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    Clinical Trial Results:
    Phase 2, Open-Label, Single Arm Study of the Efficacy and Safety of PF-02341066 in Patients With Advanced Non-Small-Cell Lung Cancer (NSCLC) Harboring a Translocation or Inversion Involving the Anaplastic Lymphoma Kinase (ALK) Gene Locus

    Summary
    EudraCT number
    		 2009-012504-13
    Trial protocol
    		 GB   NL   DE   ES   HU   PL   GR   IT   FR   IE   BG   SE  
    Global end of trial date
    29 Dec 2015

    Results information
    Results version number
    		 v1
    This version publication date
    01 Apr 2016
    First version publication date
    01 Apr 2016
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    A8081005
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00932451
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 EudraCT Number: 2009-012504-13
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 East 42nd Street, New York, United States, 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021 x, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 18007181021 x, ClinicalTrials.gov_Inquiries@pfizer.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
    07 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Mar 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1.) To assess the anti-tumor efficacy of oral single agent PF - 02341066 administered to patients with advanced NSCLC after failure of at least one line of chemotherapy and harbor a translocation or inversion event involving the ALK gene locus as measured by ORR; 2.) To assess the safety and tolerability of oral PF-02341066
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed; in particular, those affording greater protection to the safety of study participants.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Jan 2010
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    Brazil: 11
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    China: 190
    Country: Number of subjects enrolled
    France: 45
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Greece: 4
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Hungary: 2
    Country: Number of subjects enrolled
    Ireland: 3
    Country: Number of subjects enrolled
    Italy: 82
    Country: Number of subjects enrolled
    Japan: 77
    Country: Number of subjects enrolled
    Korea, Republic of: 143
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Sweden: 3
    Country: Number of subjects enrolled
    Taiwan: 34
    Country: Number of subjects enrolled
    United Kingdom: 18
    Country: Number of subjects enrolled
    United States: 302
    Worldwide total number of subjects
    1066
    EEA total number of subjects
    265
    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)
    894
    From 65 to 84 years
    172
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 1069 participants were enrolled and 1066 participants received greater than or equal to 1 dose of crizotinib. The 3 participants who were enrolled and not treated were withdrawn from the study before receiving treatment because they were not eligible and were mistakenly entered into the interactive voice response system.

    Pre-assignment
    Screening details
    		 A total of 144 participants in study NCT00932893 were also enrolled in this study to receive treatment with crizotinib, including 143 participants randomized to the chemotherapy arm then crossed over in this study and 1 participant initially erroneously randomized in the crizotinib arm but not treated.

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

    Arms
    Arm title
    		 Crizotinib 250 mg BID
    Arm description
    		 Participants were administered crizotinib at a starting dose of 250 mg orally, BID on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Crizotinib
    Investigational medicinal product code
    Other name
    PF-02341066
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    starting dose 250 mg orally, BID, continuous dosing schedule

    Number of subjects in period 1
    		Crizotinib 250 mg BID
    Started
    1066
    Completed
    0
    Not completed
    1066
         Consent withdrawn by subject
    64
         Adverse event, non-fatal
    76
         Death
    134
         Ongoing
    122
         Other reasons
    52
         Lost to follow-up
    3
         Objective progression or relapse
    329
         Global deterioration of health
    286

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Crizotinib 250 mg BID
    Reporting group description
    		 Participants were administered crizotinib at a starting dose of 250 mg orally, BID on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Reporting group values
    		 Crizotinib 250 mg BID Total
    Number of subjects
    		 1066 1066
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 894 894
        > 65 years
    		 172 172
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 52.2 ( 12.3 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 601 601
        Male
    		 465 465
    Race/Ethnicity, Customized
    Units: Subjects
        Chinese
    		 252 252
        Japanese
    		 81 81
        Korean
    		 144 144
        White
    		 532 532
        Black
    		 20 20
        Other
    		 19 19
        Other-Asian
    		 18 18
    Subject analysis sets

    Subject analysis set title
    PF-06260182
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PF-06260182 was a PF-02341066 metabolite measured in this study.

    Subject analysis set title
    Crizotinib 250 mg BID-ALT cases
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered crizotinib at a starting dose of 250 milligram [mg] orally, twice daily (BID) on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Subject analysis set title
    Crizotinib 250 mg BID-ALT controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered crizotinib at a starting dose of 250 milligram [mg] orally, twice daily (BID) on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Subject analysis sets values
    		 PF-06260182 Crizotinib 250 mg BID-ALT cases Crizotinib 250 mg BID-ALT controls
    Number of subjects
    904
    74
    115
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
        > 65 years
    0
    0
    0
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Gender, Male/Female
    Units: Participants
        Female
        Male
    Race/Ethnicity, Customized
    Units: Subjects
        Chinese
        Japanese
        Korean
        White
        Black
        Other
        Other-Asian

    End points

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    End points reporting groups
    Reporting group title
    Crizotinib 250 mg BID
    Reporting group description
    		 Participants were administered crizotinib at a starting dose of 250 mg orally, BID on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Subject analysis set title
    PF-06260182
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PF-06260182 was a PF-02341066 metabolite measured in this study.

    Subject analysis set title
    Crizotinib 250 mg BID-ALT cases
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered crizotinib at a starting dose of 250 milligram [mg] orally, twice daily (BID) on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Subject analysis set title
    Crizotinib 250 mg BID-ALT controls
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants were administered crizotinib at a starting dose of 250 milligram [mg] orally, twice daily (BID) on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Primary: Objective response rate

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    End point title
    		 Objective response rate [1]
    End point description
    The objective response rate (ORR) as a measure of anti-tumor efficacy of oral PF-02341066 in participants with advanced NSCLC with an ALK gene translocation or inversion after failure of at least one line of chemotherapy. Response-evaluable populations: defined as participants in either the SA-ALK positive by IUO population or SA-ALK positive by non-IUO population, respectively, who had adequate baseline tumor assessment.
    End point type
    Primary
    End point timeframe
    5 years
    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 analyses were done for this endpoint.
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Percentage
    number (confidence interval 95%)
        ALK Positive by IUO; N=908
    54.1 (50.8 to 57.4)
        ALK Positive by non-IUO only, N= 158
    40.5 (32.8 to 48.6)
    No statistical analyses for this end point

    Primary: Number of participants with adverse events

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    End point title
    		 Number of participants with adverse events [2]
    End point description
    Incidence of adverse events and laboratory abnormalities (severity graded by the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE], version 4.0). The safety analysis population included all participants who were enrolled and received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing).
    End point type
    Primary
    End point timeframe
    5 years
    Notes
    [2] - 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 analyses were done for this endpoint.
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Percentage of Participants
    number (not applicable)
        Serious AEs (all causalities)
    50
        Grade 3/4 AEs (all causalities)
    65.2
        Grade 5 AEs (all causalities)
    22.6
        Serious AEs (treatment related)
    11.2
        Grade 3/4 AEs (treatment related)
    39.9
        Grade 5 AEs (treatment related)
    1.4
    No statistical analyses for this end point

    Secondary: Duration of response (DR)

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    End point title
    		 Duration of response (DR)
    End point description
    DR was defined as the time from the first documentation of objective tumor response (CR or PR) that was subsequently confirmed, to the first documentation of objective tumor progression or to death on study due to any cause, whichever occurred first. DR (in months) was calculated as (first date of PD or death − first date of CR or PR that was subsequently confirmed + 1)/30.4. Response-evaluable populations: defined as participants in either the SA-ALK positive by IUO population or SA-ALK positive by non-IUO population, respectively, who had adequate baseline tumor assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Months
    median (confidence interval 95%)
        ALK Positive by IUO, N=491
    11.8 (10.4 to 12.8)
        ALK Positive by non-IUO only, N=64
    9.5 (6.9 to 15.2)
    No statistical analyses for this end point

    Secondary: Time to Tumor Response (TTR)

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    End point title
    		 Time to Tumor Response (TTR)
    End point description
    TTR was defined as the time (in weeks) from the date of Cycle 1 Day 1 dose to first documentation of objective tumor response (CR or PR) that was subsequently confirmed. For participants proceeding from PR to CR, the onset of PR was taken as the onset of response. Response-evaluable populations: defined as participants in either the SA-ALK positive by IUO population or SA-ALK positive by non-IUO population, respectively, who had adequate baseline tumor assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Weeks
    median (full range (min-max))
        ALK Positive by IUO (n=491)
    6.1 (2.7 to 164)
        ALK Positive by non-IUO only (n=64)
    6.3 (4.7 to 65.9)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    DCR at 6 and 12 weeks was defined as the percentage of participants with a confirmed CR, confirmed PR, or SD (according to RECIST v 1.1) at 6 weeks and 12 weeks, respectively. Response-evaluable populations: defined as participants in either the SA-ALK positive by IUO population or SA-ALK positive by non-IUO population, respectively, who had adequate baseline tumor assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Percentage
    number (confidence interval 95%)
        ALK Positive by IUO at Week 6, N=908
    81.7 (79 to 84.2)
        ALK Positive by IUO at Week 12, N=908
    70.8 (67.7 to 73.8)
        ALK Positive by non-IUO at Week 6, N=158
    69.6 (61.8 to 76.7)
        ALK Positive by non-IUO at Week 12, N=158
    61.4 (53.3 to 69)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    		 Progression Free Survival (PFS)
    End point description
    PFS was defined as the time from the date of the Cycle 1 Day 1 dose to the date of the first documentation of objective tumor progression or death on study due to any cause, whichever occurred first. The safety analysis populations included all participants who received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing), and were ALK positive either by IUO (SA-ALK positive by IUO population) or by non-IUO (SA-ALK positive by non-IUO population), respectively.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Months
    median (confidence interval 95%)
        ALK Positive by IUO , N= 908
    8.4 (7.1 to 9.7)
        ALK Positive by non-IUO only , N=158
    6.9 (5.6 to 9.4)
    No statistical analyses for this end point

    Secondary: Mean change from Baseline in QLQ-C30 Global Quality of Life scores.

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    End point title
    		 Mean change from Baseline in QLQ-C30 Global Quality of Life scores.
    End point description
    The EORTC QLQ-C30 consists of 30 questions which assess five functional domains (physical, role, cognitive, emotional, and social), global health status/quality of life, disease/treatment related symptoms (fatigue, pain, nausea/vomiting, dyspnea, appetite loss, sleep disturbance, constipation, and diarrhoea), and the perceived financial impact of disease. "n" is the number of participants who completed the scale at baseline and at the respective Cycles. The patient reported outcomes (PRO) evaluable population was defined as the participants from the safety analysis (SA) population who completed a baseline assessment and at least one post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    976
    Units: Units on a scale
    arithmetic mean (standard deviation)
        CYCLE2/DAY1
    7.9 ( 22.2 )
        CYCLE3/DAY1
    10.6 ( 23.7 )
        CYCLE4/DAY1
    12.2 ( 24.9 )
        CYCLE5/DAY1
    11.5 ( 23.9 )
        CYCLE6/DAY1
    11.9 ( 24.8 )
        CYCLE7/DAY1
    12.3 ( 24.7 )
        CYCLE8/DAY1
    12.3 ( 24.1 )
        CYCLE9/DAY1
    11.8 ( 23.5 )
        CYCLE10/DAY1
    11.5 ( 23.6 )
        CYCLE11/DAY1
    10.4 ( 23.9 )
        CYCLE12/DAY1
    10.1 ( 21.6 )
        CYCLE13/DAY1
    11 ( 24 )
        CYCLE14/DAY1
    10.4 ( 21.5 )
        CYCLE15/DAY1
    9.5 ( 23.9 )
        CYCLE16/DAY1
    7.4 ( 23.2 )
        CYCLE17/DAY1
    8 ( 24.3 )
        CYCLE18/DAY1
    7.8 ( 22 )
        CYCLE19/DAY1
    7.8 ( 23.1 )
        CYCLE20/DAY1
    9.1 ( 22.4 )
        CYCLE21/DAY1
    7.8 ( 22.5 )
        CYCLE22/DAY1
    5.9 ( 23.7 )
        CYCLE23/DAY1
    6.7 ( 24 )
        CYCLE24/DAY1
    6.4 ( 25 )
        CYCLE25/DAY1
    4.7 ( 23.3 )
        CYCLE26/DAY1
    8.3 ( 24.7 )
        CYCLE27/DAY1
    5.9 ( 23.2 )
        CYCLE28/DAY1
    6.7 ( 24.2 )
        CYCLE29/DAY1
    5.7 ( 23.3 )
        CYCLE30/DAY1
    6.4 ( 24.9 )
        End of treatment
    -1 ( 27.2 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline of EORTC QLQ-C30 Functional and Symptom Scale Scores

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    End point title
    		 Mean Change from Baseline of EORTC QLQ-C30 Functional and Symptom Scale Scores
    End point description
    The EORTC QLQ-C30 consists of 30 questions which assess five functional domains (physical, role, cognitive, emotional, and social), global health status/quality of life, disease/treatment related symptoms (fatigue, pain, nausea/vomiting, dyspnoea, appetite loss, sleep disturbance, constipation, and diarrhoea), and the perceived financial impact of disease. "n" is the number of participants who completed the scale at baseline and at the respective Cycles. The PRO evaluable population was defined as the participants from the SA population who completed a baseline assessment and at least one post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    976
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Physical Functioning (Cycle 2/Day 1) (N=936)
    4.3 ( 17.1 )
        Physical Functioning (Cycle 3/Day 1) (N=879)
    6.6 ( 18.6 )
        Physical Functioning (Cycle 4/Day 1) (N=836)
    8.2 ( 19.1 )
        Physical Functioning (Cycle 5/Day 1) (N=810)
    8.8 ( 18.8 )
        Physical Functioning (Cycle 6/Day 1) (N=778)
    9.5 ( 18.6 )
        Physical Functioning (Cycle 7/Day 1) (N=739)
    10 ( 19.3 )
        Physical Functioning (Cycle 8/Day 1) (N= 704)
    10.1 ( 18.8 )
        Physical Functioning (Cycle 9/Day 1) (N= 673)
    10.5 ( 18.2 )
        Physical Functioning (Cycle 10/Day 1) (N= 637)
    9.5 ( 17.9 )
        Physical Functioning (Cycle 11/Day 1) (N=577)
    9.1 ( 17.9 )
        Physical Functioning (Cycle 12/Day 1) (N=412)
    8.2 ( 17.3 )
        Physical Functioning (Cycle 13/Day 1) (N=517)
    8.7 ( 18.1 )
        Physical Functioning (Cycle 14/Day 1) (N=358)
    8.2 ( 16.5 )
        Physical Functioning (Cycle 15/Day 1) (N=466)
    7.3 ( 19.2 )
        Physical Functioning (Cycle 16/Day 1) (N=295)
    6.3 ( 19.1 )
        Physical Functioning (Cycle 17/Day 1) (N=424)
    6 ( 18.9 )
        Physical Functioning (Cycle 18/Day 1) (N=250)
    6.1 ( 18.4 )
        Physical Functioning (Cycle 19/Day 1) (N=380)
    6.6 ( 16.8 )
        Physical Functioning (Cycle 20/Day 1) (N=224)
    5.1 ( 16.8 )
        Physical Functioning (Cycle 21/Day 1) (N=346)
    5.7 ( 17.6 )
        Physical Functioning (Cycle 22/Day 1) (N=182)
    3.8 ( 17 )
        Physical Functioning (Cycle 23/Day 1) (N=311)
    3.7 ( 17.1 )
        Physical Functioning (Cycle 24/Day 1) (N=156)
    2.4 ( 18.9 )
        Physical Functioning (Cycle 25/Day 1) (N=296)
    4 ( 18 )
        Physical Functioning (Cycle 26/Day 1) (N=129)
    5.3 ( 18.1 )
        Physical Functioning (Cycle 27/Day 1) (N=275)
    3.8 ( 16.1 )
        Physical Functioning (Cycle 28/Day 1) (N=121)
    3.6 ( 20.4 )
        Physical Functioning (Cycle 29/Day 1) (N=251)
    3.7 ( 15.8 )
        Physical Functioning (Cycle 30/Day 1) (N=109)
    2.8 ( 21.9 )
        Physical Functioning (End of treatment) (N=451)
    0.1 ( 25 )
        Cognitive functioning (Cycle 2/Day 1) (N=930)
    1 ( 18.4 )
        Cognitive Functioning (Cycle 3/Day 1) (N=874)
    2.1 ( 19.4 )
        Cognitive Functioning (Cycle 4/Day 1) (N=829)
    2.1 ( 18.6 )
        Cognitive Functioning (Cycle 5/Day 1) (N=806)
    2.3 ( 18.4 )
        Cognitive Functioning (Cycle 6/Day 1) (N=773)
    2.5 ( 18.2 )
        Cognitive Functioning (Cycle 7/Day 1) (N=734)
    3.2 ( 18.6 )
        Cognitive Functioning (Cycle 8/Day 1) (N=699)
    3.3 ( 18.5 )
        Cognitive Functioning (Cycle 9/Day 1) (N=667)
    3 ( 18.4 )
        Cognitive Functioning (Cycle 10/Day 1) (N=632)
    2.7 ( 19 )
        Cognitive Functioning (Cycle 11/Day 1) (N=571)
    3 ( 18.5 )
        Cognitive Functioning (Cycle 12/Day 1) (N=411)
    1.5 ( 17.1 )
        Cognitive Functioning (Cycle 13/Day 1) (N=512)
    2 ( 19.3 )
        Cognitive Functioning (Cycle 14/Day 1) (N=352)
    1.2 ( 17.8 )
        Cognitive Functioning (Cycle 15/Day 1) (N=462)
    1.3 ( 19.7 )
        Cognitive Functioning (Cycle 16/Day 1) (N=294)
    -0.1 ( 18.1 )
        Cognitive Functioning (Cycle 17/Day 1) (N=419)
    0 ( 19.4 )
        Cognitive Functioning (Cycle 18/Day 1) (N=247)
    0.1 ( 19.2 )
        Cognitive Functioning (Cycle 19/Day 1) (N=376)
    0.1 ( 19.2 )
        Cognitive Functioning (Cycle 20/Day 1) (N=222)
    0.9 ( 18.1 )
        Cognitive Functioning (Cycle 21/Day 1) (N=340)
    -0.1 ( 17.8 )
        Cognitive Functioning (Cycle 22/Day 1) (N=179)
    -1.1 ( 17.5 )
        Cognitive Functioning (Cycle 23/Day 1) (N=305)
    -0.3 ( 17.6 )
        Cognitive Functioning (Cycle 24/Day 1) (N=154)
    -3.6 ( 21.2 )
        Cognitive Functioning (Cycle 25/Day 1) (N=293)
    -1.3 ( 18.1 )
        Cognitive Functioning (Cycle 26/Day 1) (N=127)
    -0.3 ( 20.2 )
        Cognitive Functioning (Cycle 27/Day 1) (N=269)
    -0.9 ( 17.7 )
        Cognitive Functioning (Cycle 28/Day 1) (N=120)
    -0.6 ( 20.7 )
        Cognitive Functioning (Cycle 29/Day 1) (N=247)
    -0.2 ( 16 )
        Cognitive Functioning (Cycle 30/Day 1) (N=106)
    -2.5 ( 23.7 )
        Cognitive Functioning (End of treatment) (N=449)
    -2.3 ( 21.7 )
        Emotional Functioning (Cycle 2/Day 1) (N=928)
    5.5 ( 18.4 )
        Emotional Functioning (Cycle 3/Day 1) ((N=873)
    6.8 ( 18.8 )
        Emotional Functioning (Cycle 4/Day 1) (N=827)
    8.2 ( 18.3 )
        Emotional Functioning (Cycle 5/Day 1) (N=804)
    7.8 ( 18.3 )
        Emotional Functioning (Cycle 6/Day 1) (N=772)
    8.6 ( 18 )
        Emotional Functioning (Cycle 7/Day 1) (N=731)
    8.3 ( 18.3 )
        Emotional Functioning (Cycle 8/Day 1) (N=697)
    9.2 ( 18.9 )
        Emotional Functioning (Cycle 9/Day 1) (N=665)
    8.7 ( 18.6 )
        Emotional Functioning (Cycle 10/Day 1) (N=630)
    8.5 ( 18.9 )
        Emotional Functioning (Cycle 11/Day 1) (N=571)
    8.5 ( 17.6 )
        Emotional Functioning (Cycle 12/Day 1) (N=410)
    8.4 ( 17.6 )
        Emotional Functioning (Cycle 13/Day 1) (N=511)
    8.5 ( 19.1 )
        Emotional Functioning (Cycle 14/Day 1) (N=352)
    7.9 ( 16.6 )
        Emotional Functioning (Cycle 15/Day 1) (N=461)
    8.3 ( 18.7 )
        Emotional Functioning (Cycle 16/Day 1) (N=293)
    7.5 ( 16.8 )
        Emotional Functioning (Cycle 17/Day 1) (N=418)
    6.9 ( 19.2 )
        Emotional Functioning (Cycle 18/Day 1) (N=246)
    7.5 ( 17.2 )
        Emotional Functioning (Cycle 19/Day 1) (N=376)
    7.4 ( 18.3 )
        Emotional Functioning (Cycle 20/Day 1) (N=221)
    7.4 ( 17.6 )
        Emotional Functioning (Cycle 21/Day 1) (N=340)
    6.7 ( 17.5 )
        Emotional Functioning (Cycle 22/Day 1) (N=178)
    5.2 ( 17.9 )
        Emotional Functioning (Cycle 23/Day 1) (N=305)
    6.6 ( 17.6 )
        Emotional Functioning (Cycle 24/Day 1) (N=153)
    4.4 ( 19.5 )
        Emotional Functioning (Cycle 25/Day 1) (N=293)
    6.2 ( 17.4 )
        Emotional Functioning (Cycle 26/Day 1) (N=126)
    7.5 ( 18.9 )
        Emotional Functioning (Cycle 27/Day 1) (N=269)
    6.3 ( 17.6 )
        Emotional Functioning (Cycle 28/Day 1) (N=119)
    4.1 ( 19.2 )
        Emotional Functioning (Cycle 29/Day 1) (N=247)
    5.9 ( 17.7 )
        Emotional Functioning (Cycle 30/Day 1) (N=105)
    3.2 ( 21.5 )
        Emotional Functioning (End of treatment) (N=448)
    1.9 ( 22.3 )
        Role Functioning (Cycle 2/Day 1) (N=935)
    4.2 ( 25 )
        Role Functioning (Cycle 3/Day 1) (N=879)
    7.3 ( 27.8 )
        Role Functioning (Cycle 4/Day 1) (N=835)
    9.3 ( 28.7 )
        Role Functioning (Cycle 5/Day 1) (N=809)
    9.5 ( 28.4 )
        Role Functioning (Cycle 6/Day 1) (N=778)
    10.5 ( 28.7 )
        Role Functioning (Cycle 7/Day 1) (N=738)
    10.4 ( 30.2 )
        Role Functioning (Cycle 8/Day 1) (N=702)
    10.8 ( 28.5 )
        Role Functioning (Cycle 9/Day 1) (N=671)
    10.9 ( 28.1 )
        Role Functioning (Cycle 10/Day 1) (N=635)
    10.8 ( 28.8 )
        Role Functioning (Cycle 11/Day 1) (N=576)
    10 ( 29 )
        Role Functioning (Cycle 12/Day 1) (N=413)
    8.4 ( 28 )
        Role Functioning (Cycle 13/Day 1) (N=516)
    9 ( 28.8 )
        Role Functioning (Cycle 14/Day 1) (N=358)
    8.4 ( 26.5 )
        Role Functioning (Cycle 15/Day 1) (N=465)
    8.8 ( 28.7 )
        Role Functioning (Cycle 16/Day 1) (N=296)
    6 ( 28.3 )
        Role Functioning (Cycle 17/Day 1) (N=424)
    6.1 ( 30.4 )
        Role Functioning (Cycle 18/Day 1) (N=250)
    5.2 ( 27.8 )
        Role Functioning (Cycle 19/Day 1) (N=380)
    8 ( 27.5 )
        Role Functioning (Cycle 20/Day 1) (N=224)
    5.8 ( 25.1 )
        Role Functioning (Cycle 21/Day 1) (N=346)
    5.3 ( 27.1 )
        Role Functioning (Cycle 22/Day 1) (N=182)
    4.1 ( 26.7 )
        Role Functioning (Cycle 23/Day 1) (N=311)
    3.2 ( 27.9 )
        Role Functioning (Cycle 24/Day 1) (N=157)
    2.7 ( 29.5 )
        Role Functioning (Cycle 25/Day 1) (N=297)
    2.2 ( 27.2 )
        Role Functioning (Cycle 26/Day 1) (N=129)
    6.1 ( 28 )
        Role Functioning (Cycle 27/Day 1) (N=275)
    2.4 ( 27.6 )
        Role Functioning (Cycle 28/Day 1) (N=121)
    1.5 ( 30 )
        Role Functioning (Cycle 29/Day 1)(N=251)
    1.6 ( 24.6 )
        Role Functioning (Cycle 30/Day 1) (N=109)
    1.1 ( 34 )
        Role Functioning (End of treatment) (N=451)
    -1.6 ( 31.9 )
        Social Functioning (Cycle 2/Day 1) (N=928)
    6.8 ( 25.9 )
        Social Functioning (Cycle 3/Day 1) (N=872)
    9.1 ( 26.2 )
        Social Functioning (Cycle 4/Day 1) (N=828)
    10.4 ( 27.2 )
        Social Functioning (Cycle 5/Day 1) (N=805)
    10.6 ( 26.7 )
        Social Functioning (Cycle 6/Day 1) (N=773)
    11.1 ( 27 )
        Social Functioning (Cycle 7/Day 1) (N=733)
    12.1 ( 26.5 )
        Social Functioning (Cycle 8/Day 1) (N=698)
    12.3 ( 26.4 )
        Social Functioning (Cycle 9/Day 1) (N=666)
    12 ( 26.4 )
        Social Functioning (Cycle 10/Day 1) (N=631)
    11.8 ( 26.1 )
        Social Functioning (Cycle 11/Day 1) (N=570)
    12.1 ( 27.3 )
        Social Functioning (Cycle 12/Day 1) (N=410)
    10.3 ( 26.3 )
        Social Functioning (Cycle 13/Day 1) (N=512)
    10.6 ( 27.3 )
        Social Functioning (Cycle 14/Day 1) (N=352)
    10.4 ( 25.1 )
        Social Functioning (Cycle 15/Day 1) (N=462)
    10.1 ( 28.1 )
        Social Functioning (Cycle 16/Day 1) (N=293)
    9 ( 26.4 )
        Social Functioning (Cycle 17/Day 1) (N=418)
    8.8 ( 26.9 )
        Social Functioning (Cycle 18/Day 1) (N=246)
    6.6 ( 25.4 )
        Social Functioning (Cycle 19/Day 1) (N=376)
    8 ( 25.6 )
        Social Functioning (Cycle 20/Day 1) (N=221)
    5.7 ( 23.9 )
        Social Functioning (Cycle 21/Day 1) (N=340)
    6.7 ( 26.6 )
        Social Functioning (Cycle 22/Day 1) (N=178)
    5.3 ( 22.7 )
        Social Functioning (Cycle 23/Day 1) (N=305)
    7 ( 24.9 )
        Social Functioning (Cycle 24/Day 1) (N=153)
    3.6 ( 26.5 )
        Social Functioning (Cycle 25/Day 1) (N=293)
    4.4 ( 25.8 )
        Social Functioning (Cycle 26/Day 1) (N=126)
    5.2 ( 26.6 )
        Social Functioning (Cycle 27/Day 1) (N=269)
    5.3 ( 26.4 )
        Social Functioning (Cycle 28/Day 1) (N=119)
    2.1 ( 31.4 )
        Social Functioning (Cycle 29/Day 1) (N=247)
    6.6 ( 24.1 )
        Social Functioning (Cycle 30/Day 1) (N=105)
    1.6 ( 29 )
        Social Functioning (End of treatment) (N=449)
    2.7 ( 31.2 )
        Appetite loss (Cycle 2/Day 1) (N=936)
    -2.1 ( 30.3 )
        Appetite loss (Cycle 3/Day 1) (N=877)
    -6.3 ( 31.7 )
        Appetite loss (Cycle 4/Day 1) (N=833)
    -9.1 ( 31.9 )
        Appetite loss (Cycle 5/Day 1) (N=810)
    -10.4 ( 31.9 )
        Appetite loss (Cycle 6/Day 1) (N=778)
    -11.4 ( 32.1 )
        Appetite loss (Cycle 7/Day 1) (N=738)
    -11.4 ( 32.4 )
        Appetite loss (Cycle 8/Day 1) (N=704)
    -11.5 ( 32.6 )
        Appetite loss (Cycle 9/Day 1) (N=673)
    -11.7 ( 32.5 )
        Appetite loss (Cycle 10/Day 1) (N=637)
    -11.9 ( 30.9 )
        Appetite loss (Cycle 11/Day 1) (N=577)
    -11.2 ( 30.4 )
        Appetite loss (Cycle 12/Day 1) (N=413)
    -9.1 ( 30.9 )
        Appetite loss (Cycle 13/Day 1) (N=517)
    -11.3 ( 29.8 )
        Appetite loss (Cycle 14/Day 1) (N=358)
    -9.9 ( 31.8 )
        Appetite loss (Cycle 15/Day 1) (N=466)
    -10.5 ( 30.6 )
        Appetite loss (Cycle 16/Day 1) (N=296)
    -10.4 ( 32.4 )
        Appetite loss (Cycle 17/Day 1) (N=424)
    -8.6 ( 29.5 )
        Appetite loss (Cycle 18/Day 1) (N=250)
    -10.1 ( 31.5 )
        Appetite loss (Cycle 19/Day 1) (N=380)
    -8.9 ( 30.9 )
        Appetite loss (Cycle 20/Day 1) (N=224)
    -12.8 ( 29 )
        Appetite loss (Cycle 21/Day 1) (N=346)
    -7.5 ( 30.6 )
        Appetite loss (Cycle 22/Day 1) (N=181)
    -9.2 ( 27.7 )
        Appetite loss (Cycle 23/Day 1) (N=310)
    -4.9 ( 28.5 )
        Appetite loss (Cycle 24/Day 1) (N=157)
    -10.9 ( 30.1 )
        Appetite loss (Cycle 25/Day 1) (N=297)
    -4.6 ( 29 )
        Appetite loss (Cycle 26/Day 1) (N=129)
    -12.1 ( 32.3 )
        Appetite loss (Cycle 27/Day 1) (N=275)
    -4.2 ( 29.4 )
        Appetite loss (Cycle 28/Day 1) (N=121)
    -6.6 ( 34.6 )
        Appetite loss (Cycle 29/Day 1) (N=251)
    -3.2 ( 27 )
        Appetite loss (Cycle 30/Day 1) (N=109)
    -7.6 ( 29.3 )
        Appetite loss (End of treatment) (N=451)
    0 ( 36.9 )
        Constipation (Cycle 2/Day 1) (N=929)
    15.4 ( 32.9 )
        Constipation (Cycle 3/Day 1) (N=870)
    10.9 ( 33.8 )
        Constipation (Cycle 4/Day 1) (N=)827
    7 ( 31 )
        Constipation (Cycle 5/Day 1) (N=804)
    5.5 ( 30.4 )
        Constipation (Cycle 6/Day 1) (N=771)
    5.4 ( 30.3 )
        Constipation (Cycle 7/Day 1) (N=732)
    4.7 ( 30.3 )
        Constipation (Cycle 8/Day 1) (N=698)
    4.5 ( 29.8 )
        Constipation (Cycle 9/Day 1) (N=665)
    5 ( 29.9 )
        Constipation (Cycle 10/Day 1) (N=631)
    3.8 ( 30 )
        Constipation (Cycle 11/Day 1) (N=571)
    5.2 ( 29.7 )
        Constipation (Cycle 12/Day 1) (N=410)
    6.4 ( 29.6 )
        Constipation (Cycle 13/Day 1) (N=513)
    5.2 ( 29 )
        Constipation (Cycle 14/Day 1) (N=349)
    5 ( 28.7 )
        Constipation (Cycle 15/Day 1) (N=464)
    6 ( 30.1 )
        Constipation (Cycle 16/Day 1) (N=291)
    4.4 ( 29.9 )
        Constipation (Cycle 17/Day 1) (N=420)
    8.3 ( 30.5 )
        Constipation (Cycle 18/Day 1) (N=246)
    6 ( 30.7 )
        Constipation (Cycle 19/Day 1) (N=376)
    7.4 ( 30.5 )
        Constipation (Cycle 20/Day 1) (N=221)
    5.9 ( 33.2 )
        Constipation (Cycle 21/Day 1) (N=340)
    7.7 ( 31.3 )
        Constipation (Cycle 22/Day 1) (N=178)
    6.2 ( 31.2 )
        Constipation (Cycle 23/Day 1) (N=306)
    9.7 ( 31.9 )
        Constipation (Cycle 24/Day 1) (N=154)
    9 ( 34.2 )
        Constipation (Cycle 25/Day 1) (N=293)
    10.9 ( 29.4 )
        Constipation (Cycle 26/Day 1) (N=126)
    5.6 ( 32 )
        Constipation (Cycle 27/Day 1) (N=269)
    8.3 ( 30.7 )
        Constipation (Cycle 28/Day 1) (N=119)
    9.8 ( 31.1 )
        Constipation (Cycle 29/Day 1) (N=247)
    7.8 ( 29.3 )
        Constipation (Cycle 30/Day 1) (N=105)
    11.7 ( 31.3 )
        Constipation (End of treatment) (N=444)
    8.9 ( 33 )
        Diarrhea (Cycle 2/Day 1) (N=927)
    11.4 ( 25.9 )
        Diarrhea (Cycle 3/Day 1) (N=872)
    12.8 ( 26.9 )
        Diarrhea (Cycle 4/Day 1) (N=826)
    11.7 ( 25.6 )
        Diarrhea (Cycle 5/Day 1) (N=805)
    12.6 ( 26.1 )
        Diarrhea (Cycle 6/Day 1) (N=772)
    11.6 ( 26.4 )
        Diarrhea (Cycle 7/Day 1) (N=732)
    10.9 ( 26.3 )
        Diarrhea (Cycle 8/Day 1) (N=698)
    9.8 ( 25.6 )
        Diarrhea (Cycle 9/Day 1) (N=665)
    10.5 ( 25.6 )
        Diarrhea (Cycle 10/Day 1) (N=632)
    11.1 ( 26.6 )
        Diarrhea (Cycle 11/Day 1) (N=570)
    10.1 ( 25.9 )
        Diarrhea (Cycle 12/Day 1) (N=411)
    8.1 ( 25.2 )
        Diarrhea (Cycle 13/Day 1) (N=512)
    8.8 ( 24 )
        Diarrhea (Cycle 14/Day 1) (N=352)
    10.1 ( 22.4 )
        Diarrhea (Cycle 15/Day 1) (N=461)
    8.5 ( 23.1 )
        Diarrhea (Cycle 16/Day 1) (N=293)
    10 ( 22.5 )
        Diarrhea (Cycle 17/Day 1) (N=419)
    8.6 ( 23.9 )
        Diarrhea (Cycle 18/Day 1) (N=247)
    7.4 ( 22.4 )
        Diarrhea (Cycle 19/Day 1) (N=376)
    7.8 ( 22.5 )
        Diarrhea (Cycle 20/Day 1) (N=222)
    6.8 ( 22.6 )
        Diarrhea (Cycle 21/Day 1) (N=340)
    6.6 ( 20.3 )
        Diarrhea (Cycle 22/Day 1) (N=179)
    6.8 ( 24.2 )
        Diarrhea (Cycle 23/Day 1) (N=305)
    8.7 ( 22.7 )
        Diarrhea (Cycle 24/Day 1) (N=154)
    6.4 ( 23.1 )
        Diarrhea (Cycle 25/Day 1) (N=293)
    10.1 ( 23.4 )
        Diarrhea (Cycle 26/Day 1) (N=127)
    5 ( 23.8 )
        Diarrhea (Cycle 27/Day 1) (N=269)
    8.3 ( 24.5 )
        Diarrhea (Cycle 28/Day 1) (N=119)
    5.6 ( 20.5 )
        Diarrhea (Cycle 29/Day 1) (N=247)
    9.7 ( 22.6 )
        Diarrhea (Cycle 30/Day 1) (N=106)
    10.1 ( 25.3 )
        Diarrhea (End of treatment) (N=449)
    5.9 ( 24.5 )
        Dyspnoea (Cycle 2/Day 1) (N=933)
    -9.8 ( 26.2 )
        Dyspnoea (Cycle 3/Day 1) (N=876)
    -11.4 ( 28.2 )
        Dyspnoea (Cycle 4/Day 1) (N=834)
    -12.3 ( 28.6 )
        Dyspnoea (Cycle 5/Day 1) (N=808)
    -12.2 ( 27.7 )
        Dyspnoea (Cycle 6/Day 1) (N=776)
    -13.7 ( 27.6 )
        Dyspnoea (Cycle 7/Day 1) (N=737)
    -13.8 ( 27.8 )
        Dyspnoea (Cycle 8/Day 1) (N=702)
    -13.8 ( 28.2 )
        Dyspnoea (Cycle 9/Day 1) (N=671)
    -13.3 ( 27.9 )
        Dyspnoea (Cycle 10/Day 1) (N=635)
    -13.4 ( 27.6 )
        Dyspnoea (Cycle 11/Day 1) (N=575)
    -15 ( 27.8 )
        Dyspnoea (Cycle 12/Day 1) (N=411)
    -13.1 ( 26.8 )
        Dyspnoea (Cycle 13/Day 1) (N=515)
    -13.1 ( 28.1 )
        Dyspnoea (Cycle 14/Day 1) (N=356)
    -12.7 ( 27.5 )
        Dyspnoea (Cycle 15/Day 1) (N=463)
    -12.6 ( 28.5 )
        Dyspnoea (Cycle 16/Day 1) (N=295)
    -12.2 ( 27.6 )
        Dyspnoea (Cycle 17/Day 1) (N=421)
    -11.8 ( 27.9 )
        Dyspnoea (Cycle 18/Day 1) (N=248)
    -11.5 ( 27.4 )
        Dyspnoea (Cycle 19/Day 1) (N=377)
    -14.2 ( 28 )
        Dyspnoea (Cycle 20/Day 1) (N=222)
    -9.2 ( 26.4 )
        Dyspnoea (Cycle 21/Day 1) (N=344)
    -13.4 ( 27.1 )
        Dyspnoea (Cycle 22/Day 1) (N=181)
    -8.8 ( 26.4 )
        Dyspnoea (Cycle 23/Day 1) (N=309)
    -10.9 ( 26.6 )
        Dyspnoea (Cycle 24/Day 1) (N=156)
    -8.5 ( 27.3 )
        Dyspnoea (Cycle 25/Day 1) (N=295)
    -10.5 ( 26.3 )
        Dyspnoea (Cycle 26/Day 1) (N=129)
    -10.1 ( 27.2 )
        Dyspnoea (Cycle 27/Day 1) (N=273)
    -9.3 ( 24.8 )
        Dyspnoea (Cycle 28/Day 1) (N=121)
    -12.1 ( 28.9 )
        Dyspnoea (Cycle 29/Day 1) (N=249)
    -8.8 ( 25.4 )
        Dyspnoea (Cycle 30/Day 1) (N=109)
    -11.6 ( 27.7 )
        Dyspnoea (End of treatment) (N=450)
    -4.2 ( 32.8 )
        Fatigue (Cycle 2/Day 1) (N=936)
    -4.8 ( 21.8 )
        Fatigue (Cycle 3/Day 1) (N=879)
    -8.9 ( 23.7 )
        Fatigue (Cycle 4/Day 1) (N=836)
    -11.4 ( 24.1 )
        Fatigue (Cycle 5/Day 1) (N=810)
    -12 ( 24.2 )
        Fatigue (Cycle 6/Day 1) (N=778)
    -13.7 ( 24.3 )
        Fatigue (Cycle 7/Day 1) (N=739)
    -14 ( 24.6 )
        Fatigue (Cycle 8/Day 1) (N=704)
    -15.3 ( 23.7 )
        Fatigue (Cycle 9/Day 1) (N=671)
    -14.9 ( 24 )
        Fatigue (Cycle 10/Day 1) (N=637)
    -14.4 ( 24.2 )
        Fatigue (Cycle 11/Day 1) (N=577)
    -13.7 ( 24.3 )
        Fatigue (Cycle 12/Day 1) (N=413)
    -12.2 ( 23.4 )
        Fatigue (Cycle 13/Day 1) (N=517)
    -13.4 ( 23.6 )
        Fatigue (Cycle 14/Day 1) (N=358)
    -13.2 ( 22.3 )
        Fatigue (Cycle 15/Day 1) (N=466)
    -13.1 ( 23.9 )
        Fatigue (Cycle 16/Day 1) (N=296)
    -11.3 ( 24.1 )
        Fatigue (Cycle 17/Day 1) (N=424)
    -11.3 ( 24.6 )
        Fatigue (Cycle 18/Day 1) (N=250)
    -10.4 ( 25.2 )
        Fatigue (Cycle 19/Day 1) (N=380)
    -11.9 ( 23.7 )
        Fatigue (Cycle 20/Day 1) (N=224)
    -10.6 ( 23.2 )
        Fatigue (Cycle 21/Day 1) (N=346)
    -11 ( 25 )
        Fatigue (Cycle 22/Day 1) (N=182)
    -8.4 ( 23 )
        Fatigue (Cycle 23/Day 1) (N=311)
    -8.7 ( 23.3 )
        Fatigue (Cycle 24/Day 1) (N=157)
    -6.7 ( 24.1 )
        Fatigue (Cycle 25/Day 1) (N=297)
    -7.9 ( 23.2 )
        Fatigue (Cycle 26/Day 1) (N=129)
    -12.1 ( 24.8 )
        Fatigue (Cycle 27/Day 1) (N=275)
    -7 ( 22.3 )
        Fatigue (Cycle 28/Day 1) (N=121)
    -6.7 ( 25.2 )
        Fatigue (Cycle 29/Day 1) (N=251)
    -7.1 ( 22.1 )
        Fatigue (Cycle 30/Day 1) (N=109)
    -7.2 ( 27 )
        Fatigue (End of treatment) (N=451)
    -5.3 ( 27.5 )
        Financial Difficulties (Cycle 2/Day 1) (N=928)
    -4.6 ( 24.1 )
        Financial Difficulties (Cycle 3/Day 1) (N=871)
    -4.2 ( 25.2 )
        Financial Difficulties (Cycle 4/Day 1) (N=827)
    -5.9 ( 25.7 )
        Financial Difficulties (Cycle 5/Day 1) (N=803)
    -5.1 ( 25.6 )
        Financial Difficulties (Cycle 6/Day 1) (N=772)
    -5.5 ( 25.4 )
        Financial Difficulties (Cycle 7/Day 1) (N=732)
    -6.2 ( 25.8 )
        Financial Difficulties (Cycle 8/Day 1) (N=697)
    -6.4 ( 26 )
        Financial Difficulties (Cycle 9/Day 1) (N=663)
    -5.8 ( 25.8 )
        Financial Difficulties (Cycle 10/Day 1) (N=631)
    -7.4 ( 25 )
        Financial Difficulties (End of treatment) (N=447)
    -2.2 ( 27.5 )
        Financial Difficulties (Cycle 11/Day 1) (N=569)
    -6.6 ( 25.4 )
        Financial Difficulties (Cycle 12/Day 1) (N=410)
    -4.8 ( 25.4 )
        Financial Difficulties (Cycle 13/Day 1) (N=512)
    -6.3 ( 25.8 )
        Financial Difficulties (Cycle 14/Day 1) (N=352)
    -5.8 ( 25.4 )
        Financial Difficulties (Cycle 15/Day 1) (N=461)
    -6.1 ( 26.7 )
        Financial Difficulties (Cycle 16/Day 1) (N=294)
    -4 ( 23.8 )
        Financial Difficulties (Cycle 17/Day 1) (N=418)
    -5.5 ( 26.8 )
        Financial Difficulties (Cycle 18/Day 1) (N=247)
    -3.8 ( 25.2 )
        Financial Difficulties (Cycle 19/Day 1) (N=376)
    -5.9 ( 26.8 )
        Financial Difficulties (Cycle 20/Day 1) (N=220)
    -5.2 ( 25.4 )
        Financial Difficulties (Cycle 21/Day 1) (N=339)
    -4.2 ( 25.9 )
        Financial Difficulties (Cycle 22/Day 1) (N=177)
    -2.1 ( 23.1 )
        Financial Difficulties (Cycle 23/Day 1) (N=304)
    -4.4 ( 24.9 )
        Financial Difficulties (Cycle 24/Day 1) (N=153)
    -2.8 ( 27.3 )
        Financial Difficulties (Cycle 25/Day 1) (N=292)
    -4.6 ( 24.8 )
        Financial Difficulties (Cycle 26/Day 1) (N=126)
    -2.9 ( 26 )
        Financial Difficulties (Cycle 27/Day 1) (N=268)
    -4.8 ( 25.5 )
        Financial Difficulties (Cycle 28/Day 1) (N=119)
    -4.2 ( 29.9 )
        Financial Difficulties (Cycle 29/Day 1) (N=247)
    -5.5 ( 25.2 )
        Financial Difficulties (Cycle 30/Day 1) (N105=)
    -3.5 ( 26.5 )
        Insomnia (Cycle 2/Day 1) (N=934)
    -7.6 ( 29.3 )
        Insomnia (Cycle 3/Day 1) (N=878)
    -11.3 ( 30.1 )
        Insomnia (Cycle 4/Day 1) (N=833)
    -13 ( 29.7 )
        Insomnia (Cycle 5/Day 1) (N=808)
    -12.8 ( 29.8 )
        Insomnia (Cycle 6/Day 1) (N=778)
    -13.3 ( 31.1 )
        Insomnia (Cycle 7/Day 1) (N=739)
    -13.9 ( 29.7 )
        Insomnia (Cycle 8/Day 1) (N=703)
    -12.6 ( 29.9 )
        Insomnia (Cycle 9/Day 1) (N=673)
    -13.2 ( 28.8 )
        Insomnia (Cycle 10/Day 1) (N=637)
    -13.2 ( 29.4 )
        Insomnia (Cycle 11/Day 1) (N=576)
    -12.2 ( 30 )
        Insomnia (Cycle 12/Day 1) (N=413)
    -11.3 ( 29.7 )
        Insomnia (Cycle 13/Day 1) (N=516)
    -13 ( 29.5 )
        Insomnia (Cycle 14/Day 1) (N=358)
    -11.7 ( 30.3 )
        Insomnia (Cycle 15/Day 1) (N=464)
    -12.4 ( 30 )
        Insomnia (Cycle 16/Day 1) (N=296)
    -10.9 ( 31.6 )
        Insomnia (Cycle 17/Day 1) (N=424)
    -10.8 ( 29.2 )
        Insomnia (Cycle 18/Day 1) (N=250)
    -10.4 ( 30.3 )
        Insomnia (Cycle 19/Day 1) (N=379)
    -12.6 ( 28.9 )
        Insomnia (Cycle 20/Day 1) (N=224)
    -11.5 ( 27.1 )
        Insomnia (Cycle 21/Day 1) (N=346)
    -10.2 ( 27.6 )
        Insomnia (Cycle 22/Day 1) (N=182)
    -7.9 ( 25.8 )
        Insomnia (Cycle 23/Day 1) (N=311)
    -10.5 ( 27.2 )
        Insomnia (Cycle 24/Day 1) (N=157)
    -5.7 ( 28 )
        Insomnia (Cycle 25/Day 1) (N=296)
    -7.7 ( 28.8 )
        Insomnia (Cycle 26/Day 1) (N=129)
    -10.9 ( 29.2 )
        Insomnia (Cycle 27/Day 1) (N=274)
    -10.1 ( 27.4 )
        Insomnia (Cycle 28/Day 1) (N=121)
    -6.9 ( 32.7 )
        Insomnia (Cycle 29/Day 1) (N=251)
    -8.4 ( 28.5 )
        Insomnia (Cycle 30/Day 1) (N=109)
    -11.3 ( 32.1 )
        Insomnia (End of treatment) (N=451)
    -5.7 ( 33.6 )
        Nausea and Vomiting (Cycle 2/Day 1) (N=936)
    6.2 ( 23.1 )
        Nausea and Vomiting (Cycle 3/Day 1) (N=879)
    2.4 ( 23.3 )
        Nausea and Vomiting (Cycle 4/Day 1) (N=836)
    0.3 ( 22.6 )
        Nausea and Vomiting (Cycle 5/Day 1) (N=810)
    -0.4 ( 21.1 )
        Nausea and Vomiting (Cycle 6/Day 1) (N=779)
    -1.6 ( 19.9 )
        Nausea and Vomiting (Cycle 7/Day 1) (N=739)
    -2.3 ( 21 )
        Nausea and Vomiting (Cycle 8/Day 1) (N=704)
    -1.9 ( 19.8 )
        Nausea and Vomiting (Cycle 9/Day 1) (N=673)
    -1.8 ( 21.2 )
        Nausea and Vomiting (Cycle 10/Day 1) (N=637)
    -1.4 ( 21.6 )
        Nausea and Vomiting (Cycle 11/Day 1) (N=577)
    -1.7 ( 20.9 )
        Nausea and Vomiting (Cycle 12/Day 1) (N=413)
    -1.5 ( 21.8 )
        Nausea and Vomiting (Cycle 13/Day 1) (N=517)
    -0.7 ( 21.2 )
        Nausea and Vomiting (Cycle 14/Day 1) (N=358)
    -0.4 ( 23.3 )
        Nausea and Vomiting (Cycle 15/Day 1) (N=466)
    -0.7 ( 21.2 )
        Nausea and Vomiting (Cycle 16/Day 1) (N=296)
    -0.8 ( 19.5 )
        Nausea and Vomiting (Cycle 17/Day 1) (N=424)
    -0.3 ( 20.2 )
        Nausea and Vomiting (Cycle 18/Day 1) (N=250)
    -0.9 ( 21.7 )
        Nausea and Vomiting (Cycle 19/Day 1) (N=380)
    -0.3 ( 20.1 )
        Nausea and Vomiting (Cycle 20/Day 1) (N=224)
    -2.3 ( 18.7 )
        Nausea and Vomiting (Cycle 21/Day 1) (N=346)
    -1.1 ( 18.6 )
        Nausea and Vomiting (Cycle 22/Day 1) (N=182)
    0.2 ( 19 )
        Nausea and Vomiting (Cycle 23/Day 1) (N=311)
    0.8 ( 17.4 )
        Nausea and Vomiting (Cycle 24/Day 1) (N=157)
    -1.3 ( 17.4 )
        Nausea and Vomiting (Cycle 25/Day 1) (N=297)
    0.6 ( 18 )
        Nausea and Vomiting (Cycle 26/Day 1) (N=129)
    -2.3 ( 20.2 )
        Nausea and Vomiting (Cycle 27/Day 1) (N=275)
    1.9 ( 17.5 )
        Nausea and Vomiting (Cycle 28/Day 1) (N=121)
    1.8 ( 19.7 )
        Nausea and Vomiting (Cycle 29/Day 1) (N=251)
    2.5 ( 18.9 )
        Nausea and Vomiting (Cycle 30/Day 1) (N=109)
    -0.5 ( 17.5 )
        Nausea and Vomiting (End of treatment) (N=451)
    4 ( 25.3 )
        Pain (Cycle 2/Day 1) (N=935)
    -13.1 ( 26.6 )
        Pain (Cycle 3/Day 1) (N=880)
    -16 ( 28 )
        Pain (Cycle 4/Day 1) (N=836)
    -15.7 ( 27.8 )
        Pain (Cycle 5/Day 1) (N=810)
    -15.5 ( 27.4 )
        Pain (Cycle 6/Day 1) (N=779)
    -15.5 ( 27.8 )
        Pain (Cycle 7/Day 1) (N=739)
    -16 ( 29 )
        Pain (Cycle 8/Day 1) (N=705)
    -15.9 ( 28.5 )
        Pain (Cycle 9/Day 1) (N=673)
    -15.5 ( 28.7 )
        Pain (Cycle 10/Day 1) (N=637)
    -15.1 ( 27.6 )
        Pain (Cycle 11/Day 1) (N=577)
    -14.6 ( 27.6 )
        Pain (Cycle 12/Day 1) (N=414)
    -13.6 ( 29.2 )
        Pain (Cycle 13/Day 1) (N=517)
    -13.8 ( 28 )
        Pain (Cycle 14/Day 1) (N=357)
    -13.9 ( 29.5 )
        Pain (Cycle 15/Day 1) (N=466)
    -12.1 ( 27 )
        Pain (Cycle 16/Day 1) (N=296)
    -12.5 ( 27.9 )
        Pain (Cycle 17/Day 1) (N=424)
    -10.6 ( 25.6 )
        Pain (Cycle 18/Day 1) (N=250)
    -11.1 ( 27.5 )
        Pain (Cycle 19/Day 1) (N=380)
    -10.8 ( 24.1 )
        Pain (Cycle 20/Day 1) (N=224)
    -11 ( 27.2 )
        Pain (Cycle 21/Day 1) (N=346)
    -10.1 ( 25.2 )
        Pain (Cycle 22/Day 1) (N=182)
    -7.7 ( 26.2 )
        Pain (Cycle 23/Day 1) (N=311)
    -7.4 ( 26 )
        Pain (Cycle 24/Day 1) (N=157)
    -8.8 ( 27.7 )
        Pain (Cycle 25/Day 1) (N=297)
    -8.8 ( 24.6 )
        Pain (Cycle 26/Day 1) (N=129)
    -12.5 ( 29.5 )
        Pain (Cycle 27/Day 1) (N=275)
    -7.6 ( 25.3 )
        Pain (Cycle 28/Day 1) (N=121)
    -7.9 ( 32.4 )
        Pain (Cycle 29/Day 1) (N=251)
    -8.1 ( 24.6 )
        Pain (Cycle 30/Day 1) (N=109)
    -7.5 ( 29.8 )
        Pain (End of treatment) (N=451)
    -5.3 ( 31.2 )
    No statistical analyses for this end point

    Secondary: Mean Change from Baseline of QLQ-LC13 Scale Scores

    		 Close Top of page
    End point title
    		 Mean Change from Baseline of QLQ-LC13 Scale Scores
    End point description
    The QLQ-LC13 consists of 1 multi-item scale and 9 single items that assess specific symptoms (dyspnoea, cough, hemoptysis, and site-specific pain), side effects (sore mouth, dysphagia, neuropathy, and alopecia), and pain medication use of lung cancer patients. "n" is the number of participants who completed the scale at baseline and at the respective Cycles. The PRO evaluable population was defined as the participants from the SA population who completed a baseline assessment and at least one post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    976
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Alopecia (Cycle 2/Day 1) (N=920)
    -9.1 ( 29.6 )
        Alopecia (Cycle 3/Day 1) (N=870)
    -10.2 ( 31.6 )
        Alopecia (Cycle 4/Day 1) (N=829)
    -11.6 ( 30.7 )
        Alopecia (Cycle 5/Day 1) (N=805)
    -12.2 ( 32.3 )
        Alopecia (Cycle 6/Day 1) (N=770)
    -10.5 ( 30.9 )
        Alopecia (Cycle 7/Day 1) (N=734)
    -11.9 ( 32.3 )
        Alopecia (Cycle 8/Day 1) (N=700)
    -11.9 ( 33.2 )
        Alopecia (Cycle 9/Day 1) (N=667)
    -11.3 ( 34.7 )
        Alopecia (Cycle 10/Day 1) (N=633)
    -10.8 ( 33.9 )
        Alopecia (Cycle 11/Day 1) (N=574)
    -11.3 ( 34.8 )
        Alopecia (Cycle 12/Day 1) (N=409)
    -7.8 ( 34.8 )
        Alopecia (Cycle 13/Day 1) (N=512)
    -10.8 ( 35 )
        Alopecia (Cycle 14/Day 1) (N=353)
    -8.2 ( 36.4 )
        Alopecia (Cycle 15/Day 1) (N=462)
    -11.8 ( 34.3 )
        Alopecia (Cycle 16/Day 1) (N=293)
    -7.7 ( 34.1 )
        Alopecia (Cycle 17/Day 1) (N=419)
    -9.5 ( 32.9 )
        Alopecia (Cycle 18/Day 1) (N=247)
    -6.4 ( 31.3 )
        Alopecia (Cycle 19/Day 1) (N=377)
    -8.9 ( 34.1 )
        Alopecia (Cycle 20/Day 1) (N=222)
    -9 ( 30.7 )
        Alopecia (Cycle 21/Day 1) (N=342)
    -7.8 ( 32.9 )
        Alopecia (Cycle 22/Day 1) (N=180)
    -7.6 ( 35.6 )
        Alopecia (Cycle 23/Day 1) (N=310)
    -7 ( 33.2 )
        Alopecia (Cycle 24/Day 1) (N=156)
    -4.1 ( 34.1 )
        Alopecia (Cycle 25/Day 1) (N=293)
    -8.2 ( 31.8 )
        Alopecia (Cycle 26/Day 1) (N=126)
    -4.5 ( 31.1 )
        Alopecia (Cycle 27/Day 1) (N=271)
    -8.5 ( 31.5 )
        Alopecia (Cycle 28/Day 1) (N=119)
    -3.9 ( 33.1 )
        Alopecia (Cycle 29/Day 1) (N=247)
    -9.2 ( 28.3 )
        Alopecia (Cycle 30/Day 1) (N=107)
    -5 ( 31.7 )
        Alopecia (End of treatment) (N=447)
    -9.9 ( 35.3 )
        Coughing (Cycle 2/Day 1) (N=926)
    -12.9 ( 28.8 )
        Coughing (Cycle 3/Day 1) (N=879)
    -15.5 ( 31.8 )
        Coughing (Cycle 4/Day 1) (N=832)
    -17.7 ( 31.1 )
        Coughing (Cycle 5/Day 1) (N=807)
    -17.3 ( 31.8 )
        Coughing (Cycle 6/Day 1) (N=775)
    -18.3 ( 32.1 )
        Coughing (Cycle 7/Day 1) (N=735)
    -20.1 ( 32.2 )
        Coughing (Cycle 8/Day 1) (N=703)
    -20.8 ( 31.8 )
        Coughing (Cycle 9/Day 1) (N=669)
    -20.2 ( 30.9 )
        Coughing (Cycle 10/Day 1) (N=636)
    -19.9 ( 32 )
        Coughing (Cycle 11/Day 1) (N=575)
    -19.9 ( 31.6 )
        Coughing (Cycle 12/Day 1) (N=414)
    -19.2 ( 29.5 )
        Coughing (Cycle 13/Day 1) (N=513)
    -18.6 ( 32.6 )
        Coughing (Cycle 14/Day 1) (N=355)
    -17.9 ( 32.1 )
        Coughing (Cycle 15/Day 1) (N=461)
    -17.8 ( 31.7 )
        Coughing (Cycle 16/Day 1) (N=294)
    -17.3 ( 29.5 )
        Coughing (Cycle 17/Day 1) (N=421)
    -18.4 ( 32.5 )
        Coughing (Cycle 18/Day 1) (N=249)
    -16.9 ( 33.1 )
        Coughing (Cycle 19/Day 1) (N=379)
    -18.8 ( 30.3 )
        Coughing (Cycle 20/Day 1) (N=222)
    -18.3 ( 32.7 )
        Coughing (Cycle 21/Day 1) (N=343)
    -18 ( 31 )
        Coughing (Cycle 22/Day 1) (N=181)
    -16.7 ( 33.1 )
        Coughing (Cycle 23/Day 1) (N=311)
    -18.4 ( 32.1 )
        Coughing (Cycle 24/Day 1) (N=155)
    -18.9 ( 31.3 )
        Coughing (Cycle 25/Day 1) (N=294)
    -18.1 ( 31.3 )
        Coughing (Cycle 26/Day 1) (N=125)
    -21.9 ( 30.8 )
        Coughing (Cycle 27/Day 1) (N=272)
    -17.8 ( 32.2 )
        Coughing (Cycle 28/Day 1) (N=119)
    -19.6 ( 30.8 )
        Coughing (Cycle 29/Day 1) (N=249)
    -17.1 ( 31.3 )
        Coughing (Cycle 30/Day 1) (N=106)
    -16.7 ( 29.5 )
        Coughing (End of treatment) (N=452)
    -11.1 ( 33.5 )
        Dysphagia (Cycle 2/Day 1) (N=926)
    0 ( 19.6 )
        Dysphagia (Cycle 3/Day 1) (N=879)
    -1.1 ( 20.1 )
        Dysphagia (Cycle 4/Day 1) (N=831)
    -2.2 ( 20.8 )
        Dysphagia (Cycle 5/Day 1) (N=807)
    -2.3 ( 20 )
        Dysphagia (Cycle 6/Day 1) (N=776)
    -3 ( 19.9 )
        Dysphagia (Cycle 7/Day 1) (N=737)
    -3.1 ( 20.7 )
        Dysphagia (Cycle 8/Day 1) (N=702)
    -3.1 ( 18.6 )
        Dysphagia (Cycle 9/Day 1) (N=670)
    -2.7 ( 20.2 )
        Dysphagia (Cycle 10/Day 1) (N=637)
    -2.9 ( 19.4 )
        Dysphagia (End of treatment) (N=449)
    1.9 ( 23.5 )
        Dysphagia (Cycle 11/Day 1) (N=577)
    -3 ( 19.2 )
        Dysphagia (Cycle 12/Day 1) (N=414)
    -2.7 ( 18.1 )
        Dysphagia (Cycle 13/Day 1) (N=513)
    -3.1 ( 17.8 )
        Dysphagia (Cycle 14/Day 1) (N=355)
    -1.7 ( 18.2 )
        Dysphagia (Cycle 15/Day 1) (N=463)
    -2.8 ( 17.5 )
        Dysphagia (Cycle 16/Day 1) (N=294)
    -1.3 ( 20.1 )
        Dysphagia (Cycle 17/Day 1) (N=422)
    -2.2 ( 19 )
        Dysphagia (Cycle 18/Day 1) (N=249)
    -2.5 ( 18.4 )
        Dysphagia (Cycle 19/Day 1) (N=378)
    -2 ( 17.3 )
        Dysphagia (Cycle 20/Day 1) (N=223)
    -3.4 ( 18.5 )
        Dysphagia (Cycle 21/Day 1) (N=344)
    -2.5 ( 18.2 )
        Dysphagia (Cycle 22/Day 1) (N=182)
    -1.8 ( 19.7 )
        Dysphagia (Cycle 23/Day 1) (N=311)
    -3.4 ( 17 )
        Dysphagia (Cycle 24/Day 1) (N=156)
    -1.4 ( 16.5 )
        Dysphagia (Cycle 25/Day 1) (N=295)
    -2.8 ( 17.3 )
        Dysphagia (Cycle 26/Day 1) (N=126)
    -1.1 ( 15.7 )
        Dysphagia (Cycle 27/Day 1) (N=274)
    -1.6 ( 17.5 )
        Dysphagia (Cycle 28/Day 1) (N=120)
    -1.4 ( 16.4 )
        Dysphagia (Cycle 29/Day 1) (N=248)
    -1.5 ( 16.5 )
        Dysphagia (Cycle 30/Day 1) (N=107)
    -0.9 ( 18 )
        Dyspnoea (Cycle 2/Day 1) (N=928)
    -8 ( 19 )
        Dyspnoea (Cycle 3/Day 1) (N=878)
    -9.7 ( 21.5 )
        Dyspnoea (Cycle 4/Day 1) (N=833)
    -10.7 ( 21.7 )
        Dyspnoea (Cycle 5/Day 1) (N=809)
    -10.6 ( 21.4 )
        Dyspnoea (Cycle 6/Day 1) (N=775)
    -10.6 ( 21.7 )
        Dyspnoea (Cycle 7/Day 1) (N=737)
    -11.1 ( 21.1 )
        Dyspnoea (Cycle 8/Day 1) (N=704)
    -12 ( 20.7 )
        Dyspnoea (Cycle 9/Day 1) (N=669)
    -11 ( 20.7 )
        Dyspnoea (Cycle 10/Day 1) (N=637)
    -10.7 ( 21.1 )
        Dyspnoea (Cycle 11/Day 1) (N=577)
    -10.6 ( 20.8 )
        Dyspnoea (Cycle 12/Day 1) (N=414)
    -9 ( 20.2 )
        Dyspnoea (Cycle 13/Day 1) (N=514)
    -9.8 ( 21.1 )
        Dyspnoea (Cycle 14/Day 1) (N=354)
    -9.2 ( 20 )
        Dyspnoea (Cycle 15/Day 1) (N=463)
    -8.9 ( 21.6 )
        Dyspnoea (Cycle 16/Day 1) (N=293)
    -7.7 ( 21.3 )
        Dyspnoea (Cycle 17/Day 1) (N=421)
    -7.3 ( 20.5 )
        Dyspnoea (Cycle 18/Day 1) (N=249)
    -6.9 ( 21.3 )
        Dyspnoea (Cycle 19/Day 1) (N=379)
    -8.6 ( 19.7 )
        Dyspnoea (Cycle 20/Day 1) (N=223)
    -5.8 ( 19.8 )
        Dyspnoea (Cycle 21/Day 1) (N=344)
    -7.8 ( 19.5 )
        Dyspnoea (Cycle 22/Day 1) (N=182)
    -5.6 ( 18.3 )
        Dyspnoea (Cycle 23/Day 1) (N=311)
    -6.1 ( 19.3 )
        Dyspnoea (Cycle 24/Day 1) (N=156)
    -6.2 ( 18.3 )
        Dyspnoea (Cycle 25/Day 1) (N=295)
    -6.1 ( 19.7 )
        Dyspnoea (Cycle 26/Day 1) (N=126)
    -6.6 ( 19.3 )
        Dyspnoea (Cycle 27/Day 1) (N=273)
    -5.7 ( 19 )
        Dyspnoea (Cycle 28/Day 1) (N=120)
    -5.8 ( 19.5 )
        Dyspnoea (Cycle 29/Day 1) (N=249)
    -3.9 ( 19.2 )
        Dyspnoea (Cycle 30/Day 1) (N=107)
    -4.6 ( 17.5 )
        Dyspnoea (End of treatment) (N=448)
    -3 ( 25.7 )
        Haemoptysis (Cycle 2/Day 1) (N=925)
    -2.6 ( 12.6 )
        Haemoptysis (Cycle 3/Day 1) (N=879)
    -3 ( 12.6 )
        Haemoptysis (Cycle 4/Day 1) (N=833)
    -2.9 ( 12.7 )
        Haemoptysis (Cycle 5/Day 1) (N=808)
    -2.6 ( 12.9 )
        Haemoptysis (Cycle 6/Day 1) (N=774)
    -2.8 ( 12 )
        Haemoptysis (Cycle 7/Day 1) (N=735)
    -2.9 ( 12.7 )
        Haemoptysis (Cycle 8/Day 1) (N=703)
    -3.1 ( 11.9 )
        Haemoptysis (Cycle 9/Day 1) (N=669)
    -3 ( 11.7 )
        Haemoptysis (Cycle 10/Day 1) (N=635)
    -2.6 ( 11.7 )
        Haemoptysis (Cycle 11/Day 1) (N=576)
    -2.7 ( 11.6 )
        Haemoptysis (Cycle 12/Day 1) (N=413)
    -2.6 ( 10.3 )
        Haemoptysis (Cycle 13/Day 1) (N=514)
    -2.1 ( 12 )
        Haemoptysis (Cycle 14/Day 1) (N=354)
    -2.7 ( 11.3 )
        Haemoptysis (Cycle 15/Day 1) (N=462)
    -2.2 ( 10.8 )
        Haemoptysis (Cycle 16/Day 1) (N=294)
    -2.5 ( 11.4 )
        Haemoptysis (Cycle 17/Day 1) (N=420)
    -1.9 ( 11.4 )
        Haemoptysis (Cycle 18/Day 1) (N=249)
    -2.4 ( 12.1 )
        Haemoptysis (Cycle 19/Day 1) (N=378)
    -2.1 ( 11.5 )
        Haemoptysis (Cycle 20/Day 1) (N=223)
    -2.4 ( 13.6 )
        Haemoptysis (Cycle 21/Day 1) (N=342)
    -2.5 ( 11.5 )
        Haemoptysis (Cycle 22/Day 1) (N=182)
    -2.9 ( 11.2 )
        Haemoptysis (Cycle 23/Day 1) (N=309)
    -2.7 ( 12.5 )
        Haemoptysis (Cycle 24/Day 1) (N=156)
    -2.4 ( 12 )
        Haemoptysis (Cycle 25/Day 1) (N=294)
    -2.8 ( 12.4 )
        Haemoptysis (Cycle 26/Day 1) (N=126)
    -3.2 ( 12.9 )
        Haemoptysis (Cycle 27/Day 1) (N=272)
    -2.9 ( 11.4 )
        Haemoptysis (Cycle 28/Day 1) (N=119)
    -3.1 ( 12.3 )
        Haemoptysis (Cycle 29/Day 1) (N=248)
    -1.7 ( 12.1 )
        Haemoptysis (Cycle 30/Day 1) (N=107)
    -2.8 ( 11.3 )
        Haemoptysis (End of treatment) (N=451)
    -1.4 ( 15.9 )
        Pain in Arm or Shoulder (Cycle 2/Day 1) (N=926)
    -9.6 ( 26.9 )
        Pain in Arm or Shoulder (Cycle 3/Day 1) (N=876)
    -12.2 ( 27 )
        Pain in Arm or Shoulder (Cycle 4/Day 1) (N=832)
    -12.5 ( 28.2 )
        Pain in Arm or Shoulder (Cycle 5/Day 1) (N=807)
    -11.7 ( 27.1 )
        Pain in Arm or Shoulder (Cycle 6/Day 1) (N=773)
    -11.6 ( 26.3 )
        Pain in Arm or Shoulder (Cycle 7/Day 1) (N=738)
    -11.3 ( 28.1 )
        Pain in Arm or Shoulder (Cycle 8/Day 1) (N=702)
    -11.7 ( 28.5 )
        Pain in Arm or Shoulder (Cycle 9/Day 1) (N=669)
    -11.9 ( 28.5 )
        Pain in Arm or Shoulder (Cycle 10/Day 1) (N=635)
    -11.3 ( 28 )
        Pain in Arm or Shoulder (Cycle 11/Day 1) (N=576)
    -12.1 ( 27.3 )
        Pain in Arm or Shoulder (Cycle 12/Day 1) (N=414)
    -11 ( 27.7 )
        Pain in Arm or Shoulder (Cycle 13/Day 1) (N=513)
    -10.9 ( 27.2 )
        Pain in Arm or Shoulder (Cycle 14/Day 1) (N=355)
    -11.3 ( 27.3 )
        Pain in Arm or Shoulder (Cycle 15/Day 1) (N=461)
    -10.3 ( 25.6 )
        Pain in Arm or Shoulder (Cycle 16/Day 1) (N=293)
    -9.9 ( 28 )
        Pain in Arm or Shoulder (Cycle 17/Day 1) (N=421)
    -8.2 ( 26.5 )
        Pain in Arm or Shoulder (Cycle 18/Day 1) (N=249)
    -9.4 ( 27.6 )
        Pain in Arm or Shoulder (Cycle 19/Day 1) (N=379)
    -9.1 ( 26.5 )
        Pain in Arm or Shoulder (Cycle 20/Day 1) (N=222)
    -7.4 ( 27.3 )
        Pain in Arm or Shoulder (Cycle 21/Day 1) (N=344)
    -9 ( 27 )
        Pain in Arm or Shoulder (Cycle 22/Day 1) (N=182)
    -9 ( 29.1 )
        Pain in Arm or Shoulder (Cycle 23/Day 1) (N=311)
    -8.9 ( 25.5 )
        Pain in Arm or Shoulder (Cycle 24/Day 1) (N=155)
    -9.7 ( 30.6 )
        Pain in Arm or Shoulder (Cycle 25/Day 1) (N=295)
    -9.2 ( 26 )
        Pain in Arm or Shoulder (Cycle 26/Day 1) (N=126)
    -10.8 ( 33.7 )
        Pain in Arm or Shoulder (Cycle 27/Day 1) (N=274)
    -8.6 ( 26.5 )
        Pain in Arm or Shoulder (Cycle 28/Day 1) (N=119)
    -8.7 ( 29.6 )
        Pain in Arm or Shoulder (Cycle 29/Day 1) (N=248)
    -7.9 ( 27.2 )
        Pain in Arm or Shoulder (Cycle 30/Day 1) (N=107)
    -8.1 ( 30.3 )
        Pain in Arm or Shoulder (End of treatment)(N=445)
    -5.8 ( 30.7 )
        Pain in Chest (Cycle 2/Day 1) (N=928)
    -9.5 ( 23.4 )
        Pain in Chest (Cycle 3/Day 1) (N=875)
    -11.9 ( 25.1 )
        Pain in Chest (Cycle 4/Day 1) (N=833)
    -12.1 ( 26.1 )
        Pain in Chest (Cycle 5/Day 1) (N=808)
    -11.8 ( 25.8 )
        Pain in Chest (Cycle 6/Day 1) (N=774)
    -12.1 ( 25.3 )
        Pain in Chest (Cycle 7/Day 1) (N=735)
    -12.6 ( 25.4 )
        Pain in Chest (Cycle 8/Day 1) (N=703)
    -13.2 ( 25 )
        Pain in Chest (Cycle 9/Day 1) (N=665)
    -13.1 ( 25.8 )
        Pain in Chest (Cycle 10/Day 1) (N=633)
    -12.9 ( 26 )
        Pain in Chest (Cycle 11/Day 1) (N=574)
    -12 ( 25.5 )
        Pain in Chest (Cycle 12/Day 1) (N=414)
    -10.7 ( 25.5 )
        Pain in Chest (Cycle 13/Day 1) (N=513)
    -12.6 ( 24.5 )
        Pain in Chest (Cycle 14/Day 1) (N=355)
    -11.5 ( 24.4 )
        Pain in Chest (Cycle 15/Day 1) (N=462)
    -11.9 ( 24.7 )
        Pain in Chest (Cycle 16/Day 1) (N=294)
    -11 ( 23.4 )
        Pain in Chest (Cycle 17/Day 1) (N=421)
    -11.6 ( 23.8 )
        Pain in Chest (Cycle 18/Day 1) (N=249)
    -8 ( 23.1 )
        Pain in Chest (Cycle 19/Day 1) (N=378)
    -11.2 ( 23.8 )
        Pain in Chest (Cycle 20/Day 1) (N=222)
    -9.4 ( 24.3 )
        Pain in Chest (Cycle 21/Day 1) (N=343)
    -11.9 ( 23.5 )
        Pain in Chest (Cycle 22/Day 1) (N=182)
    -10.1 ( 21.9 )
        Pain in Chest (Cycle 23/Day 1) (N=308)
    -10.8 ( 24 )
        Pain in Chest (Cycle 24/Day 1) (N=156)
    -7.1 ( 26.8 )
        Pain in Chest (Cycle 25/Day 1) (N=293)
    -10.2 ( 22.3 )
        Pain in Chest (Cycle 26/Day 1) (N=126)
    -10.6 ( 25.2 )
        Pain in Chest (Cycle 27/Day 1) (N=272)
    -9.2 ( 22 )
        Pain in Chest (Cycle 28/Day 1) (N=120)
    -9.4 ( 26.7 )
        Pain in Chest (Cycle 29/Day 1) (N=248)
    -9.5 ( 24.4 )
        Pain in Chest (Cycle 30/Day 1) (N=107)
    -5.3 ( 26.8 )
        Pain in Chest (End of treatment) (N=451)
    -6.7 ( 28 )
        Pain in Other Parts (Cycle 2/Day 1) (N=893)
    -10 ( 31.3 )
        Pain in Other Parts (Cycle 3/Day 1) (N=854)
    -12 ( 31.9 )
        Pain in Other Parts (Cycle 4/Day 1) (N=806)
    -13.5 ( 31 )
        Pain in Other Parts (Cycle 5/Day 1) (N=793)
    -12.2 ( 30.2 )
        Pain in Other Parts (Cycle 6/Day 1) (N=752)
    -12.5 ( 30.9 )
        Pain in Other Parts (Cycle 7/Day 1) (N=715)
    -11.8 ( 30.3 )
        Pain in Other Parts (Cycle 8/Day 1) (N=680)
    -11.7 ( 30.5 )
        Pain in Other Parts (Cycle 9/Day 1) (N=650)
    -13.1 ( 29.9 )
        Pain in Other Parts (Cycle 10/Day 1) (N=616)
    -12.1 ( 30.4 )
        Pain in Other Parts (Cycle 11/Day 1) (N=562)
    -10.8 ( 29.3 )
        Pain in Other Parts (Cycle 12/Day 1) (N=399)
    -11.6 ( 30.9 )
        Pain in Other Parts (Cycle 13/Day 1) (N=499)
    -9.9 ( 30 )
        Pain in Other Parts (Cycle 14/Day 1) (N=342)
    -11.5 ( 31.3 )
        Pain in Other Parts (Cycle 15/Day 1) (N=451)
    -10.1 ( 28.9 )
        Pain in Other Parts (Cycle 16/Day 1) (N=282)
    -9.6 ( 30.3 )
        Pain in Other Parts (Cycle 17/Day 1) (N=411)
    -8.8 ( 28.1 )
        Pain in Other Parts (Cycle 18/Day 1) (N=239)
    -8.6 ( 31 )
        Pain in Other Parts (Cycle 19/Day 1) (N=370)
    -8.8 ( 29 )
        Pain in Other Parts (Cycle 20/Day 1) (N=210)
    -9.4 ( 31.3 )
        Pain in Other Parts (Cycle 21/Day 1) (N=337)
    -8.2 ( 28.6 )
        Pain in Other Parts (Cycle 22/Day 1) (N=176)
    -10.4 ( 30.2 )
        Pain in Other Parts (Cycle 23/Day 1) (N=300)
    -6.6 ( 29.2 )
        Pain in Other Parts (Cycle 24/Day 1) (N=149)
    -7.8 ( 35.2 )
        Pain in Other Parts (Cycle 25/Day 1) (N=286)
    -7.2 ( 30.2 )
        Pain in Other Parts (Cycle 26/Day 1) (N=121)
    -8.8 ( 34.6 )
        Pain in Other Parts (Cycle 27/Day 1) (N=267)
    -5.9 ( 29.5 )
        Pain in Other Parts (Cycle 28/Day 1) (N=116)
    -3.2 ( 34.6 )
        Pain in Other Parts (Cycle 29/Day 1) (N=242)
    -6.3 ( 27.1 )
        Pain in Other Parts (Cycle 30/Day 1) (N=102)
    -6.5 ( 34.8 )
        Pain in Other Parts (End of treatment) (N=427)
    -4.6 ( 34.8 )
        Peripheral Neuropathy (Cycle 2/Day 1) (N=925)
    0.6 ( 25.3 )
        Peripheral Neuropathy (Cycle 3/Day 1) (N=876)
    -0.4 ( 25.6 )
        Peripheral Neuropathy (Cycle 4/Day 1) (N=833)
    -1.7 ( 26.5 )
        Peripheral Neuropathy (Cycle 5/Day 1) (N=807)
    -1.2 ( 26.3 )
        Peripheral Neuropathy (Cycle 6/Day 1) (N=775)
    -1.4 ( 26.5 )
        Peripheral Neuropathy (Cycle 7/Day 1) (N=737)
    -2.6 ( 27.2 )
        Peripheral Neuropathy (Cycle 8/Day 1) (N=703)
    -2.1 ( 25.6 )
        Peripheral Neuropathy (Cycle 9/Day 1) (N=668)
    -1.8 ( 27.2 )
        Peripheral Neuropathy (Cycle 10/Day 1) (N=635)
    -1 ( 26.4 )
        Peripheral Neuropathy (Cycle 11/Day 1) (N=575)
    -1.6 ( 27.5 )
        Peripheral Neuropathy (Cycle 12/Day 1) (N=413)
    -0.8 ( 27.3 )
        Peripheral Neuropathy (Cycle 13/Day 1) (N=512)
    -1.5 ( 27 )
        Peripheral Neuropathy (Cycle 14/Day 1) (N=354)
    -2.1 ( 28.6 )
        Peripheral Neuropathy (Cycle 15/Day 1) (N=462)
    -0.7 ( 27.5 )
        Peripheral Neuropathy (Cycle 16/Day 1) (N=294)
    -1.5 ( 29.9 )
        Peripheral Neuropathy (Cycle 17/Day 1) (N=418)
    -0.3 ( 28.3 )
        Peripheral Neuropathy (Cycle 18/Day 1) (N=249)
    -0.7 ( 28.3 )
        Peripheral Neuropathy (Cycle 19/Day 1) (N=378)
    -1.5 ( 23.9 )
        Peripheral Neuropathy (Cycle 20/Day 1) (N=221)
    0 ( 28.1 )
        Peripheral Neuropathy (Cycle 21/Day 1) (N=342)
    0.2 ( 27.6 )
        Peripheral Neuropathy (Cycle 22/Day 1) (N=182)
    -3.7 ( 27.6 )
        Peripheral Neuropathy (Cycle 23/Day 1) (N=310)
    -1 ( 26.2 )
        Peripheral Neuropathy (Cycle 24/Day 1) (N=156)
    -1.7 ( 26.4 )
        Peripheral Neuropathy (Cycle 25/Day 1) (N=295)
    2.3 ( 25.5 )
        Peripheral Neuropathy (Cycle 26/Day 1) (N=126)
    -1.6 ( 24.9 )
        Peripheral Neuropathy (Cycle 27/Day 1) (N=274)
    2.1 ( 27.1 )
        Peripheral Neuropathy (Cycle 28/Day 1) (N=119)
    -0.6 ( 27.1 )
        Peripheral Neuropathy (Cycle 29/Day 1) (N=249)
    1.5 ( 26.3 )
        Peripheral Neuropathy (Cycle 30/Day 1) (N=107)
    -0.6 ( 28.2 )
        Peripheral Neuropathy (End of treatment) (N=451)
    -0.6 ( 26.6 )
        Sore Mouth (Cycle 2/Day 1) (N=928)
    1 ( 20 )
        Sore Mouth (Cycle 3/Day 1) (N=879)
    -0.2 ( 19.8 )
        Sore Mouth (Cycle 4/Day 1) (N=834)
    -0.6 ( 19.1 )
        Sore Mouth (Cycle 5/Day 1) (N=808)
    -1.3 ( 17.9 )
        Sore Mouth (Cycle 6/Day 1) (N=776)
    -1.8 ( 17.1 )
        Sore Mouth (Cycle 7/Day 1) (N=738)
    -1.2 ( 18.3 )
        Sore Mouth (Cycle 8/Day 1) (N=704)
    -2.2 ( 17 )
        Sore Mouth (Cycle 9/Day 1) (N=669)
    -2.1 ( 18.3 )
        Sore Mouth (Cycle 10/Day 1) (N=636)
    -1.7 ( 19.1 )
        Sore Mouth (Cycle 11/Day 1) (N=577)
    -1.8 ( 17.2 )
        Sore Mouth (Cycle 12/Day 1) (N=414)
    -1.9 ( 17.1 )
        Sore Mouth (Cycle 13/Day 1) (N=514)
    -1.5 ( 18 )
        Sore Mouth (Cycle 14/Day 1) (N=354)
    -1.3 ( 14.8 )
        Sore Mouth (Cycle 15/Day 1) (N=463)
    -0.9 ( 16.1 )
        Sore Mouth (Cycle 16/Day 1) (N=294)
    0.1 ( 16.6 )
        Sore Mouth (Cycle 17/Day 1) (N=422)
    -1.4 ( 17.6 )
        Sore Mouth (Cycle 18/Day 1) (N=249)
    -0.9 ( 18 )
        Sore Mouth (Cycle 19/Day 1) (N=379)
    -0.9 ( 17.3 )
        Sore Mouth (Cycle 20/Day 1) (N=223)
    -1.3 ( 17.7 )
        Sore Mouth (Cycle 21/Day 1) (N=344)
    -0.6 ( 18 )
        Sore Mouth (Cycle 22/Day 1) (N=182)
    -1.1 ( 14.8 )
        Sore Mouth (Cycle 23/Day 1) (N=311)
    0.3 ( 17.7 )
        Sore Mouth (Cycle 24/Day 1) (N=156)
    2.6 ( 17.2 )
        Sore Mouth (Cycle 25/Day 1) (N=294)
    -1.6 ( 17.6 )
        Sore Mouth (Cycle 26/Day 1) (N=126)
    -2.4 ( 14.7 )
        Sore Mouth (Cycle 27/Day 1) (N=274)
    -0.6 ( 18.4 )
        Sore Mouth (Cycle 28/Day 1) (N=120)
    -0.3 ( 15.3 )
        Sore Mouth (Cycle 29/Day 1) (N=249)
    -1.7 ( 16.4 )
        Sore Mouth (Cycle 30/Day 1) (N=107)
    -1.2 ( 12.9 )
        Sore Mouth (End of treatment) (N=451)
    -0.4 ( 20 )
    No statistical analyses for this end point

    Secondary: Patient reported outcomes (PROs) of health-related quality of life (HRQoL): Mean change from baseline of EQ-5D Visual Analog Score (VAS) Scale

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    End point title
    		 Patient reported outcomes (PROs) of health-related quality of life (HRQoL): Mean change from baseline of EQ-5D Visual Analog Score (VAS) Scale
    End point description
    The EQ-5D descriptive system measured a patient’s health state on 5 dimensions which included: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The respondent’s self-rated health was assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS. "n" is the number of participants who completedthe scale at baseline and at the respective Cycles. The PRO evaluable population was defined as the participants from the SA population who completed a baseline assessment and at least one post-baseline assessment
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    974
    Units: Units on a scale
    arithmetic mean (standard deviation)
        CYCLE 2/DAY 1 (N=926)
    5.72 ( 17.51 )
        CYCLE 3/DAY 1 (N=875)
    8.57 ( 18.82 )
        CYCLE 4/DAY 1 (N=836)
    10.01 ( 19.73 )
        CYCLE 5/DAY 1 (N=804)
    10.38 ( 19.85 )
        CYCLE 6/DAY 1 (N=771)
    10.17 ( 20.38 )
        CYCLE 7/DAY 1 (N=728)
    10.17 ( 20.38 )
        CYCLE 8/DAY 1 (N=693)
    10.35 ( 19.22 )
        CYCLE 9/DAY 1 (N=667)
    10.69 ( 19.82 )
        CYCLE 10/DAY 1 (N=633)
    10.34 ( 19.15 )
        CYCLE 11/DAY 1 (N=573)
    10.09 ( 19.72 )
        CYCLE 12/DAY 1 (N=409)
    9.69 ( 18.81 )
        CYCLE 13/DAY 1 (N=512)
    9.74 ( 19.64 )
        CYCLE 14/DAY 1 (N=351)
    10.93 ( 18.67 )
        CYCLE 15/DAY 1 (N=461)
    8.71 ( 20.53 )
        CYCLE 16/DAY 1 (N=289)
    8.47 ( 20.66 )
        CYCLE 17/DAY 1 (N=417)
    7.99 ( 20.8 )
        CYCLE 18/DAY 1 (N=244)
    7.62 ( 19.86 )
        CYCLE 19/DAY 1 (N=372)
    8.17 ( 18.92 )
        CYCLE 20/DAY 1 (N=219)
    8.03 ( 18.45 )
        CYCLE 21/DAY 1 (N=339)
    6.96 ( 18.71 )
        CYCLE 22/DAY 1 (N=179)
    6.59 ( 18.97 )
        CYCLE 23/DAY 1 (N=310)
    5.53 ( 19.5 )
        CYCLE 24/DAY 1 (N=154)
    7.61 ( 19.58 )
        CYCLE 25/DAY 1 (N=299)
    4.97 ( 17.98 )
        CYCLE 26/DAY 1 (N=128)
    8.54 ( 18.97 )
        CYCLE 27/DAY 1 (N=272)
    5.24 ( 17.61 )
        CYCLE 28/DAY 1 (N=120)
    7.93 ( 19.53 )
        CYCLE 29/DAY 1 (N=249)
    5.05 ( 17.07 )
        CYCLE 30/DAY 1 (N=108)
    8.07 ( 19.95 )
        End of Treatment (N=450)
    0.09 ( 23.92 )
    No statistical analyses for this end point

    Secondary: Percentage of participants with Visual Symptom Assessment Questionnaire (VSAQ-ALK)

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    End point title
    		 Percentage of participants with Visual Symptom Assessment Questionnaire (VSAQ-ALK)
    End point description
    The participants who responded to the question: "Have you experienced any visual disturbances?" Only the participants who answered yes were instructed to complete the rest of the questionnaire. "n" is the number of participants who completed the first question. The safety analysis population included all participants who were enrolled and received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing).
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Percentage of participants
    number (not applicable)
        Cycle 2/Day 1 (Yes) (N=798)
    64.5
        Cycle 2/Day 1 (No) (N=798)
    35.5
        Cycle 3/Day 1 (Yes) (N=768)
    56.5
        Cycle 3/Day 1 (No) (N=768)
    43.5
        Cycle 4/Day 1 (Yes) (N=754)
    52.3
        Cycle 4/Day 1 (No) (N=754)
    47.7
        Cycle 5/Day 1 (Yes) (N=743)
    49.1
        Cycle 5/Day 1 (No) (N=743)
    50.9
        Cycle 6/Day 1 (Yes) (N=731)
    48.8
        Cycle 6/Day 1 (No) (N=731)
    51.2
        Cycle 7/Day 1 (Yes) (N=699)
    45.8
        Cycle 7/Day 1 (No) (N=699)
    54.2
        Cycle 8/Day 1 (Yes) (N=670)
    43.7
        Cycle 8/Day 1 (No) (N=670)
    56.3
        Cycle 9/Day 1 (Yes) (N=653)
    43.5
        Cycle 9/Day 1 (No) (N=653)
    56.5
        Cycle 10/Day 1 (Yes) (N=621)
    42.7
        Cycle 10/Day 1 (No) (N=621)
    57.3
        Cycle 11/Day 1 (Yes) (N=565)
    40.2
        Cycle 11/Day 1 (No) (N=565)
    59.8
        Cycle 12/Day 1 (Yes) (N=403)
    42.9
        Cycle 12/Day 1 (No) (N=403)
    57.1
        Cycle 13/Day 1 (Yes) (N=507)
    41.2
        Cycle 13/Day 1 (No) (N=507)
    58.8
        Cycle 14/Day 1 (Yes) (N=354)
    41.5
        Cycle 14/Day 1 (No) (N=354)
    58.5
        Cycle 15/Day 1 (Yes) (N=468)
    39.1
        Cycle 15/Day 1 (No) (N=468)
    60.9
        Cycle 16/Day 1 (Yes) (N=296)
    43.6
        Cycle 16/Day 1 (No) (N=296)
    56.4
        Cycle 17/Day 1 (Yes) (N=418)
    37.3
        Cycle 17/Day 1 (No) (N=418)
    62.7
        Cycle 18/Day 1 (Yes) (N=249)
    40.2
        Cycle 18/Day 1 (No) (N=249)
    59.8
        Cycle 19/Day 1 (Yes) (N=378)
    36.8
        Cycle 19/Day 1 (No) (N=378)
    63.2
        Cycle 20/Day 1 (Yes) (N=221)
    38.9
        Cycle 20/Day 1 (No) (N=221)
    61.1
        Cycle 21/Day 1 (Yes) (N=344)
    39
        Cycle 21/Day 1 (No) (N=344)
    61
        Cycle 22/Day 1 (Yes) (N=181)
    39.2
        Cycle 22/Day 1 (No) (N=181)
    60.8
        Cycle 23/Day 1 (Yes) (N=312)
    34.9
        Cycle 23/Day 1 (No) (N=312)
    65.1
        Cycle 24/Day 1 (Yes) (N=155)
    34.8
        Cycle 24/Day 1 (No) (N=155)
    65.2
        Cycle 25/Day 1 (Yes) (N=302)
    35.8
        Cycle 25/Day 1 (No) (N=302)
    64.2
        Cycle 26/Day 1 (Yes) (N=130)
    30.8
        Cycle 26/Day 1 (No) (N=130)
    69.2
        Cycle 27/Day 1 (Yes) (N=276)
    32.6
        Cycle 27/Day 1 (No) (N=276)
    67.4
        Cycle 28/Day 1 (Yes) (N=118)
    31.4
        Cycle 28/Day 1 (No) (N=118)
    68.6
        Cycle 29/Day 1 (Yes) (N=249)
    30.5
        Cycle 29/Day 1 (No) (N=249)
    69.5
        Cycle 30/Day 1 (Yes) (N=106)
    27.4
        Cycle 30/Day 1 (No) (N=106)
    72.6
        End of Treatment (Yes) (N=428)
    39.3
        End of Treatment (No) (N=428)
    60.7
    No statistical analyses for this end point

    Secondary: Plasma concentrations of crizotinib (PF-02341066) and its metabolite PF-06260182

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    End point title
    		 Plasma concentrations of crizotinib (PF-02341066) and its metabolite PF-06260182
    End point description
    Plasma concentration of crizotinib (PF-02341066) and its metabolite PF-06260182. The method of dispersion is % coefficient of variation. All participants who have ≥ 1 measurement of PF-02341066 or PF-06260182 at the time of reporting are included in PK analysis. Pre-dose concentrations of PF-02341066 and PF-06260182 were performed in only Chinese sub study participants for Cycle 1 and steady state concentrations in those who received at least 14 continuous days of 250 mg BID dosing.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID PF-06260182
    Number of subjects analysed
    906
    904
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Cycle 1 (N= 13, 13)
    1.95 ( 55 )
    0.00601 ( 167 )
        Cycle 2 (N=447, 431)
    279 ( 46 )
    76.2 ( 79 )
        Cycle 3 (N=398, 385)
    297 ( 44 )
    80.8 ( 58 )
        Cycle 5 (N=297, 290)
    294 ( 48 )
    81.4 ( 61 )
    No statistical analyses for this end point

    Secondary: Molecular Profiling (ALK Status) Descriptive Statistics for ALK Percentage of Positive Cells by Central Laboratory Test (SA [ALK positive by IUO] Population)

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    End point title
    		 Molecular Profiling (ALK Status) Descriptive Statistics for ALK Percentage of Positive Cells by Central Laboratory Test (SA [ALK positive by IUO] Population)
    End point description
    Molecular profiling outcomes included:Types of EML4-ALK fusion variants and ALK protein expression; Protein expression of identified biomarkers in serial tumor samples from surgery or biopsy, when available. The safety analysis population included all participants who received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing) and were ALK positive by IUO (SA-ALK positive by IUO population).
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    908
    Units: Number
        median (full range (min-max))
    60 (15 to 100)
    No statistical analyses for this end point

    Secondary: Genotypes of alleles possibly associated with adverse hepatic drug reactions (Pharmacogenomic evaluable population)

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    End point title
    		 Genotypes of alleles possibly associated with adverse hepatic drug reactions (Pharmacogenomic evaluable population)
    End point description
    Frequency of candidate gene alleles, HLA-DQA1*02:01, HLA-DQB1*02:02, HLA-DRB1*07:01 and TNXB/rs12153855, were measured in alanine transaminase (ALT) Cases and Controls to evaluate if there were statistically significant associations that would support/suggest any predictive (ie, diagnostic) value of these markers in identifying participants at increased risk for hepatic toxicity. Frequency of 2 additional HLA gene alleles, HLA-B*57:01 and HLA-DRB1*15:01, were also measured in ALT Cases and Controls. ALT Cases are participants with baseline ALT ≤1xULN and at least one on-treatment ALT assessment >3x upper limit of normal (ULN); and ALT Controls are those with baseline and on-treatment assessments of ALT ≤1xULN. All Genotyped Population was all participants in safety analysis population who had at least 1 genotype result. Pharmacogenomic Evaluable (PE) Population was participants in All Genotyped Population who had an HLA genotype result and were designated as ALT Case or Control.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID-ALT cases Crizotinib 250 mg BID-ALT controls
    Number of subjects analysed
    74
    115
    Units: Percentage of participants
    number (not applicable)
        HLA-DQA1*02:01
    20.3
    20
        HLA-DQB1*02:02
    17.6
    16.5
        HLA-DRB1*07:01
    20.3
    20
        TNXB/rs12153855
    10.8
    16.5
        HLA-B*57:01
    2.7
    4.3
        HLA-DRB1*15:01
    17.6
    20.9
    No statistical analyses for this end point

    Secondary: QTc prolongation in participants

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    End point title
    		 QTc prolongation in participants
    End point description
    The number and percentage of participants with maximum post-dose QTcF/QTcB (<450, 450 - <480, 480 - <500, and ≥500 msec) were evaluated. Participants from the SA population who had a Baseline (last ECG [electrocardiogram] prior to Cycle 1 Day 1 dose) and ≥1 post Baseline ECG measurement and were not included in the ECG sub-study.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    999
    Units: Percentage
    number (not applicable)
        Maximum QTcF Interval (<450)
    89.8
        Maximum QTcF Interval (450-<480)
    7.7
        Maximum QTcF Interval (480 - <500)
    1
        Maximum QTcF Interval (≥500)
    1.5
        Maximum QTcB Interval (<450)
    74.2
        Maximum QTcB Interval (450-<480)
    21.4
        Maximum QTcB Interval (480-<500)
    2.4
        Maximum QTcB Interval (≥500)
    2.1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS was defined as the time from the Cycle 1 Day 1 dose to the date of death due to any cause. OS (in months) was calculated as (date of death − date of Cycle 1 Day 1 dose + 1)/30.4. The safety analysis populations included all participants who received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing), and were ALK positive either by IUO (SA-ALK positive by IUO population) or by non-IUO (SA-ALK positive by non-IUO population), respectively.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Months
    median (confidence interval 95%)
        ALK-positive by IUO (N= 908)
    21.8 (19.4 to 24)
        ALK-positive by non-IUO (N= 158)
    16.9 (13.4 to 21.5)
    No statistical analyses for this end point

    Secondary: Probability of Survival

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    End point title
    		 Probability of Survival
    End point description
    Six-month and 1-year survival probabilities were defined as the probabilities of survival at 6 months and 1 year, respectively, after the date of the Cycle 1 Day 1 dose based on the Kaplan-Meier estimate. The safety analysis populations included all participants who received at least 1 dose of study medication (excluding day-7 pharmacokinetic [PK] dosing), and were ALK positive either by IUO (SA-ALK positive by IUO population) or by non-IUO (SA-ALK positive by non-IUO population), respectively.
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 Crizotinib 250 mg BID
    Number of subjects analysed
    1066
    Units: Percentage
    number (confidence interval 95%)
        ALK positive by IUO at 6 Months
    81.7 (79 to 84)
        ALK positive by non IUO at 6 Months
    77.5 (70.1 to 83.3)
        ALK positive by IUO at 12 Months
    66.5 (63.3 to 69.5)
        ALK positive by non IUO at 12 Months
    62.4 (54.3 to 69.6)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Active reporting period is from the time of informed consent until at least 28 days after study treatment last dose. For Serious adverse events: those with the possibility of being related to study drug must be reported as minimum thereafter.
    Adverse event reporting additional description
    All causality (serious and non-serious) adverse events have been reported. Non-serious adverse events above the 5% threshold are reported herein. 15 fatalities causally related to crizotinib have been reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Crizotinib 250 mg BID
    Reporting group description
    		 Participants were administered crizotinib at a starting dose of 250 mg orally, BID on a continuous dosing period as two 100-mg tablets and one 50-mg tablet at approximately 12 hours apart the same time each day.

    Serious adverse events
    		 Crizotinib 250 mg BID
    Total subjects affected by serious adverse events
         subjects affected / exposed
    533 / 1066 (50.00%)
         number of deaths (all causes)
    241
         number of deaths resulting from adverse events
    15
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder cancer
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Malignant melanoma
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Metastases to meninges
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neuroendocrine tumour
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small cell lung cancer
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    14 / 1066 (1.31%)
         occurrences causally related to treatment / all
    4 / 15
         deaths causally related to treatment / all
    1 / 1
    Embolism
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Haematoma
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral embolism
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Phlebitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Superior vena cava syndrome
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Thrombophlebitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombosis
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Vasculitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vena cava thrombosis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Venous thrombosis
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Pleural decortication
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Chest discomfort
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Chills
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Condition aggravated
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    8 / 1066 (0.75%)
         occurrences causally related to treatment / all
    6 / 8
         deaths causally related to treatment / all
    6 / 8
    Device dislocation
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Disease progression
         subjects affected / exposed
    135 / 1066 (12.66%)
         occurrences causally related to treatment / all
    0 / 136
         deaths causally related to treatment / all
    0 / 133
    Fatigue
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Gait disturbance
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    9 / 1066 (0.84%)
         occurrences causally related to treatment / all
    1 / 11
         deaths causally related to treatment / all
    0 / 3
    Generalised oedema
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Mass
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    5 / 8
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    18 / 1066 (1.69%)
         occurrences causally related to treatment / all
    0 / 19
         deaths causally related to treatment / all
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Contrast media allergy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic pain
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    Alveolitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atelectasis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchial hyperreactivity
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cough
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    39 / 1066 (3.66%)
         occurrences causally related to treatment / all
    8 / 46
         deaths causally related to treatment / all
    2 / 8
    Epistaxis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    1 / 2
    Lung disorder
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung infiltration
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    13 / 1066 (1.22%)
         occurrences causally related to treatment / all
    1 / 15
         deaths causally related to treatment / all
    0 / 2
    Pleuritic pain
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Pneumonitis
         subjects affected / exposed
    16 / 1066 (1.50%)
         occurrences causally related to treatment / all
    17 / 20
         deaths causally related to treatment / all
    4 / 4
    Pneumothorax
         subjects affected / exposed
    8 / 1066 (0.75%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    Pulmonary arterial hypertension
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary artery thrombosis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    26 / 1066 (2.44%)
         occurrences causally related to treatment / all
    5 / 30
         deaths causally related to treatment / all
    1 / 7
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary thrombosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Rales
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    17 / 1066 (1.59%)
         occurrences causally related to treatment / all
    1 / 23
         deaths causally related to treatment / all
    0 / 10
    Thoracic haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Confusional state
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Disorientation
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mania
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    Blood albumin decreased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Troponin I increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone fissure
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dislocation of vertebra
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fall
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Femur fracture
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation necrosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiation pneumonitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radius fracture
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Road traffic accident
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Traumatic haematoma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Angina pectoris
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure congestive
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac tamponade
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cyanosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Myocarditis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 2
    Pericarditis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Tachycardia
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ataxia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain oedema
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cerebellar infarction
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Cerebral infarction
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cerebrovascular accident
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chorea
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Coma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Depressed level of consciousness
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dizziness
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Neurological decompensation
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Paraplegia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensorimotor neuropathy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    3 / 11
         deaths causally related to treatment / all
    0 / 2
    Spinal cord compression
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vocal cord paralysis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Basophilia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Monocytosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Glaucoma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Optic atrophy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retinal detachment
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Dysphagia
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    9 / 1066 (0.84%)
         occurrences causally related to treatment / all
    4 / 10
         deaths causally related to treatment / all
    0 / 0
    Oesophagitis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Oesophageal stenosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic atrophy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Peritoneal disorder
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Peptic ulcer haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Retroperitoneal haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Hepatitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Paraneoplastic pemphigus
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rash
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Dysuria
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal cyst
         subjects affected / exposed
    13 / 1066 (1.22%)
         occurrences causally related to treatment / all
    20 / 20
         deaths causally related to treatment / all
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ureteral polyp
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Back pain
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Bursitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest wall mass
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Muscular weakness
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Myalgia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Myopathy
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck pain
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pathological fracture
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Spinal column stenosis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spondylolisthesis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    8 / 1066 (0.75%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bone abscess
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Candiduria
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis
         subjects affected / exposed
    12 / 1066 (1.13%)
         occurrences causally related to treatment / all
    4 / 15
         deaths causally related to treatment / all
    0 / 0
    Chest wall abscess
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 1066 (0.56%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Infective spondylitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Lung abscess
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lung infection
         subjects affected / exposed
    14 / 1066 (1.31%)
         occurrences causally related to treatment / all
    3 / 20
         deaths causally related to treatment / all
    2 / 5
    Meningitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Osteomyelitis chronic
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    74 / 1066 (6.94%)
         occurrences causally related to treatment / all
    7 / 99
         deaths causally related to treatment / all
    4 / 20
    Pneumonia bacterial
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia staphylococcal
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyelonephritis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal abscess
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    8 / 1066 (0.75%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 4
    Septic shock
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 4
    Skin infection
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 1066 (0.66%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 1066 (0.28%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Failure to thrive
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    2 / 1066 (0.19%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    5 / 1066 (0.47%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    4 / 1066 (0.38%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 1066 (0.09%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Crizotinib 250 mg BID
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1038 / 1066 (97.37%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    155 / 1066 (14.54%)
         occurrences all number
    240
    Chest pain
         subjects affected / exposed
    104 / 1066 (9.76%)
         occurrences all number
    121
    Fatigue
         subjects affected / exposed
    323 / 1066 (30.30%)
         occurrences all number
    524
    Oedema
         subjects affected / exposed
    95 / 1066 (8.91%)
         occurrences all number
    124
    Oedema peripheral
         subjects affected / exposed
    444 / 1066 (41.65%)
         occurrences all number
    744
    Pyrexia
         subjects affected / exposed
    181 / 1066 (16.98%)
         occurrences all number
    284
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    256 / 1066 (24.02%)
         occurrences all number
    362
    Dyspnoea
         subjects affected / exposed
    221 / 1066 (20.73%)
         occurrences all number
    312
    Haemoptysis
         subjects affected / exposed
    55 / 1066 (5.16%)
         occurrences all number
    68
    Oropharyngeal pain
         subjects affected / exposed
    76 / 1066 (7.13%)
         occurrences all number
    89
    Productive cough
         subjects affected / exposed
    71 / 1066 (6.66%)
         occurrences all number
    99
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    76 / 1066 (7.13%)
         occurrences all number
    82
    Insomnia
         subjects affected / exposed
    137 / 1066 (12.85%)
         occurrences all number
    172
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    300 / 1066 (28.14%)
         occurrences all number
    715
    Aspartate aminotransferase increased
         subjects affected / exposed
    232 / 1066 (21.76%)
         occurrences all number
    479
    Blood alkaline phosphatase increased
         subjects affected / exposed
    75 / 1066 (7.04%)
         occurrences all number
    112
    Blood creatinine increased
         subjects affected / exposed
    103 / 1066 (9.66%)
         occurrences all number
    158
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    59 / 1066 (5.53%)
         occurrences all number
    79
    Weight decreased
         subjects affected / exposed
    109 / 1066 (10.23%)
         occurrences all number
    212
    Neutrophil count decreased
         subjects affected / exposed
    84 / 1066 (7.88%)
         occurrences all number
    263
    Weight increased
         subjects affected / exposed
    98 / 1066 (9.19%)
         occurrences all number
    203
    White blood cell count decreased
         subjects affected / exposed
    98 / 1066 (9.19%)
         occurrences all number
    277
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    58 / 1066 (5.44%)
         occurrences all number
    69
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    92 / 1066 (8.63%)
         occurrences all number
    113
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    262 / 1066 (24.58%)
         occurrences all number
    342
    Dysgeusia
         subjects affected / exposed
    213 / 1066 (19.98%)
         occurrences all number
    253
    Headache
         subjects affected / exposed
    214 / 1066 (20.08%)
         occurrences all number
    322
    Hypoaesthesia
         subjects affected / exposed
    64 / 1066 (6.00%)
         occurrences all number
    80
    Paraesthesia
         subjects affected / exposed
    83 / 1066 (7.79%)
         occurrences all number
    99
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    136 / 1066 (12.76%)
         occurrences all number
    276
    Leukopenia
         subjects affected / exposed
    101 / 1066 (9.47%)
         occurrences all number
    353
    Lymphopenia
         subjects affected / exposed
    71 / 1066 (6.66%)
         occurrences all number
    159
    Neutropenia
         subjects affected / exposed
    178 / 1066 (16.70%)
         occurrences all number
    749
    Eye disorders
    Photopsia
         subjects affected / exposed
    96 / 1066 (9.01%)
         occurrences all number
    113
    Vision blurred
         subjects affected / exposed
    80 / 1066 (7.50%)
         occurrences all number
    103
    Visual impairment
         subjects affected / exposed
    459 / 1066 (43.06%)
         occurrences all number
    536
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    118 / 1066 (11.07%)
         occurrences all number
    148
    Abdominal pain upper
         subjects affected / exposed
    104 / 1066 (9.76%)
         occurrences all number
    134
    Constipation
         subjects affected / exposed
    475 / 1066 (44.56%)
         occurrences all number
    693
    Diarrhoea
         subjects affected / exposed
    548 / 1066 (51.41%)
         occurrences all number
    1015
    Dyspepsia
         subjects affected / exposed
    80 / 1066 (7.50%)
         occurrences all number
    94
    Dysphagia
         subjects affected / exposed
    54 / 1066 (5.07%)
         occurrences all number
    69
    Nausea
         subjects affected / exposed
    603 / 1066 (56.57%)
         occurrences all number
    1074
    Vomiting
         subjects affected / exposed
    564 / 1066 (52.91%)
         occurrences all number
    1223
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    67 / 1066 (6.29%)
         occurrences all number
    75
    Pruritus
         subjects affected / exposed
    84 / 1066 (7.88%)
         occurrences all number
    103
    Rash
         subjects affected / exposed
    132 / 1066 (12.38%)
         occurrences all number
    170
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    129 / 1066 (12.10%)
         occurrences all number
    184
    Back pain
         subjects affected / exposed
    184 / 1066 (17.26%)
         occurrences all number
    245
    Muscle spasms
         subjects affected / exposed
    79 / 1066 (7.41%)
         occurrences all number
    103
    Muscular weakness
         subjects affected / exposed
    57 / 1066 (5.35%)
         occurrences all number
    71
    Pain in extremity
         subjects affected / exposed
    73 / 1066 (6.85%)
         occurrences all number
    84
    Musculoskeletal pain
         subjects affected / exposed
    137 / 1066 (12.85%)
         occurrences all number
    182
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    114 / 1066 (10.69%)
         occurrences all number
    185
    Upper respiratory tract infection
         subjects affected / exposed
    142 / 1066 (13.32%)
         occurrences all number
    227
    Urinary tract infection
         subjects affected / exposed
    62 / 1066 (5.82%)
         occurrences all number
    86
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    55 / 1066 (5.16%)
         occurrences all number
    107
    Decreased appetite
         subjects affected / exposed
    324 / 1066 (30.39%)
         occurrences all number
    494
    Hypoalbuminaemia
         subjects affected / exposed
    96 / 1066 (9.01%)
         occurrences all number
    219
    Hypocalcaemia
         subjects affected / exposed
    96 / 1066 (9.01%)
         occurrences all number
    194
    Hypokalaemia
         subjects affected / exposed
    77 / 1066 (7.22%)
         occurrences all number
    129

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2009
    Participants who were ineligible to enroll in Study A8081007 because they were treated with docetaxel as part of their platinum-based prior chemotherapy, yet had NSCLC that was predominantly squamous-cell carcinoma, and thus, were not eligible to be dosed with pemetrexed, were allowed to enroll in this study.
    27 Aug 2009
    The RECIST version was modified to Version 1.1, and participants with spinal cord compression, carcinomatous meningitis, or leptomeningeal disease were no longer excluded.
    21 Dec 2009
    The NCI CTCAE version was modified to version 4.0, the primary endpoint was modified to add safety as a co-primary endpoint, timing of tumor measurements was modified from a per cycle basis to a calendar basis, and the administration of crizotinib was allowed to be administered without regards to meals.
    22 Jun 2010
    The patient-reported VSAQ-ALK was included, additional ECG monitoring was added for participants with QTc >500 msec, modifications of the eligibility criteria (which included cutoffs for hemoglobin and platelet counts) were included, washout period for cardiovascular (CV) or cerebrovascular events was decreased, hypertension exclusion criteria was deleted, all available scans were required to be reviewed by a third-party radiology laboratory, a treatment delay to up to 42 days without requiring discontinuation was now allowed; and metabolites of crizotinib were to be evaluated, if possible.
    05 Aug 2010
    Additional safety monitoring for the potential AEs of pneumonitis were added and an exclusion criterion to exclude patients with known interstitial fibrosis or interstitial lung disease was added.
    12 Jan 2011
    Entry criteria changed to allow A8081007 eligible participants to enroll into this protocol once enrollment is closed in a specific country and approved by a site’s IRB/IEC. Other entry criteria changed or updated: non-measurable disease now allowed, washout for palliative radiation changed, criteria for known brain metastases clarified, other ALK testing may be allowed after Sponsor review and approval. ECG substudy was added; sample size increased; dose modifications for PF-02341066 updated; PK analysis updated; endpoint descriptions updated; safety guidelines for potential cases of drug-induced liver injury added.
    21 Sep 2011
    Increase the number of participants to 800 in order to better evaluate possible genetic associations in patients with significant toxicities, especially those related to liver and kidney. Study objective and related endpoint for evaluation of pharmacogenetic markers of adverse hepatic and renal drug reactions were added. Monitoring guidance for the potential adverse hepatic and renal drug reactions were added. Entry criteria changed or updated: entry of participants with ALT/AST abnormalities expanded to x 5 ULN after agreement with Sponsor; entry of participants ineligible for Study A8081007 allowed if due to ECOG PS; once enrollment of the phase 3 A8081007 is closed, entry of partcipants receiving only one prior treatment for advanced NSCLC allowed. Dose administration modality as a oral solution allowed in participants unable to swallow the tablets, with agreement by the Sponsor. Visit frequency reduced for participants on study after 10 cycles; PK sampling collection not required any longer in participants newly enrolled; follow-up of visual symptoms, if present at end of treatment, added. Text modified is some sections following compliance with the Sponsor protocol template.
    26 Apr 2012
    The total number of participants enrolled was revised to manage country-specific regulatory requirements. Entry criteria changed to allow participants from the comparator arm of study A8081007 to enroll into this protocol once the study A8081007 has met the primary endpoint. Background safety information was updated. Dose modification rules were revised based on the updated safety information. Required imaging frequency was clarified. PK sampling collection required for ECG subgroup participants was clarified. Adverse event guidelines were updated to be consistent with Sponsor standards. Editing errors from prior Amendment were rectified.
    18 Dec 2012
    Inclusion criterion and related language elsewhere was modified to comply with the FDA requirement for all participants in the chemotherapy arm of Study A8081007 to have disease progression confirmed by independent radiology review (IRR) before they are allowed to cross over to receive crizotinib on Study A8081005. Detailed description of participants of childbearing potential language as an inclusion criterion and detailed contraception guidelines were introduced to ensure consistency with updated Pfizer protocol template. Text was added or replaced to ensure consistency with updated Pfizer protocol template language especially with respect to medication error, and serious adverse event reporting for Oncology studies after the active safety reporting period was clarified. Use of prophylactic antiemetics, prohibited medications by topical administration, and concomitant acetaminophen/paracetamol was clarified. Pregnancy testing in response to IRBs/IECs and/or local regulations was clarified. Reporting of local cardiologist manual ECG overread was clarified. Requirements for data retention were revised in consistency with the updated Pfizer protocol template language. Corrections of typographical errors and other administrative inconsistencies were made throughout the protocol.
    26 Nov 2014
    Blood samples for hematology and blood chemistries will now be collected also during the non-visit cycles after Cycle 10 to ensure consistency with the Investigator’s Brochure. Dose modification and adverse event management guidances were revised for QTc prolongation, bradycardia, and pneumonitis based on the updated safety information for PF-02341066. Reduced Schedule of Activities was introduced for participants still ongoing after the Primary Completion Date. Text was added or replaced to ensure consistency with updated Pfizer protocol template language, especially with respect to contraception guidelines, pregnancy testing, and serious adverse event reporting for Oncology studies after permanent discontinuation of PF- 02341066 treatment. Corrections of typographical errors and other administrative inconsistencies were made throughout the protocol.

    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.
    Pharmacogenetic analysis of renal adverse events was not performed as no gene alleles have been identified with sufficient supportive data establishing an association with renal toxicity to support a case-control candidate gene assessment.
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    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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