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    Clinical Trial Results:
    A Phase III, Randomized, Open-Label, Multi Center, Safety and Efficacy Study to Evaluate Nab Paclitaxel (Abraxane®) as Maintenance Treatment after Induction with Nab-Paclitaxel plus Carboplatin in Subjects with Squamous Cell Non–Small Cell Lung Cancer (NSLSC)

    Summary
    EudraCT number
    		 2014-003804-66
    Trial protocol
    		 DE   ES   GB   IT  
    Global end of trial date
    01 Aug 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Aug 2020
    First version publication date
    16 Aug 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    ABI-007-NSCL-003
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02027428
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Celgene Corporation
    Sponsor organisation address
    86 Morris Avenue, Summit, United States, 07901
    Public contact
    Clinical Trial Disclosure, Celgene Corporation, 01 908-673-9100, ClinicalTrialDisclosure@celgene.com
    Scientific contact
    Teng Ong, MD, Celgene Corporation, 01 (908) 3768941, TOng@celgene.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
    01 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate progression free survival (PFS) with nab-paclitaxel as maintenance treatment after response or stable disease (SD) with nab-paclitaxel plus carboplatin in subjects with squamous cell NSCLC.
    Protection of trial subjects
    Patient Confidentiality, Informed Consent, Archival of Essential Documents
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Feb 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 18 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Spain: 40
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 310
    Worldwide total number of subjects
    427
    EEA total number of subjects
    117
    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)
    162
    From 65 to 84 years
    262
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 87 sites in Germany, Italy, Spain, the United Kingdom and the United States.

    Pre-assignment
    Screening details
    		 Participants with a response or stable disease during Induction were randomized 2:1 into investigative treatment (nab-paclitaxel plus best supportive care [BSC] or BSC only) stratified by disease stage, response during induction and Eastern Cooperative Oncology Group (ECOG) performance status.

    Period 1
    Period 1 title
    Baseline Period: Induction
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All Participants - Induction
    Arm description
    		 During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL by IV infusion on Day 1 of each 21-day cycle. If the participant had radiological or clinical progressive disease (PD), they were discontinued from the study and not followed. If the participant had a complete response (CR), partial response (PR), or stable disease (SD) without PD at the end of 4 cycles, he/she were eligible to be randomised to the maintenance phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nab-Paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    nab-Paclitaxel 100 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle

    Investigational medicinal product name
    Carboplatin
    Investigational medicinal product code
    Other name
    Paraplatin,
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle

    Number of subjects in period 1
    		All Participants - Induction
    Started
    427
    Received Study Drug
    420
    Completed
    202
    Not completed
    225
         Adverse event, serious fatal
    21
         Consent withdrawn by subject
    22
         Adverse event, non-fatal
    51
         Symptomatic deterioration
    16
         Progressive Disease
    77
         Miscellaneous
    14
         Study terminated by sponsor
    12
         Induction - Ongoing
    4
         Never treated
    7
         Protocol deviation
    1
    Period 2
    Period 2 title
    Maintenance
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nab-Paclitaxel + Best Supportive Care (BSC)
    Arm description
    		 Maintenance Phase: Subjects were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care (BSC) until disease progression.
    Arm type
    		 Experimental

    Investigational medicinal product name
    nab-paclitaxel
    Investigational medicinal product code
    Other name
    Abraxane
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    nab-paclitaxel 100 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle

    Arm title
    		 Best Supportive Care (BSC)
    Arm description
    		 Participants were administered best supportive care (only) until disease progression.
    Arm type
    		 Palliative Care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: The study was not designed for the induction period to be the baseline period. The maintenance period is considered as the baseline period.
    Number of subjects in period 2 [2]
    		Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Started
    136
    66
    Completed
    12
    6
    Not completed
    124
    60
         Adverse event, serious fatal
    3
    2
         Consent withdrawn by subject
    6
    5
         AE
    21
    1
         Symptomatic deterioration
    4
    1
         Not specified
    6
    3
         Progressive Disease
    84
    -
         Lack of efficacy
    -
    47
         Protocol deviation
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The maintenance period is considered the baseline period of the trial as the primary objective was to evaluate PFS with nab-paclitaxel as maintenance treatment after response or stable disease with nab-paclitaxel in the induction period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nab-Paclitaxel + Best Supportive Care (BSC)
    Reporting group description
    		 Maintenance Phase: Subjects were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care (BSC) until disease progression.

    Reporting group title
    Best Supportive Care (BSC)
    Reporting group description
    		 Participants were administered best supportive care (only) until disease progression.

    Reporting group values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC) Total
    Number of subjects
    		 136 66 202
    Age Categorical
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: participants
        <65 years
    		 48 27 75
        ≥65 years
    		 88 39 127
    Age Continuous
    Continuous age values in Total column represent the 202 participants in the Maintenance Period. Induction includes participants who were enrolled and treated however, baseline characteristics for non-randomized participants is not displayed. The total number represents the ITT population in the maintenance phase.
    Units: years
        arithmetic mean (standard deviation)
    		 67.1 ( 9.02 ) 66.8 ( 8.06 ) -
    Sex: Female, Male
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units:
        Female
    		 49 23 72
        Male
    		 87 43 130
    Ethnicity (NIH/OMB)
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Hispanic or Latino
    		 3 5 8
        Not Hispanic or Latino
    		 132 61 193
        Missing
    		 1 0 1
    Race/Ethnicity, Customized
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        American Indian or Alaska Native
    		 1 0 1
        Asian
    		 1 0 1
        Black or African American
    		 9 2 11
        White
    		 125 62 187
        Other
    		 0 2 2
    Overall Tumor Response at End of Induction
    Tumor response to Induction part chemotherapy for stratification is the response assessed at the last computed tomography (CT) scan before randomization. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Complete response
    		 1 2 3
        Partial response
    		 92 42 134
        Stable disease
    		 41 21 62
        Progressive disease
    		 2 0 2
        Not evaluable
    		 0 1 1
    Confirmed Histology
    The histology categories included those with a tumor histology of squamous versus non-squamous types. Baseline characteristics for non-randomized participants is not displayed. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Squamous cell carcinoma
    		 136 66 202
        Squamous cell carcinoma not confirmed
    		 0 0 0
    Disease Stage at Enrollment
    Disease stage = how big the tumor is and how far it has spread. Disease stages range from 0 (not spread) to IV (spread throughout the body). Stage 0: the cancer has not spread beyond the inner lining of the lung. Stage I: the cancer is small and hasn't spread to the lymph nodes (LN). Stage II: the cancer has spread to some LN near the original tumor. Stage III: the cancer has spread to nearby tissue or spread to far away LN. Stage IV: the cancer has spread to other organs such as lung, brain, or liver. BLC are displayed for participants randomized in the maintenance phase.
    Units: Subjects
        Stage IIIB
    		 18 8 26
        Stage IV
    		 118 58 176
    Subject analysis sets

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention as determined by the investigator.

    Subject analysis set title
    TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention, as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. Nab-paclitaxel was administered during Induction and Maintenance.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. Carboplatin was administered during Induction.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to BSC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to best supportive care (BSC) as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. BSC was administered during Maintenance.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    BSC: TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention, as determined by the investigator, for participants randomized to the BSC treatment arm. Nab-paclitaxel was administered during Induction.

    Subject analysis set title
    BSC: TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator, for participants randomized to the BSC treatment arm. Carboplatin was administered during Induction.

    Subject analysis set title
    BSC: TEAE Specific to BSC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to best supportive care (BSC) as determined by the investigator, for participants randomized to the BSC treatment arm. BSC was administered during Maintenance.

    Subject analysis sets values
    		 Nab-Paclitaxel + BSC: Induction + Maintenance BSC: Induction + Maintenance Nab-Paclitaxel + BSC: Induction + Maintenance Nab-Paclitaxel + BSC: Induction + Maintenance BSC: Induction + Maintenance TEAE Specific to Nab-Paclitaxel TEAE Specific to Carboplatin Nab-Paclitaxel + BSC: Induction + Maintenance Nab-Paclitaxel + BSC: TEAE Specific to Nab-Paclitaxel Nab-Paclitaxel + BSC: TEAE Specific to Carboplatin Nab-Paclitaxel + BSC: TEAE Specific to BSC BSC: Induction + Maintenance BSC: TEAE Specific to Nab-Paclitaxel BSC: TEAE Specific to Carboplatin BSC: TEAE Specific to BSC
    Number of subjects
    136
    66
    136
    94
    38
    420
    420
    130
    130
    130
    130
    62
    62
    62
    62
    Age Categorical
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: participants
        <65 years
        ≥65 years
    Age Continuous
    Continuous age values in Total column represent the 202 participants in the Maintenance Period. Induction includes participants who were enrolled and treated however, baseline characteristics for non-randomized participants is not displayed. The total number represents the ITT population in the maintenance phase.
    Units: years
        arithmetic mean (standard deviation)
    69.1 ( )
    57.6 ( )
    99.3 ( )
    1.478 ( )
    1.413 ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    ( )
    Sex: Female, Male
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units:
        Female
        Male
    Ethnicity (NIH/OMB)
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Hispanic or Latino
        Not Hispanic or Latino
        Missing
    Race/Ethnicity, Customized
    Induction includes participants who were enrolled and treated in the induction phase. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        American Indian or Alaska Native
        Asian
        Black or African American
        White
        Other
    Overall Tumor Response at End of Induction
    Tumor response to Induction part chemotherapy for stratification is the response assessed at the last computed tomography (CT) scan before randomization. Baseline characteristics are displayed only for participants randomized in the maintenance phase. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Complete response
        Partial response
        Stable disease
        Progressive disease
        Not evaluable
    Confirmed Histology
    The histology categories included those with a tumor histology of squamous versus non-squamous types. Baseline characteristics for non-randomized participants is not displayed. The total number represents the ITT population in the maintenance phase.
    Units: Subjects
        Squamous cell carcinoma
        Squamous cell carcinoma not confirmed
    Disease Stage at Enrollment
    Disease stage = how big the tumor is and how far it has spread. Disease stages range from 0 (not spread) to IV (spread throughout the body). Stage 0: the cancer has not spread beyond the inner lining of the lung. Stage I: the cancer is small and hasn't spread to the lymph nodes (LN). Stage II: the cancer has spread to some LN near the original tumor. Stage III: the cancer has spread to nearby tissue or spread to far away LN. Stage IV: the cancer has spread to other organs such as lung, brain, or liver. BLC are displayed for participants randomized in the maintenance phase.
    Units: Subjects
        Stage IIIB
        Stage IV

    End points

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    End points reporting groups
    Reporting group title
    All Participants - Induction
    Reporting group description
    		 During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 by intravenous (IV) infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL by IV infusion on Day 1 of each 21-day cycle. If the participant had radiological or clinical progressive disease (PD), they were discontinued from the study and not followed. If the participant had a complete response (CR), partial response (PR), or stable disease (SD) without PD at the end of 4 cycles, he/she were eligible to be randomised to the maintenance phase.
    Reporting group title
    Nab-Paclitaxel + Best Supportive Care (BSC)
    Reporting group description
    		 Maintenance Phase: Subjects were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care (BSC) until disease progression.

    Reporting group title
    Best Supportive Care (BSC)
    Reporting group description
    		 Participants were administered best supportive care (only) until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention as determined by the investigator.

    Subject analysis set title
    TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator.

    Subject analysis set title
    Nab-Paclitaxel + BSC: Induction + Maintenance
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention, as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. Nab-paclitaxel was administered during Induction and Maintenance.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. Carboplatin was administered during Induction.

    Subject analysis set title
    Nab-Paclitaxel + BSC: TEAE Specific to BSC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to best supportive care (BSC) as determined by the investigator, for participants randomized to the Nab-Paclitaxel + BSC treatment arm. BSC was administered during Maintenance.

    Subject analysis set title
    BSC: Induction + Maintenance
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants randomized to this treatment arm for Maintenance, inclusive of their experience during Induction. During induction, participants received nab-paclitaxel plus carboplatin as standard of care. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she continued to the maintenance phase. Maintenance: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Subject analysis set title
    BSC: TEAE Specific to Nab-Paclitaxel
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to nab-paclitaxel intervention, as determined by the investigator, for participants randomized to the BSC treatment arm. Nab-paclitaxel was administered during Induction.

    Subject analysis set title
    BSC: TEAE Specific to Carboplatin
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to carboplatin intervention as determined by the investigator, for participants randomized to the BSC treatment arm. Carboplatin was administered during Induction.

    Subject analysis set title
    BSC: TEAE Specific to BSC
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    TEAE categories specific to best supportive care (BSC) as determined by the investigator, for participants randomized to the BSC treatment arm. BSC was administered during Maintenance.

    Primary: Kaplan-Meier Estimate of Progression-Free Survival (PFS) from Randomization into Maintenance

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    End point title
    		 Kaplan-Meier Estimate of Progression-Free Survival (PFS) from Randomization into Maintenance
    End point description
    PFS is defined as the time in months from the date of randomization to the date of disease progression based on the investigator’s assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1 criteria (documented by computerized tomography, not including symptomatic deterioration) or death (any cause) on or prior to 01 Aug 2019. RECIST 1.1 definition: Complete response (CR) disappearance of all target lesions; Partial response (PR) at least a 30% decrease in the sum of diameters of target lesions from baseline; Stable disease (SD) neither sufficient shrinkage to qualify for partial response nor sufficient increase of lesions to qualify for progressive disease (PD); PD = At least a 20% increase in the sum of diameters of target lesions from nadir, and/or the appearance of new lesions. The intent to treat population (ITT) in the maintenance part = all randomized subjects regardless of whether they received study drug or had any efficacy exams collected.
    End point type
    Primary
    End point timeframe
    From the date of randomization to the date of disease progression or death of any cause; up to August 2019; up to 42 months
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: months
        median (confidence interval 95%)
    3.12 (2.73 to 4.60)
    2.60 (1.64 to 3.45)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    5% level of significance. Hazard ratio is based on stratified Cox proportional hazards regression model. The following stratification factors were evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at the end of Induction.
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3486 [1]
    Method
    		 stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.85
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 1.19
    Notes
    [1] - Stratification factors evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at end of Induction.

    Secondary: Kaplan-Meier Estimate of Overall Survival (OS) From Randomization Into Maintenance

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    End point title
    		 Kaplan-Meier Estimate of Overall Survival (OS) From Randomization Into Maintenance
    End point description
    Overall survival (OS) was defined as the duration in months between randomization and death from any cause. Participants who were still alive as of the clinical cut-off date had their OS censored at the date of last contact or clinical cut-off (01 August 2019 whichever was earlier. The last contact date was the date of the last record in the database, or if the subject was lost to follow-up, the last known date that the subject was alive. The intent to treat population in the maintenance part included all randomized subjects regardless of whether the subject received any study drug or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    From the date of randomization to death from any cause; up to 01 August 2019; up to 55.89 months
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: months
        median (confidence interval 95%)
    17.61 (13.86 to 21.09)
    12.16 (7.56 to 18.99)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    5% level of significance. Hazard ratio is based on stratified Cox proportional hazards regression model. The following stratification factors were evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at the end of Induction.
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0365 [2]
    Method
    		 stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.98
    Notes
    [2] - Stratification factors evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at end of Induction.

    Secondary: Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) Over Entire Study

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    End point title
    		 Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) Over Entire Study
    End point description
    Overall response was defined as the percentage of participants with a confirmed assessment of complete response (CR) or partial response (PR) according to RECIST 1.1 criteria and confirmed in no less than 28 days. The 95% confidence interval (CI) was calculated using Clopper-Pearson method. RECIST 1.1 Definition: - Complete response-disappearance of all target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. - Partial response-at least a 30% decrease in the sum of diameters of target lesions from baseline. The intent to treat population in the maintenance part included all randomized subjects regardless of whether the subject received any study drug or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Day 1 of treatment in the induction period and subsequent anticancer therapy, death or discontinuation up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study.
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: percentage of participants
        number (confidence interval 95%)
    69.1 (60.6 to 76.8)
    57.6 (44.8 to 69.7)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    5% level of significance. The rate ratio and its 95% CI were based on the non-stratified analysis.
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.087 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Response ratio
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.948
         upper limit
    		 1.519
    Notes
    [3] - Stratification factors evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at the end of Induction, and tumor response (CR/PR or SD) at the end of Induction.

    Secondary: Kaplan-Meier Estimate of Progression-Free Survival (PFS) Over Entire Study

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    End point title
    		 Kaplan-Meier Estimate of Progression-Free Survival (PFS) Over Entire Study
    End point description
    PFS was defined as the time in months from Day 1 of treatment for the Induction part to the date of disease progression according to RECIST 1.1 criteria (documented by CT-scan, not including symptomatic deterioration) or death (any cause) on or prior to 01 August 2019, whichever occurred earlier. RECIST 1.1 Definition: - Progressive Disease (PD) - At least a 20% increase in the sum of diameters of target lesions from nadir; the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of new lesions is also considered progression. The intent to treat population in the maintenance part included all randomized subjects regardless of whether the subject received any study drug or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Between Day 1 of the Induction Part through to the date of disease progression or death; up to 01 August 2019; the maximum treatment duration was 234.1 weeks for the entire study.
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: months
        median (confidence interval 95%)
    6.47 (5.65 to 7.79)
    5.55 (4.96 to 6.67)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    5% level of significance. Hazard ratio is based on stratified Cox proportional hazards regression model. The following stratification factors were evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at the end of Induction.
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4164 [4]
    Method
    		 stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.62
         upper limit
    		 1.22
    Notes
    [4] - Stratification factors evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at end of Induction.

    Secondary: Kaplan-Meier Estimate of Overall Survival (OS) Over Entire Study

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    End point title
    		 Kaplan-Meier Estimate of Overall Survival (OS) Over Entire Study
    End point description
    Overall survival was defined as the time in months from Day 1 of treatment for the Induction part to death from any cause. Subjects who were alive at the time of analysis had their OS censored at the date or last contact or clinical cut-off, whichever was earlier. The last contact date was the date of the last record in the database, or if the subject was lost to follow-up, the last known date that the subject was alive. The intent to treat population in the maintenance part included all randomized subjects regardless of whether the subject received any study drug or had any efficacy assessments collected.
    End point type
    Secondary
    End point timeframe
    Between Day 1 of treatment in the Induction Part to death from any cause; up to 01 August 2019; survival follow up was 55.89 months.
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: months
        median (confidence interval 95%)
    20.57 (17.05 to 24.05)
    15.05 (10.81 to 22.14)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    5% level of significance. Hazard ratio is based on stratified Cox proportional hazards regression model. The following stratification factors were evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at the end of Induction.
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0381 [5]
    Method
    		 stratified log-rank test
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 0.98
    Notes
    [5] - Stratification factors evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at end of Induction, and tumor response (CR/PR or SD) at end of Induction.

    Secondary: Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) In Maintenance Beyond the Response in Induction

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    End point title
    		 Percentage of Participants Who Achieved a Confirmed Overall Response of Complete Response or Partial Response (Overall Response Rate) In Maintenance Beyond the Response in Induction
    End point description
    Overall response in the maintenance period was defined as the percentage of participants who showed an improvement in best overall response from stable disease (SD) or partial response (PR) during Induction to a Complete Response (CR) or PR during Maintenance according to RECIST 1.1 criteria and confirmed in no less than 28 days. Evaluation takes as reference the lesion measurement or status at the last tumor assessment before randomization to maintenance. The 95% CI was calculated using Clopper-Pearson method. RECIST 1.1 Definition: - CR-disappearance of all target lesions; any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. - PR-at least a 30% decrease in the sum of diameters of target lesions from baseline. - SD-neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for progressive disease. Included the ITT population of participants randomized to maintenance period.
    End point type
    Secondary
    End point timeframe
    For the Induction period the maximum treatment was 19 weeks. For the maintenance period the maximum treatment was 150 weeks.
    End point values
    		 Nab-Paclitaxel + Best Supportive Care (BSC) Best Supportive Care (BSC)
    Number of subjects analysed
    136
    66
    Units: percentage of participants
        number (confidence interval 95%)
    9.6 (5.2 to 15.8)
    3.0 (0.4 to 10.5)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Nab-Paclitaxel + Best Supportive Care (BSC) v Best Supportive Care (BSC)
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.0978
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Overall Response Rate Ratio
    Point estimate
    3.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.733
         upper limit
    		 13.574
    Notes
    [6] - 5% level of significance.

    Secondary: Percentage of Participants Who Achieved Disease Control (Disease Control Rate) by Investigator Assessment During Induction and Over the Entire Study

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    End point title
    		 Percentage of Participants Who Achieved Disease Control (Disease Control Rate) by Investigator Assessment During Induction and Over the Entire Study
    End point description
    Disease control rate was defined as the percentage of subjects who had radiologic CR, PR or SD for >= 6 weeks according to RECIST 1.1 criteria (investigator judgement). Only subjects with a confirmed CR/PR are included. Two timeframes are offered: Time to confirmed response within the Induction timeframe and Time to Confirmed Response Over the Entire Study, i.e. the time from Day 1 of treatment in Induction to the first occurrence of CR/PR any time during the study. RECIST 1.1 definition: CR- disappearance of all target lesions; any pathological lymph nodes (whether target or non target) must have reduction in short axis to < 10 mm. PR- at least a 30% decrease in the sum of diameters of target lesions from baseline; SD- neither sufficient shrinkage to qualify for PR nor sufficient increase of lesions to qualify for PD. Induction = the ITT population of subjects treated during Induction. Entire Study = the entire experience of the ITT population of subjects randomized to maintenance.
    End point type
    Secondary
    End point timeframe
    Induction is from Day 1 to a maximum treatment time of 19 weeks;entire study from Day 1 Induction through Maintenance up to PD; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study.
    End point values
    		 All Participants - Induction Nab-Paclitaxel + BSC: Induction + Maintenance BSC: Induction + Maintenance
    Number of subjects analysed
    420
    136
    66
    Units: percentage of participants
        number (confidence interval 95%)
    47.9 (43.0 to 52.8)
    99.3 (96.0 to 100.0)
    100.0 (94.6 to 100.0)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    The rate ratio and its 95% confidence interval are based on non-stratified analysis.
    Comparison groups
    Nab-Paclitaxel + BSC: Induction + Maintenance v BSC: Induction + Maintenance
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Disease control rate ratio
    Point estimate
    0.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.978
         upper limit
    		 1.007

    Secondary: Time to Confirmed Response During Induction and Over the Entire Study

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    End point title
    		 Time to Confirmed Response During Induction and Over the Entire Study
    End point description
    Time to confirmed complete or partial response (CR/PR) is defined as the time from day 1 of treatment in Induction to the first occurrence of confirmed CR/PR. Two timeframes are offered: - Time to confirmed response within the Induction timeframe. - Time to Confirmed Response Over the Entire Study, i.e. the time from Day 1 of treatment in Induction to the first occurrence of confirmed CR/PR any time during the study. Only participants with a confirmed CR or PR are included in this summary. Includes the ITT population of participants who had a response. Induction includes the ITT population of participants treated during Induction who had a response. Induction+Maintenance includes the ITT population of participants randomized to Maintenance who had a response.
    End point type
    Secondary
    End point timeframe
    Induction is from Day 1 to a maximum treatment time of 19 weeks; entire study from Day 1 Induction through Maintenance up to PD; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study.
    End point values
    		 All Participants - Induction Nab-Paclitaxel + BSC: Induction + Maintenance BSC: Induction + Maintenance
    Number of subjects analysed
    126
    94
    38
    Units: months
        median (full range (min-max))
    1.446 (1.15 to 4.60)
    1.478 (1.15 to 8.51)
    1.413 (1.18 to 4.21)
    No statistical analyses for this end point

    Secondary: Kaplan-Meier Estimate for Duration of Response Over the Entire Study

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    End point title
    		 Kaplan-Meier Estimate for Duration of Response Over the Entire Study
    End point description
    Duration of overall response was measured from the time criteria were first met for CR/PR until the first date the recurrent or progressive disease (PD) was radiologically documented. Participants who did not have PD after the response were censored on the date of last tumor assessment. If a participant died before PD, the participant was censored on the date of death. The ITT population of participants randomized to the maintenance period and had a confirmed partial or complete response.
    End point type
    Secondary
    End point timeframe
    Between Day 1 of the Induction Part through to the date of disease progression or death; up to 01 August 2019; maximum treatment duration was 234.1 weeks for entire study.
    End point values
    		 Nab-Paclitaxel + BSC: Induction + Maintenance BSC: Induction + Maintenance
    Number of subjects analysed
    94
    38
    Units: months
        median (confidence interval 95%)
    5.95 (4.60 to 7.06)
    4.60 (3.68 to 5.49)
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Hazard ratio was based on stratified Cox proportional hazards regression model. The following stratification factors were evaluated in the sparse strata elimination algorithm: stage of disease (IIIB or IV) at diagnosis, ECOG performance status (0 or 1) at the end of Induction, and tumor response (CR/PR or SD) at the end of Induction.
    Comparison groups
    Nab-Paclitaxel + BSC: Induction + Maintenance v BSC: Induction + Maintenance
    Number of subjects included in analysis
    132
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.47

    Secondary: Participants with Treatment-Emergent Adverse Events (TEAEs) in the Induction Part

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    End point title
    		 Participants with Treatment-Emergent Adverse Events (TEAEs) in the Induction Part
    End point description
    TEAE in the Induction part is defined as any adverse event (AE) with an onset on or after Day 1 of treatment for the Induction part, and on or before the day of randomization for subjects who entered into the Maintenance part, or, for subjects who did not enter into the Maintenance part, before the treatment discontinuation date plus 28 days or any serious AE which occurred thereafter but was determined to be related to any study drug by the investigator. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild, Grade 2 = Moderate Grade, 3 = Severe Grade, 4 = Life threatening, Grade 5 = Death. Relation to study drug was determined by the investigator. Safety population of participants treated during induction period.
    End point type
    Secondary
    End point timeframe
    Day 1 of Induction up Week 23 (maximum treatment in Induction plus 4 weeks if not continuing into Maintenance)
    End point values
    		 All Participants - Induction TEAE Specific to Nab-Paclitaxel TEAE Specific to Carboplatin
    Number of subjects analysed
    420
    420 [7]
    420
    Units: participants
        TEAE
    419
    99999
    99999
        Serious TEAE
    177
    99999
    99999
        Severity Grade 3/4 TEAE
    337
    99999
    99999
        Severity Grade 3 or higher TEAE
    340
    99999
    99999
        Treatment-related (trt-related) TEAE
    408
    407
    394
        Trt-related serious TEAE
    82
    80
    73
        TEAE-study drug dose reduced or interrupted
    341
    340
    291
        Trt-related TEAE-dose reduced or interrupted
    301
    292
    236
        TEAE-study drug withdrawn
    55
    55
    53
        Trt-related TEAE-study drug withdrawn
    35
    34
    29
        TEAE-outcome of death
    32
    99999
    99999
        Trt-related TEAE-outcome of death
    7
    7
    6
    Notes
    [7] - 99999 = Category not specific to study intervention
    No statistical analyses for this end point

    Secondary: Participants with Treatment-Emergent Adverse Events (TEAEs) Over the Entire Study

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    End point title
    		 Participants with Treatment-Emergent Adverse Events (TEAEs) Over the Entire Study
    End point description
    TEAE over entire study is defined as any adverse event (AE) with an onset on or after Day 1 of treatment for the Induction part, and before the treatment discontinuation date plus 28 days, or any serious AE which occurred thereafter but was determined to be related to any study drug by the investigator. The severity of AEs was graded based on National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0 and the scale: Grade 1 = Mild, Grade 2 = Moderate, Grade 3 = Severe, Grade 4 = Life threatening, Grade 5 = Death. Relation to study drug was determined by the investigator. Safety population of participants randomized into maintenance, inclusive of both the induction and maintenance periods.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study drug treatment up to 01 August 2019; maximum treatment duration was 234.1 weeks, plus 28 days (4 weeks)
    End point values
    		 Nab-Paclitaxel + BSC: Induction + Maintenance Nab-Paclitaxel + BSC: TEAE Specific to Nab-Paclitaxel Nab-Paclitaxel + BSC: TEAE Specific to Carboplatin Nab-Paclitaxel + BSC: TEAE Specific to BSC BSC: Induction + Maintenance BSC: TEAE Specific to Nab-Paclitaxel BSC: TEAE Specific to Carboplatin BSC: TEAE Specific to BSC
    Number of subjects analysed
    130
    130
    130
    130
    62
    62
    62
    62
    Units: participants
        TEAE
    130
    99999
    99999
    99999
    62
    99999
    99999
    99999
        Serious TEAE
    54
    99999
    99999
    99999
    21
    99999
    99999
    99999
        Severity Grade 3/4 TEAE
    108
    99999
    99999
    99999
    48
    99999
    99999
    99999
        Severity Grade 3 or higher TEAE
    109
    99999
    99999
    99999
    48
    99999
    99999
    99999
        Treatment-related (trt-related) TEAE
    129
    129
    123
    18
    61
    61
    58
    1
        Trt-related serious TEAE
    22
    22
    16
    1
    8
    8
    7
    0
        TEAE-study drug dose reduced or interrupted
    115
    113
    95
    17
    52
    52
    45
    1
        Trt-related TEAE-dose reduced or interrupted
    107
    104
    85
    0
    45
    45
    37
    0
        TEAE-study drug withdrawn
    22
    22
    1
    20
    0
    1
    1
    0
        Trt-related TEAE- study drug withdrawn
    18
    18
    1
    2
    1
    0
    0
    0
        TEAE-outcome of death
    4
    99999
    99999
    99999
    2
    99999
    99999
    99999
        Trt-related TEAE-outcome of death
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    1. Induction: Day 1 up to 23 weeks (maximum treatment in induction plus (+) 4 weeks if not continuing into maintenance) 2. Nab-Paclitaxel + Best Supportive Care Randomization into maintenance up to 154 weeks (maximum treatment in maintenance + 4 weeks)
    Adverse event reporting additional description
    3. BSC: Randomization into Maintenance up to 120 weeks (maximum treatment in Maintenance + 4 weeks); TEAEs are reported up to the data cut off date of 01 August 2019. All-Cause Mortality is reported for the ITT population (received at least 1 dose of study treatment regardless of whether any efficacy exams were collected) up to 01 August 2019.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    V21.0
    Reporting groups
    Reporting group title
    All Participants - Induction
    Reporting group description
    		 During induction, participants received nab-paclitaxel plus carboplatin as standard of care: nab-paclitaxel 100 mg/m^2 IV infusion over 30 minutes on Days 1, 8, and 15 of each 21-day cycle and carboplatin AUC = 6 mg*min/mL IV on Day 1 of each 21-day cycle. If the participant had radiological or clinical progressive disease (PD), they were discontinued from the study and not followed. If the participant had a complete response, partial response, or stable disease without PD at the end of 4 cycles, he/she were eligible to be randomised to the maintenance phase.

    Reporting group title
    Nab-Paclitaxel + Best Supportive Care (Maintenance)
    Reporting group description
    		 Maintenance Phase: Following randomization, participants in this treatment arm were administered nab-paclitaxel 100 mg/m^2 by IV infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, plus best supportive care until disease progression.

    Reporting group title
    Best Supportive Care (Maintenance)
    Reporting group description
    		 Maintenance Phase: Following randomization, participants in this treatment arm were administered best supportive care (only) until disease progression.

    Serious adverse events
    		 All Participants - Induction Nab-Paclitaxel + Best Supportive Care (Maintenance) Best Supportive Care (Maintenance)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    177 / 420 (42.14%)
    32 / 130 (24.62%)
    13 / 62 (20.97%)
         number of deaths (all causes)
    32
    3
    2
         number of deaths resulting from adverse events
    7
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    11 / 420 (2.62%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    4 / 12
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    6 / 420 (1.43%)
    3 / 130 (2.31%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 6
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site pain
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    5 / 420 (1.19%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 5
    0 / 1
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    4 / 420 (0.95%)
    0 / 130 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    6 / 420 (1.43%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    4 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchial haemorrhage
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    7 / 420 (1.67%)
    0 / 130 (0.00%)
    2 / 62 (3.23%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    Cough
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    15 / 420 (3.57%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 16
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    5 / 420 (1.19%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    7 / 420 (1.67%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngospasm
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    6 / 420 (1.43%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    9 / 420 (2.14%)
    2 / 130 (1.54%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 10
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    7 / 420 (1.67%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    3 / 9
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Aspiration bronchial
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    8 / 420 (1.90%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 11
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial haemorrhage
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Carotid artery stenosis
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral sensory neuropathy
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    4 / 420 (0.95%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 420 (4.05%)
    3 / 130 (2.31%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    21 / 23
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    8 / 420 (1.90%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    4 / 420 (0.95%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    12 / 420 (2.86%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    12 / 12
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    4 / 420 (0.95%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    4 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    5 / 420 (1.19%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 420 (0.71%)
    1 / 130 (0.77%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    11 / 420 (2.62%)
    1 / 130 (0.77%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    6 / 11
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterovesical fistula
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis relapsing
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 420 (0.48%)
    2 / 130 (1.54%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    7 / 420 (1.67%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    5 / 7
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prerenal failure
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Arthritis bacterial
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis bacterial
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 420 (0.00%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 420 (0.48%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    4 / 420 (0.95%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Oesophageal candidiasis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paraspinal abscess
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    24 / 420 (5.71%)
    4 / 130 (3.08%)
    3 / 62 (4.84%)
         occurrences causally related to treatment / all
    6 / 28
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    0 / 1
    Sepsis
         subjects affected / exposed
    9 / 420 (2.14%)
    3 / 130 (2.31%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    5 / 11
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    2 / 3
    0 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 420 (0.24%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    5 / 420 (1.19%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 420 (0.00%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    14 / 420 (3.33%)
    1 / 130 (0.77%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    8 / 14
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrolyte imbalance
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 420 (0.71%)
    0 / 130 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    2 / 420 (0.48%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    1 / 420 (0.24%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All Participants - Induction Nab-Paclitaxel + Best Supportive Care (Maintenance) Best Supportive Care (Maintenance)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    417 / 420 (99.29%)
    122 / 130 (93.85%)
    45 / 62 (72.58%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    50 / 420 (11.90%)
    9 / 130 (6.92%)
    1 / 62 (1.61%)
         occurrences all number
    63
    12
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    73 / 420 (17.38%)
    12 / 130 (9.23%)
    1 / 62 (1.61%)
         occurrences all number
    121
    16
    1
    Chills
         subjects affected / exposed
    22 / 420 (5.24%)
    3 / 130 (2.31%)
    1 / 62 (1.61%)
         occurrences all number
    23
    3
    1
    Fatigue
         subjects affected / exposed
    175 / 420 (41.67%)
    24 / 130 (18.46%)
    0 / 62 (0.00%)
         occurrences all number
    267
    40
    0
    Oedema peripheral
         subjects affected / exposed
    48 / 420 (11.43%)
    23 / 130 (17.69%)
    3 / 62 (4.84%)
         occurrences all number
    59
    35
    3
    Pyrexia
         subjects affected / exposed
    29 / 420 (6.90%)
    10 / 130 (7.69%)
    2 / 62 (3.23%)
         occurrences all number
    35
    11
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    72 / 420 (17.14%)
    15 / 130 (11.54%)
    9 / 62 (14.52%)
         occurrences all number
    83
    22
    10
    Dyspnoea
         subjects affected / exposed
    76 / 420 (18.10%)
    13 / 130 (10.00%)
    3 / 62 (4.84%)
         occurrences all number
    94
    16
    3
    Epistaxis
         subjects affected / exposed
    79 / 420 (18.81%)
    4 / 130 (3.08%)
    1 / 62 (1.61%)
         occurrences all number
    97
    4
    1
    Haemoptysis
         subjects affected / exposed
    28 / 420 (6.67%)
    5 / 130 (3.85%)
    2 / 62 (3.23%)
         occurrences all number
    32
    5
    2
    Productive cough
         subjects affected / exposed
    19 / 420 (4.52%)
    10 / 130 (7.69%)
    3 / 62 (4.84%)
         occurrences all number
    20
    13
    4
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    30 / 420 (7.14%)
    4 / 130 (3.08%)
    0 / 62 (0.00%)
         occurrences all number
    31
    5
    0
    Insomnia
         subjects affected / exposed
    53 / 420 (12.62%)
    5 / 130 (3.85%)
    2 / 62 (3.23%)
         occurrences all number
    57
    5
    2
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    22 / 420 (5.24%)
    5 / 130 (3.85%)
    0 / 62 (0.00%)
         occurrences all number
    33
    8
    0
    Neutrophil count decreased
         subjects affected / exposed
    29 / 420 (6.90%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    40
    0
    0
    Platelet count decreased
         subjects affected / exposed
    26 / 420 (6.19%)
    0 / 130 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    47
    0
    0
    Weight decreased
         subjects affected / exposed
    42 / 420 (10.00%)
    9 / 130 (6.92%)
    2 / 62 (3.23%)
         occurrences all number
    52
    13
    2
    Weight increased
         subjects affected / exposed
    6 / 420 (1.43%)
    8 / 130 (6.15%)
    0 / 62 (0.00%)
         occurrences all number
    8
    11
    0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    39 / 420 (9.29%)
    7 / 130 (5.38%)
    0 / 62 (0.00%)
         occurrences all number
    61
    8
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    57 / 420 (13.57%)
    12 / 130 (9.23%)
    1 / 62 (1.61%)
         occurrences all number
    66
    17
    1
    Dysgeusia
         subjects affected / exposed
    56 / 420 (13.33%)
    2 / 130 (1.54%)
    0 / 62 (0.00%)
         occurrences all number
    58
    2
    0
    Headache
         subjects affected / exposed
    23 / 420 (5.48%)
    4 / 130 (3.08%)
    5 / 62 (8.06%)
         occurrences all number
    26
    5
    5
    Peripheral sensory neuropathy
         subjects affected / exposed
    152 / 420 (36.19%)
    56 / 130 (43.08%)
    6 / 62 (9.68%)
         occurrences all number
    233
    107
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    256 / 420 (60.95%)
    24 / 130 (18.46%)
    6 / 62 (9.68%)
         occurrences all number
    587
    36
    8
    Leukopenia
         subjects affected / exposed
    80 / 420 (19.05%)
    1 / 130 (0.77%)
    1 / 62 (1.61%)
         occurrences all number
    187
    1
    1
    Neutropenia
         subjects affected / exposed
    225 / 420 (53.57%)
    14 / 130 (10.77%)
    0 / 62 (0.00%)
         occurrences all number
    566
    23
    0
    Thrombocytopenia
         subjects affected / exposed
    163 / 420 (38.81%)
    9 / 130 (6.92%)
    2 / 62 (3.23%)
         occurrences all number
    348
    11
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    27 / 420 (6.43%)
    4 / 130 (3.08%)
    2 / 62 (3.23%)
         occurrences all number
    32
    4
    2
    Constipation
         subjects affected / exposed
    130 / 420 (30.95%)
    14 / 130 (10.77%)
    0 / 62 (0.00%)
         occurrences all number
    170
    18
    0
    Diarrhoea
         subjects affected / exposed
    158 / 420 (37.62%)
    18 / 130 (13.85%)
    4 / 62 (6.45%)
         occurrences all number
    239
    27
    7
    Dyspepsia
         subjects affected / exposed
    37 / 420 (8.81%)
    3 / 130 (2.31%)
    1 / 62 (1.61%)
         occurrences all number
    39
    3
    1
    Nausea
         subjects affected / exposed
    191 / 420 (45.48%)
    16 / 130 (12.31%)
    2 / 62 (3.23%)
         occurrences all number
    284
    22
    2
    Stomatitis
         subjects affected / exposed
    44 / 420 (10.48%)
    2 / 130 (1.54%)
    1 / 62 (1.61%)
         occurrences all number
    56
    2
    1
    Vomiting
         subjects affected / exposed
    93 / 420 (22.14%)
    12 / 130 (9.23%)
    2 / 62 (3.23%)
         occurrences all number
    131
    14
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    105 / 420 (25.00%)
    6 / 130 (4.62%)
    2 / 62 (3.23%)
         occurrences all number
    123
    6
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    26 / 420 (6.19%)
    12 / 130 (9.23%)
    2 / 62 (3.23%)
         occurrences all number
    27
    16
    2
    Back pain
         subjects affected / exposed
    23 / 420 (5.48%)
    12 / 130 (9.23%)
    6 / 62 (9.68%)
         occurrences all number
    31
    13
    8
    Muscular weakness
         subjects affected / exposed
    30 / 420 (7.14%)
    4 / 130 (3.08%)
    3 / 62 (4.84%)
         occurrences all number
    38
    5
    4
    Myalgia
         subjects affected / exposed
    26 / 420 (6.19%)
    2 / 130 (1.54%)
    1 / 62 (1.61%)
         occurrences all number
    31
    2
    1
    Pain in extremity
         subjects affected / exposed
    24 / 420 (5.71%)
    10 / 130 (7.69%)
    1 / 62 (1.61%)
         occurrences all number
    29
    15
    3
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    11 / 420 (2.62%)
    9 / 130 (6.92%)
    1 / 62 (1.61%)
         occurrences all number
    11
    12
    1
    Upper respiratory tract infection
         subjects affected / exposed
    18 / 420 (4.29%)
    11 / 130 (8.46%)
    2 / 62 (3.23%)
         occurrences all number
    18
    12
    3
    Urinary tract infection
         subjects affected / exposed
    28 / 420 (6.67%)
    7 / 130 (5.38%)
    4 / 62 (6.45%)
         occurrences all number
    30
    7
    6
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    101 / 420 (24.05%)
    17 / 130 (13.08%)
    3 / 62 (4.84%)
         occurrences all number
    123
    18
    3
    Dehydration
         subjects affected / exposed
    57 / 420 (13.57%)
    4 / 130 (3.08%)
    1 / 62 (1.61%)
         occurrences all number
    75
    4
    1
    Hypocalcaemia
         subjects affected / exposed
    23 / 420 (5.48%)
    3 / 130 (2.31%)
    0 / 62 (0.00%)
         occurrences all number
    35
    3
    0
    Hypokalaemia
         subjects affected / exposed
    61 / 420 (14.52%)
    6 / 130 (4.62%)
    2 / 62 (3.23%)
         occurrences all number
    92
    10
    2
    Hypomagnesaemia
         subjects affected / exposed
    58 / 420 (13.81%)
    9 / 130 (6.92%)
    2 / 62 (3.23%)
         occurrences all number
    97
    11
    2
    Hyponatraemia
         subjects affected / exposed
    29 / 420 (6.90%)
    3 / 130 (2.31%)
    0 / 62 (0.00%)
         occurrences all number
    49
    4
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Oct 2014
    1. Incorporated the recommendation received from the US FDA to remove the cross-over part of the trial 2. Enabled potential participation of centers outside of the US.
    07 May 2015
    1. Incorporated the intention to produce and review summaries of the QoL and biomarker data (Induction part only, pre-randomization) while the study was ongoing. 2. Clarified the secondary objectives (DCR over entire study was added) and the definitions of the analysis populations for the Induction and Maintenance parts.
    18 Apr 2016
    1. Addendum A clarified protocol details following requests from the United Kingdom regulatory health authority. Addendum A was implemented only in the United Kingdom. 2. Added text regarding true abstinence and periodic abstinence for Inclusion Criterion 17. 3. Added text to Table of Events regarding investigator discussion of possible side effects, peripheral neuropathy assessment, and AE evaluation. 4. Added text to concomitant medications and procedures regarding concurrent carboplatin therapy with nephrotoxic drugs, ototoxic drugs, and warfarin. Added text regarding concomitant administration of paclitaxel with medications known to inhibit or induce either Cytochrome P450 (CYP) 2C8 or CYP3A4. 5. Added text regarding events considered sufficient reasons for discontinuing a subject from IP.
    13 Mar 2017
    1. Incorporated changes to the study sample size (reduction of subject population and targeted number of PFS events).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

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