0hr. (pre dose) (n=45)
    885 ± 75.5
        Cmin C6D1: 0hr. (pre dose) (n=40)
    785 ± 120.4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Arm 1@(PrALKi=Y@PrBRad=Y)
    Reporting group description
    		 Arm 1@(PrALKi=Y@PrBRad=Y)

    Reporting group title
    Arm 2@(PrALKi=Y@PrBRad=N)
    Reporting group description
    		 Arm 2@(PrALKi=Y@PrBRad=N)

    Reporting group title
    Arm 3@(PrALKi=N@PrBRad=Y)
    Reporting group description
    		 Arm 3@(PrALKi=N@PrBRad=Y)

    Reporting group title
    Arm 4@(PrALKi=N@PrBRad=N)
    Reporting group description
    		 Arm 4@(PrALKi=N@PrBRad=N)

    Reporting group title
    Arm 5@(LepDis)
    Reporting group description
    		 Arm 5@(LepDis)

    Reporting group title
    All Patients
    Reporting group description
    		 All Patients

    Serious adverse events
    		 Arm 1@(PrALKi=Y@PrBRad=Y) Arm 2@(PrALKi=Y@PrBRad=N) Arm 3@(PrALKi=N@PrBRad=Y) Arm 4@(PrALKi=N@PrBRad=N) Arm 5@(LepDis) All Patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 42 (66.67%)
    17 / 40 (42.50%)
    4 / 12 (33.33%)
    15 / 44 (34.09%)
    11 / 18 (61.11%)
    75 / 156 (48.08%)
         number of deaths (all causes)
    8
    5
    3
    6
    9
    31
         number of deaths resulting from adverse events
    1
    0
    0
    0
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm rupture
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Embolism
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    General physical health deterioration
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Hyperthermia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Interstitial lung disease
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Respiratory failure
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Bradyphrenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Delirium
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical condition abnormal
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inflammatory marker increased
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural complication
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 40 (5.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    4 / 156 (2.56%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
    0 / 0
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Tachycardia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysmetria
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    3 / 156 (1.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extrapyramidal disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Headache
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Memory impairment
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    1 / 18 (5.56%)
    6 / 156 (3.85%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagopleural fistula
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary hypersecretion
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Vascular purpura
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Colonic abscess
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung infection pseudomonal
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nocardia sepsis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 40 (10.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    2 / 18 (11.11%)
    12 / 156 (7.69%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 4
    0 / 1
    0 / 1
    0 / 2
    2 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    Respiratory tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    3 / 44 (6.82%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 1
    1 / 3
    0 / 1
    3 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm 1@(PrALKi=Y@PrBRad=Y) Arm 2@(PrALKi=Y@PrBRad=N) Arm 3@(PrALKi=N@PrBRad=Y) Arm 4@(PrALKi=N@PrBRad=N) Arm 5@(LepDis) All Patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    42 / 42 (100.00%)
    40 / 40 (100.00%)
    11 / 12 (91.67%)
    43 / 44 (97.73%)
    18 / 18 (100.00%)
    154 / 156 (98.72%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 40 (7.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    1
    4
    1
    1
    1
    8
    Hypotension
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    11 / 42 (26.19%)
    9 / 40 (22.50%)
    4 / 12 (33.33%)
    9 / 44 (20.45%)
    5 / 18 (27.78%)
    38 / 156 (24.36%)
         occurrences all number
    18
    24
    6
    12
    6
    66
    Fatigue
         subjects affected / exposed
    13 / 42 (30.95%)
    14 / 40 (35.00%)
    3 / 12 (25.00%)
    9 / 44 (20.45%)
    3 / 18 (16.67%)
    42 / 156 (26.92%)
         occurrences all number
    19
    16
    3
    11
    3
    52
    Feeling cold
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Gait disturbance
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    6 / 156 (3.85%)
         occurrences all number
    5
    0
    0
    1
    1
    7
    General physical health deterioration
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences all number
    0
    1
    1
    1
    0
    3
    Hyperthermia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences all number
    1
    0
    1
    0
    0
    2
    Influenza like illness
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    3 / 44 (6.82%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    2
    0
    0
    3
    0
    5
    Malaise
         subjects affected / exposed
    0 / 42 (0.00%)
    3 / 40 (7.50%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    5 / 156 (3.21%)
         occurrences all number
    0
    8
    1
    0
    1
    10
    Non-cardiac chest pain
         subjects affected / exposed
    9 / 42 (21.43%)
    7 / 40 (17.50%)
    1 / 12 (8.33%)
    3 / 44 (6.82%)
    0 / 18 (0.00%)
    20 / 156 (12.82%)
         occurrences all number
    11
    10
    1
    5
    0
    27
    Oedema peripheral
         subjects affected / exposed
    8 / 42 (19.05%)
    6 / 40 (15.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    2 / 18 (11.11%)
    19 / 156 (12.18%)
         occurrences all number
    8
    7
    1
    2
    2
    20
    Pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    2 / 18 (11.11%)
    4 / 156 (2.56%)
         occurrences all number
    2
    0
    0
    1
    2
    5
    Pyrexia
         subjects affected / exposed
    6 / 42 (14.29%)
    14 / 40 (35.00%)
    0 / 12 (0.00%)
    3 / 44 (6.82%)
    1 / 18 (5.56%)
    24 / 156 (15.38%)
         occurrences all number
    10
    19
    0
    3
    2
    34
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 42 (23.81%)
    8 / 40 (20.00%)
    1 / 12 (8.33%)
    6 / 44 (13.64%)
    4 / 18 (22.22%)
    29 / 156 (18.59%)
         occurrences all number
    14
    13
    1
    8
    4
    40
    Dyspnoea
         subjects affected / exposed
    4 / 42 (9.52%)
    8 / 40 (20.00%)
    2 / 12 (16.67%)
    5 / 44 (11.36%)
    2 / 18 (11.11%)
    21 / 156 (13.46%)
         occurrences all number
    5
    8
    2
    6
    2
    23
    Dyspnoea exertional
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    4 / 156 (2.56%)
         occurrences all number
    1
    1
    1
    1
    0
    4
    Haemoptysis
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    3 / 44 (6.82%)
    0 / 18 (0.00%)
    6 / 156 (3.85%)
         occurrences all number
    3
    0
    0
    3
    0
    6
    Oropharyngeal pain
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    4 / 156 (2.56%)
         occurrences all number
    1
    0
    1
    1
    1
    4
    Pleural effusion
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 40 (7.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    1
    3
    0
    1
    0
    5
    Productive cough
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    4 / 44 (9.09%)
    1 / 18 (5.56%)
    10 / 156 (6.41%)
         occurrences all number
    6
    1
    1
    4
    1
    13
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Agitation
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    4 / 156 (2.56%)
         occurrences all number
    3
    0
    0
    0
    1
    4
    Anxiety
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    4 / 156 (2.56%)
         occurrences all number
    1
    1
    1
    1
    0
    4
    Bradyphrenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Depression
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences all number
    3
    0
    0
    0
    0
    3
    Disorientation
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Hallucination, auditory
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Hallucinations, mixed
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Insomnia
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 40 (10.00%)
    1 / 12 (8.33%)
    4 / 44 (9.09%)
    1 / 18 (5.56%)
    13 / 156 (8.33%)
         occurrences all number
    3
    4
    1
    4
    1
    13
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    18 / 42 (42.86%)
    24 / 40 (60.00%)
    3 / 12 (25.00%)
    23 / 44 (52.27%)
    6 / 18 (33.33%)
    74 / 156 (47.44%)
         occurrences all number
    31
    30
    7
    33
    8
    109
    Amylase increased
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    3 / 44 (6.82%)
    1 / 18 (5.56%)
    9 / 156 (5.77%)
         occurrences all number
    2
    2
    1
    3
    1
    9
    Aspartate aminotransferase increased
         subjects affected / exposed
    18 / 42 (42.86%)
    19 / 40 (47.50%)
    2 / 12 (16.67%)
    13 / 44 (29.55%)
    4 / 18 (22.22%)
    56 / 156 (35.90%)
         occurrences all number
    36
    21
    4
    15
    9
    85
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    3
    3
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 42 (7.14%)
    8 / 40 (20.00%)
    1 / 12 (8.33%)
    6 / 44 (13.64%)
    2 / 18 (11.11%)
    20 / 156 (12.82%)
         occurrences all number
    4
    9
    1
    6
    2
    22
    Blood bilirubin increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Blood creatinine increased
         subjects affected / exposed
    4 / 42 (9.52%)
    4 / 40 (10.00%)
    2 / 12 (16.67%)
    10 / 44 (22.73%)
    2 / 18 (11.11%)
    22 / 156 (14.10%)
         occurrences all number
    6
    5
    2
    21
    2
    36
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Cardiac murmur
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    8 / 156 (5.13%)
         occurrences all number
    10
    1
    0
    0
    1
    12
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 42 (19.05%)
    13 / 40 (32.50%)
    2 / 12 (16.67%)
    9 / 44 (20.45%)
    3 / 18 (16.67%)
    35 / 156 (22.44%)
         occurrences all number
    9
    14
    2
    14
    3
    42
    Lipase increased
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    8 / 44 (18.18%)
    2 / 18 (11.11%)
    13 / 156 (8.33%)
         occurrences all number
    7
    0
    0
    10
    2
    19
    Neutrophil count decreased
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    Weight decreased
         subjects affected / exposed
    6 / 42 (14.29%)
    8 / 40 (20.00%)
    4 / 12 (33.33%)
    2 / 44 (4.55%)
    3 / 18 (16.67%)
    23 / 156 (14.74%)
         occurrences all number
    8
    10
    4
    2
    4
    28
    Weight increased
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 40 (5.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    4 / 156 (2.56%)
         occurrences all number
    0
    2
    0
    1
    1
    4
    Injury, poisoning and procedural complications
    Procedural dizziness
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Subcutaneous haematoma
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    2
    0
    0
    1
    3
    Palpitations
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 40 (7.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    4 / 156 (2.56%)
         occurrences all number
    1
    3
    0
    0
    0
    4
    Sinus bradycardia
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    4 / 156 (2.56%)
         occurrences all number
    3
    1
    0
    0
    0
    4
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    2 / 18 (11.11%)
    2 / 156 (1.28%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Aphasia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    0
    0
    1
    1
    2
    Balance disorder
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    2 / 156 (1.28%)
         occurrences all number
    0
    0
    1
    1
    0
    2
    Dizziness
         subjects affected / exposed
    6 / 42 (14.29%)
    8 / 40 (20.00%)
    1 / 12 (8.33%)
    4 / 44 (9.09%)
    3 / 18 (16.67%)
    22 / 156 (14.10%)
         occurrences all number
    8
    10
    1
    4
    3
    26
    Dysarthria
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 40 (7.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    3 / 18 (16.67%)
    9 / 156 (5.77%)
         occurrences all number
    1
    3
    1
    1
    4
    10
    Dysgeusia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    5 / 44 (11.36%)
    1 / 18 (5.56%)
    6 / 156 (3.85%)
         occurrences all number
    0
    0
    0
    5
    1
    6
    Headache
         subjects affected / exposed
    12 / 42 (28.57%)
    13 / 40 (32.50%)
    3 / 12 (25.00%)
    10 / 44 (22.73%)
    4 / 18 (22.22%)
    42 / 156 (26.92%)
         occurrences all number
    20
    26
    8
    10
    5
    69
    Memory impairment
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    5
    1
    0
    1
    1
    8
    Paraesthesia
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    3 / 44 (6.82%)
    1 / 18 (5.56%)
    9 / 156 (5.77%)
         occurrences all number
    4
    1
    0
    3
    1
    9
    Partial seizures
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Seizure
         subjects affected / exposed
    2 / 42 (4.76%)
    4 / 40 (10.00%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    3 / 18 (16.67%)
    11 / 156 (7.05%)
         occurrences all number
    2
    7
    0
    2
    3
    14
    Somnolence
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    2 / 18 (11.11%)
    5 / 156 (3.21%)
         occurrences all number
    3
    1
    0
    1
    2
    7
    Tremor
         subjects affected / exposed
    1 / 42 (2.38%)
    3 / 40 (7.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    1
    3
    0
    1
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 42 (19.05%)
    6 / 40 (15.00%)
    0 / 12 (0.00%)
    5 / 44 (11.36%)
    3 / 18 (16.67%)
    22 / 156 (14.10%)
         occurrences all number
    10
    7
    0
    6
    4
    27
    Neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    2 / 18 (11.11%)
    7 / 156 (4.49%)
         occurrences all number
    1
    1
    1
    2
    2
    7
    Thrombocytopenia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 42 (9.52%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    0 / 18 (0.00%)
    7 / 156 (4.49%)
         occurrences all number
    5
    0
    1
    3
    0
    9
    Eye disorders
    Vitreous detachment
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    5 / 42 (11.90%)
    4 / 40 (10.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    11 / 156 (7.05%)
         occurrences all number
    5
    4
    1
    2
    0
    12
    Abdominal pain
         subjects affected / exposed
    7 / 42 (16.67%)
    12 / 40 (30.00%)
    4 / 12 (33.33%)
    6 / 44 (13.64%)
    4 / 18 (22.22%)
    33 / 156 (21.15%)
         occurrences all number
    11
    13
    4
    6
    4
    38
    Abdominal pain upper
         subjects affected / exposed
    6 / 42 (14.29%)
    6 / 40 (15.00%)
    1 / 12 (8.33%)
    10 / 44 (22.73%)
    2 / 18 (11.11%)
    25 / 156 (16.03%)
         occurrences all number
    7
    6
    1
    11
    2
    27
    Bowel movement irregularity
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Constipation
         subjects affected / exposed
    10 / 42 (23.81%)
    9 / 40 (22.50%)
    2 / 12 (16.67%)
    7 / 44 (15.91%)
    4 / 18 (22.22%)
    32 / 156 (20.51%)
         occurrences all number
    12
    9
    3
    8
    4
    36
    Diarrhoea
         subjects affected / exposed
    27 / 42 (64.29%)
    34 / 40 (85.00%)
    8 / 12 (66.67%)
    32 / 44 (72.73%)
    6 / 18 (33.33%)
    107 / 156 (68.59%)
         occurrences all number
    51
    63
    15
    43
    6
    178
    Dyspepsia
         subjects affected / exposed
    7 / 42 (16.67%)
    6 / 40 (15.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    0 / 18 (0.00%)
    16 / 156 (10.26%)
         occurrences all number
    8
    6
    1
    2
    0
    17
    Dysphagia
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    3
    1
    1
    0
    0
    5
    Epigastric discomfort
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    3 / 156 (1.92%)
         occurrences all number
    2
    0
    0
    0
    1
    3
    Faecaloma
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Ileus
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Mouth ulceration
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    4
    0
    1
    1
    0
    6
    Nausea
         subjects affected / exposed
    23 / 42 (54.76%)
    29 / 40 (72.50%)
    8 / 12 (66.67%)
    19 / 44 (43.18%)
    8 / 18 (44.44%)
    87 / 156 (55.77%)
         occurrences all number
    36
    42
    14
    28
    15
    135
    Stomatitis
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 40 (5.00%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    6 / 156 (3.85%)
         occurrences all number
    5
    2
    0
    1
    0
    8
    Vomiting
         subjects affected / exposed
    22 / 42 (52.38%)
    24 / 40 (60.00%)
    4 / 12 (33.33%)
    13 / 44 (29.55%)
    9 / 18 (50.00%)
    72 / 156 (46.15%)
         occurrences all number
    42
    48
    7
    23
    17
    137
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences all number
    0
    2
    1
    0
    0
    3
    Dry skin
         subjects affected / exposed
    2 / 42 (4.76%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    4 / 44 (9.09%)
    0 / 18 (0.00%)
    6 / 156 (3.85%)
         occurrences all number
    2
    0
    0
    4
    0
    6
    Eczema
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Pruritus
         subjects affected / exposed
    3 / 42 (7.14%)
    3 / 40 (7.50%)
    2 / 12 (16.67%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    9 / 156 (5.77%)
         occurrences all number
    3
    3
    2
    1
    0
    9
    Rash
         subjects affected / exposed
    4 / 42 (9.52%)
    6 / 40 (15.00%)
    4 / 12 (33.33%)
    7 / 44 (15.91%)
    1 / 18 (5.56%)
    22 / 156 (14.10%)
         occurrences all number
    6
    6
    5
    8
    1
    26
    Rash maculo-papular
         subjects affected / exposed
    3 / 42 (7.14%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    3
    0
    0
    2
    0
    5
    Skin fissures
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Skin striae
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Proteinuria
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Urinary incontinence
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 42 (11.90%)
    5 / 40 (12.50%)
    2 / 12 (16.67%)
    3 / 44 (6.82%)
    0 / 18 (0.00%)
    15 / 156 (9.62%)
         occurrences all number
    6
    5
    3
    4
    0
    18
    Back pain
         subjects affected / exposed
    9 / 42 (21.43%)
    8 / 40 (20.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    19 / 156 (12.18%)
         occurrences all number
    9
    8
    1
    1
    0
    19
    Coccydynia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Flank pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Joint swelling
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    2
    2
    Muscle hypertrophy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Muscle spasms
         subjects affected / exposed
    3 / 42 (7.14%)
    5 / 40 (12.50%)
    0 / 12 (0.00%)
    4 / 44 (9.09%)
    0 / 18 (0.00%)
    12 / 156 (7.69%)
         occurrences all number
    4
    7
    0
    5
    0
    16
    Muscular weakness
         subjects affected / exposed
    4 / 42 (9.52%)
    3 / 40 (7.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    3 / 18 (16.67%)
    10 / 156 (6.41%)
         occurrences all number
    5
    4
    0
    0
    3
    12
    Musculoskeletal chest pain
         subjects affected / exposed
    3 / 42 (7.14%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    3
    1
    0
    2
    1
    7
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    6 / 42 (14.29%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    1 / 18 (5.56%)
    11 / 156 (7.05%)
         occurrences all number
    6
    1
    2
    3
    1
    13
    Myalgia
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    0 / 18 (0.00%)
    5 / 156 (3.21%)
         occurrences all number
    0
    2
    1
    3
    0
    6
    Myopathy
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Neck pain
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    0 / 18 (0.00%)
    3 / 156 (1.92%)
         occurrences all number
    0
    2
    1
    1
    0
    4
    Pain in extremity
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    2
    2
    1
    1
    1
    7
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 42 (2.38%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    0 / 18 (0.00%)
    6 / 156 (3.85%)
         occurrences all number
    2
    7
    1
    2
    0
    12
    Mucosal infection
         subjects affected / exposed
    2 / 42 (4.76%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    4 / 156 (2.56%)
         occurrences all number
    2
    1
    0
    0
    1
    4
    Nasopharyngitis
         subjects affected / exposed
    0 / 42 (0.00%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    3 / 44 (6.82%)
    0 / 18 (0.00%)
    6 / 156 (3.85%)
         occurrences all number
    0
    2
    1
    3
    0
    6
    Oral candidiasis
         subjects affected / exposed
    2 / 42 (4.76%)
    3 / 40 (7.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    2
    3
    0
    1
    1
    7
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    2 / 18 (11.11%)
    5 / 156 (3.21%)
         occurrences all number
    1
    1
    1
    0
    2
    5
    Respiratory tract infection
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    2 / 156 (1.28%)
         occurrences all number
    0
    1
    0
    0
    1
    2
    Tuberculosis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 42 (7.14%)
    2 / 40 (5.00%)
    2 / 12 (16.67%)
    4 / 44 (9.09%)
    0 / 18 (0.00%)
    11 / 156 (7.05%)
         occurrences all number
    3
    2
    2
    5
    0
    12
    Urinary tract infection
         subjects affected / exposed
    3 / 42 (7.14%)
    4 / 40 (10.00%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    2 / 18 (11.11%)
    11 / 156 (7.05%)
         occurrences all number
    3
    6
    0
    2
    2
    13
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 42 (50.00%)
    14 / 40 (35.00%)
    3 / 12 (25.00%)
    6 / 44 (13.64%)
    6 / 18 (33.33%)
    50 / 156 (32.05%)
         occurrences all number
    26
    16
    4
    6
    6
    58
    Hypercalcaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    0 / 18 (0.00%)
    1 / 156 (0.64%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    4 / 42 (9.52%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    5 / 44 (11.36%)
    4 / 18 (22.22%)
    16 / 156 (10.26%)
         occurrences all number
    4
    3
    1
    7
    4
    19
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 42 (4.76%)
    2 / 40 (5.00%)
    1 / 12 (8.33%)
    2 / 44 (4.55%)
    1 / 18 (5.56%)
    8 / 156 (5.13%)
         occurrences all number
    2
    2
    1
    2
    1
    8
    Hypocalcaemia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    0 / 12 (0.00%)
    2 / 44 (4.55%)
    1 / 18 (5.56%)
    4 / 156 (2.56%)
         occurrences all number
    1
    0
    0
    2
    1
    4
    Hypokalaemia
         subjects affected / exposed
    8 / 42 (19.05%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    4 / 18 (22.22%)
    14 / 156 (8.97%)
         occurrences all number
    12
    1
    0
    1
    5
    19
    Hypomagnesaemia
         subjects affected / exposed
    0 / 42 (0.00%)
    1 / 40 (2.50%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    3 / 156 (1.92%)
         occurrences all number
    0
    1
    1
    0
    1
    3
    Hypophagia
         subjects affected / exposed
    1 / 42 (2.38%)
    0 / 40 (0.00%)
    1 / 12 (8.33%)
    0 / 44 (0.00%)
    1 / 18 (5.56%)
    3 / 156 (1.92%)
         occurrences all number
    1
    0
    1
    0
    1
    3
    Hypophosphataemia
         subjects affected / exposed
    4 / 42 (9.52%)
    1 / 40 (2.50%)
    0 / 12 (0.00%)
    1 / 44 (2.27%)
    1 / 18 (5.56%)
    7 / 156 (4.49%)
         occurrences all number
    5
    2
    0
    1
    1
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Nov 2014
    The purpose of this amendment was to revise protocol sections and provide additional clarifications on study procedures related to ALK testing and BIRC review.
    08 Jun 2015
    The purpose of this amendment was to revise protocol sections and provide additional clarifications related to safety and practical operationalization of the study, based on feedback from participating countries. The amendment reflected the availability of updated safety information and clarified sections of the protocol where additional guidance was required.
    11 Nov 2015
    The purpose of this amendment is to revise protocol language regarding the requirement to confirm ALK rearrangement at the Novartis designated central laboratory before initiating treatment with ceritinib.
    22 Aug 2016
    Arms of the study and to allow one early analysis CSR. Also to include analysis of the secondary endpoints of IDCR (intracranial disease control rate) and EDCR.
    31 May 2017
    The purpose of this amendment was to include potential interim analysis for Arm 5 patients in order to get an early assessment of the benefit and risk of ceritinib in patients with leptomeningeal disease, as well as the preliminary exploratory analysis of CSF concentration in relation to available paired matching plasma PK samples.
    16 May 2018
    The purpose of this amendment was to update the end of study criteria to allow ongoing patients benefiting from ceritinib to continue treatment with ceritinib by rolling over to a separate rollover study (and/or other options for continued treatment with ceritinib that are considered acceptable at the country level such as access to commercially available drug or managed access program). In addition withdrawal of consent language and abbreviations sections of protocol were also updated.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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