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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study of Rovalpituzumab Tesirine as Maintenance Therapy Following First-Line Platinum-Based Chemotherapy in Subjects with Extensive Stage Small Cell Lung Cancer (MERU)

    Summary
    EudraCT number
    		 2016-003503-64
    Trial protocol
    		 EE   AT   DK   FI   IE   GB   SE   DE   NL   LV   PT   HU   GR   PL   ES   CZ   BG   LT   BE   HR   NO  
    Global end of trial date
    29 Nov 2019

    Results information
    Results version number
    		 v2(current)
    This version publication date
    06 Jan 2021
    First version publication date
    27 Nov 2020
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Update to full data set.

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-298
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03033511
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 8006339110, abbvieclinicaltrials@abbvie.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
    29 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to evaluate if rovalpituzumab tesirine improves progression-free survival (PFS), assessed by a central radiographic assessment committee, and overall survival (OS) in subjects with extensive stage disease small cell lung cancer (ED SCLC) tumors with a high level of delta-like protein 3 (DLL3) expression (DLL3high) who have ongoing clinical benefit (stable disease [SD], partial response [PR], or complete response [CR]) following the completion of 4 cycles of first-line, platinum-based chemotherapy (cisplatin or carboplatin plus irinotecan or etoposide) compared to placebo.
    Protection of trial subjects
    The study was conducted in accordance with the protocol, International Conference on Harmonization (ICH) guidelines applicable regulations and guidelines governing clinical study conduct and the ethical principles that have their origin in the Declaration of Helsinki. The investigator or his/her representative explained the nature of the study to the subject, and answered all questions regarding this study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Feb 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    South Africa: 7
    Country: Number of subjects enrolled
    Spain: 47
    Country: Number of subjects enrolled
    Sweden: 9
    Country: Number of subjects enrolled
    Switzerland: 19
    Country: Number of subjects enrolled
    Taiwan: 18
    Country: Number of subjects enrolled
    Turkey: 44
    Country: Number of subjects enrolled
    Ukraine: 20
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    United States: 100
    Country: Number of subjects enrolled
    Australia: 16
    Country: Number of subjects enrolled
    Austria: 15
    Country: Number of subjects enrolled
    Belarus: 8
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    China: 13
    Country: Number of subjects enrolled
    Croatia: 4
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 9
    Country: Number of subjects enrolled
    Estonia: 5
    Country: Number of subjects enrolled
    France: 32
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hong Kong: 3
    Country: Number of subjects enrolled
    Hungary: 10
    Country: Number of subjects enrolled
    Ireland: 8
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Italy: 11
    Country: Number of subjects enrolled
    Japan: 57
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Latvia: 17
    Country: Number of subjects enrolled
    Lithuania: 13
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Netherlands: 27
    Country: Number of subjects enrolled
    Norway: 23
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Portugal: 10
    Country: Number of subjects enrolled
    Russian Federation: 36
    Country: Number of subjects enrolled
    Serbia: 3
    Worldwide total number of subjects
    748
    EEA total number of subjects
    326
    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)
    388
    From 65 to 84 years
    356
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening procedures were performed within 21 days prior to randomization, with the exception of radiographic assessments (computed tomography [CT] scan or magnetic resonance imaging [MRI] including the head, chest, and abdomen) which may have been performed within 28 days prior to randomization.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    AbbVie, the Investigator, the study site personnel, and subject remained blinded to each subject's treatment with rovalpituzumab tesirine or placebo and dexamethasone or placebo and throughout the course of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo every 6 weeks (q6 wk); omitting every third cycle Placebo for rovalpituzumab tesirine: Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Placebo for dexamethasone: Placebo for dexamethasone administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for rovalpituzumab tesirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle

    Investigational medicinal product name
    Placebo for dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo for administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Arm title
    		 Rovalpituzumab Tesirine/Dexamethasone
    Arm description
    		 Rovalpituzumab tesirine/dexamethasone q6 wk; omitting every third cycle Rovalpituzumab tesirine: Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Dexamethasone: Dexamethasone 8 mg administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rovalpituzumab tesirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dexamethasone 8 mg administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Number of subjects in period 1
    		Placebo Rovalpituzumab Tesirine/Dexamethasone
    Started
    376
    372
    Completed
    376
    372

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo every 6 weeks (q6 wk); omitting every third cycle Placebo for rovalpituzumab tesirine: Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Placebo for dexamethasone: Placebo for dexamethasone administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Reporting group title
    Rovalpituzumab Tesirine/Dexamethasone
    Reporting group description
    		 Rovalpituzumab tesirine/dexamethasone q6 wk; omitting every third cycle Rovalpituzumab tesirine: Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Dexamethasone: Dexamethasone 8 mg administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Reporting group values
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone Total
    Number of subjects
    		 376 372 748
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.8 ( 8.20 ) 64.1 ( 8.40 ) -
    Gender categorical
    Units: Subjects
        Female
    		 137 114 251
        Male
    		 239 258 497
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 18 15 33
        Not Hispanic or Latino
    		 356 355 711
        Missing
    		 2 2 4
    Race
    Units: Subjects
        White
    		 301 314 615
        Black or African American
    		 7 2 9
        Asian
    		 66 55 121
        American Indian or Alaska Native
    		 2 0 2
        Multiple Races
    		 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo every 6 weeks (q6 wk); omitting every third cycle Placebo for rovalpituzumab tesirine: Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Placebo for dexamethasone: Placebo for dexamethasone administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Reporting group title
    Rovalpituzumab Tesirine/Dexamethasone
    Reporting group description
    		 Rovalpituzumab tesirine/dexamethasone q6 wk; omitting every third cycle Rovalpituzumab tesirine: Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Dexamethasone: Dexamethasone 8 mg administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Primary: Overall Survival (OS) in Participants With Extensive-Stage Small Cell Lung Cancer With Delta-Like Protein 3 High Expression in Tumor (DLL3high)

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    End point title
    		 Overall Survival (OS) in Participants With Extensive-Stage Small Cell Lung Cancer With Delta-Like Protein 3 High Expression in Tumor (DLL3high)
    End point description
    OS is defined as the number of months from randomization to death of any cause. Caculated using the Kaplan-Meier methodology. DLL3 High Set: all randomized participants with extensive-stage small cell lung cancer with delta-like protein 3 high expression in tumor (DLL3high), defined as ≥ 75% tumor cells staining positive according to the VENTANA DLL3 [SP347] immunohistochemistry [IHC] assay.
    End point type
    Primary
    End point timeframe
    Survival follow-up continued until the endpoint of death, the subject was lost to follow-up or withdrew consent, or termination of the study by AbbVie, whichever occurred first. Median time on study overall was 11.9 months.
    End point values
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone
    Number of subjects analysed
    240
    217
    Units: months
        median (confidence interval 95%)
    9.79 (8.38 to 10.87)
    8.48 (7.26 to 10.18)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Placebo v Rovalpituzumab Tesirine/Dexamethasone
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.537 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.36
    Notes
    [1] - stratified log-rank test

    Secondary: OS in All Randomized Participants

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    End point title
    		 OS in All Randomized Participants
    End point description
    OS is defined as the number of months from randomization to death of any cause. Calculated using the Kaplan-Meier methodology. Randomized Set: all randomized participants, grouped according to the treatment arm to which they were randomized regardless the actual treatment received.
    End point type
    Secondary
    End point timeframe
    Survival follow-up continued until the endpoint of death, the subject was lost to follow-up or withdrew consent, or termination of the study by AbbVie, whichever occurred first. Median time on study overall was 11.9 months.
    End point values
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone
    Number of subjects analysed
    376
    372
    Units: months
        median (confidence interval 95%)
    9.89 (8.61 to 11.01)
    8.80 (7.95 to 9.53)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Rovalpituzumab Tesirine/Dexamethasone v Placebo
    Number of subjects included in analysis
    748
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.237 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 1.36
    Notes
    [2] - stratified log-rank test

    Secondary: Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) Physical Functioning Domain Over Time

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    End point title
    		 Change From Baseline in European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core (EORTC QLQ-C30) Physical Functioning Domain Over Time
    End point description
    The EORTC QLQ-C30 is composed of global health status/QoL scale; five functional domains (physical, role, emotional, cognitive, and social); three symptom domains (fatigue, nausea and vomiting, and pain); and six single items (dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties). The Physical Functioning domain includes 5 questions in which participants were asked to rate their overall health and overall quality of life as it relates to physical functioning during the past week on a scale from 1 (very poor) to 7 (excellent). The 5 scores were averaged and transformed to a scale from 0 to 100, where a high score represents a high QoL. A positive change from baseline indicates better quality of life. Randomized Set: all randomized participants, grouped according to the treatment arm to which they were randomized regardless the actual treatment received. Participants with an assessment at given time point.
    End point type
    Secondary
    End point timeframe
    Baseline, Weeks 6, 12, 18, 24, 30, 36, 42, 48, 54, 60, 66, 72, 78, Final Visit (up to Week 78)
    End point values
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone
    Number of subjects analysed
    376 [3]
    372 [4]
    Units: score on a scale
    least squares mean (standard error)
        Change at Week 6; n=287, 296
    -3.97 ( 1.00 )
    -4.34 ( 0.95 )
        Change at Week 12; n=104, 191
    -1.70 ( 1.67 )
    -12.13 ( 1.27 )
        Change at Week 18; n=9, 14
    8.15 ( 4.02 )
    -19.52 ( 4.92 )
        Change at Week 24; n=7, 11
    -0.95 ( 7.32 )
    -19.39 ( 6.61 )
        Change at Week 30; n=5, 10
    5.33 ( 4.22 )
    -16.67 ( 6.78 )
        Change at Week 36; n=2, 1
    -13.33 ( 99999 )
    -13.33 ( 99999 )
        Change at Week 42; n=1, 2
    -6.67 ( 99999 )
    -3.33 ( 99999 )
        Change at Week 48; n=3, 2
    -6.67 ( 99999 )
    -63.33 ( 99999 )
        Change at Week 54; n=1, 0
    -6.67 ( 99999 )
    99999 ( 99999 )
        Change at Week 60; n=1, 1
    0.00 ( 99999 )
    0.00 ( 99999 )
        Change at Week 66; n=2, 2
    0.00 ( 99999 )
    0.00 ( 99999 )
        Change at Week 72; n=1, 0
    0.00 ( 99999 )
    99999 ( 99999 )
        Change at Week 78; n=1, 1
    0.00 ( 99999 )
    0.00 ( 99999 )
        Change at Week Final Visit; n=298, 312
    -4.14 ( 1.02 )
    -13.31 ( 1.12 )
    Attachments
    		 Untitled (Filename: EORTC QLQ-C30 Stat Analyses.docx)
    Notes
    [3] - n=participants with assessment at given time point. 99999=not available
    [4] - n=participants with assessment at given time point. 99999=not available
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 of study treatment through 70 days after last treatment. Mean number of weeks on study treatment was 12.8 in the Placebo arm and 17.5 weeks in the Rovalpituzumab Tesirine Plus Dexamethasone arm.
    Adverse event reporting additional description
    Safety Set: all subjects who were enrolled, randomized, and received at least 1 dose of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo q6 wk; omitting every third cycle Placebo for rovalpituzumab tesirine: Placebo for rovalpituzumab tesirine administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Placebo for dexamethasone: Placebo for dexamethasone administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Reporting group title
    Rovalpituzumab Tesirine/Dexamethasone
    Reporting group description
    		 Rovalpituzumab tesirine/dexamethasone q6 wk; omitting every third cycle Rovalpituzumab tesirine: Rovalpituzumab tesirine 0.3 mg/kg administered intravenously Day 1 of each 6-week cycle, omitting every third cycle Dexamethasone: Dexamethasone 8 mg administered orally twice daily on Day –1, Day 1 (the day of dosing), and Day 2 of each 6 week cycle, omitting every third cycle

    Serious adverse events
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    87 / 373 (23.32%)
    157 / 368 (42.66%)
         number of deaths (all causes)
    198
    223
         number of deaths resulting from adverse events
    37
    35
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    INFECTED NEOPLASM
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ADENOCARCINOMA GASTRIC
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG NEOPLASM
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    MALIGNANT NEOPLASM PROGRESSION
         subjects affected / exposed
    21 / 373 (5.63%)
    16 / 368 (4.35%)
         occurrences causally related to treatment / all
    0 / 25
    0 / 17
         deaths causally related to treatment / all
    0 / 19
    0 / 16
    METASTASES TO CENTRAL NERVOUS SYSTEM
         subjects affected / exposed
    7 / 373 (1.88%)
    7 / 368 (1.90%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    METASTASES TO LIVER
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    METASTATIC NEOPLASM
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METASTASES TO MENINGES
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NEOPLASM PROGRESSION
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NEUROENDOCRINE CARCINOMA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINONASAL PAPILLOMA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL CELL CARCINOMA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SMALL CELL LUNG CANCER METASTATIC
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUMOUR PAIN
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    HYPOTENSION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SHOCK
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JUGULAR VEIN THROMBOSIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPERIOR VENA CAVA SYNDROME
         subjects affected / exposed
    3 / 373 (0.80%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR COMPRESSION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    VENA CAVA THROMBOSIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASTHENIA
         subjects affected / exposed
    1 / 373 (0.27%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DISEASE PROGRESSION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DEATH
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    EUTHANASIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    FACE OEDEMA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    8 / 373 (2.14%)
    9 / 368 (2.45%)
         occurrences causally related to treatment / all
    0 / 10
    2 / 11
         deaths causally related to treatment / all
    0 / 2
    1 / 3
    GENERALISED OEDEMA
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOTHERMIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MALAISE
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MULTIPLE ORGAN DYSFUNCTION SYNDROME
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEROSITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    2 / 373 (0.54%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUDDEN DEATH
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SWELLING FACE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY DISTRESS SYNDROME
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    2 / 373 (0.54%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    BRONCHIAL OBSTRUCTION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COUGH
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSPNOEA
         subjects affected / exposed
    4 / 373 (1.07%)
    12 / 368 (3.26%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 14
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPISTAXIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOXIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG DISORDER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLEURAL EFFUSION
         subjects affected / exposed
    2 / 373 (0.54%)
    22 / 368 (5.98%)
         occurrences causally related to treatment / all
    0 / 2
    18 / 23
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    7 / 368 (1.90%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 11
         deaths causally related to treatment / all
    0 / 0
    3 / 3
    PULMONARY ARTERY THROMBOSIS
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISORDER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY DISTRESS
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 373 (0.27%)
    5 / 368 (1.36%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    Psychiatric disorders
    DELIRIUM
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MENTAL STATUS CHANGES
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLOOD URIC ACID INCREASED
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OXYGEN SATURATION DECREASED
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    HEPATIC ENZYME INCREASED
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATIC ENZYMES INCREASED
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ANKLE FRACTURE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FALL
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HIP FRACTURE
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HUMERUS FRACTURE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RADIATION PNEUMONITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PERICARDIAL EFFUSION
         subjects affected / exposed
    2 / 373 (0.54%)
    4 / 368 (1.09%)
         occurrences causally related to treatment / all
    2 / 2
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUPRAVENTRICULAR TACHYCARDIA
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    BRAIN OEDEMA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COGNITIVE DISORDER
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIZZINESS
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSMETRIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EPILEPSY
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FACIAL PARESIS
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMORRHAGE INTRACRANIAL
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERAESTHESIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOAESTHESIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METABOLIC ENCEPHALOPATHY
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NERVOUS SYSTEM DISORDER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PARAPLEGIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEIZURE
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TRANSIENT ISCHAEMIC ATTACK
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOCAL CORD PARALYSIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    3 / 373 (0.80%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEUKOPENIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NEUTROPENIA
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THROMBOCYTOPENIA
         subjects affected / exposed
    0 / 373 (0.00%)
    8 / 368 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    ANGLE CLOSURE GLAUCOMA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    EYELID OEDEMA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERIORBITAL SWELLING
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VISUAL IMPAIRMENT
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL ADHESIONS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 373 (0.54%)
    6 / 368 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASCITES
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 373 (0.27%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL OBSTRUCTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DUODENAL ULCER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRIC PERFORATION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PANCREATITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STOMATITIS
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER GASTROINTESTINAL HAEMORRHAGE
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FAILURE
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATIC FUNCTION ABNORMAL
         subjects affected / exposed
    1 / 373 (0.27%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HEPATOTOXICITY
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    JAUNDICE CHOLESTATIC
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LIVER DISORDER
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    DERMATITIS BULLOUS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RASH ERYTHEMATOUS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN EXFOLIATION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    2 / 373 (0.54%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DYSURIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL FAILURE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INAPPROPRIATE ANTIDIURETIC HORMONE SECRETION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BONE PAIN
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FIBROMYALGIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULAR WEAKNESS
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MYALGIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOLYSIS
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILIARY TRACT INFECTION
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER GASTROENTERITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONA VIRUS INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS CHORIORETINITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA URINARY TRACT INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOPHILUS INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    KLEBSIELLA INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUNG ABSCESS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    METAPNEUMOVIRUS INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    8 / 373 (2.14%)
    14 / 368 (3.80%)
         occurrences causally related to treatment / all
    0 / 8
    5 / 16
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    PNEUMONIA BACTERIAL
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA PSEUDOMONAL
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PSEUDOMONAS INFECTION
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 373 (0.54%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RHINITIS
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    2 / 373 (0.54%)
    6 / 368 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 8
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URINARY TRACT INFECTION
         subjects affected / exposed
    1 / 373 (0.27%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    CACHEXIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DECREASED APPETITE
         subjects affected / exposed
    1 / 373 (0.27%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEHYDRATION
         subjects affected / exposed
    0 / 373 (0.00%)
    4 / 368 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERCALCAEMIA
         subjects affected / exposed
    1 / 373 (0.27%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOALBUMINAEMIA
         subjects affected / exposed
    0 / 373 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOKALAEMIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPONATRAEMIA
         subjects affected / exposed
    5 / 373 (1.34%)
    6 / 368 (1.63%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOPROTEINAEMIA
         subjects affected / exposed
    0 / 373 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Rovalpituzumab Tesirine/Dexamethasone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    248 / 373 (66.49%)
    315 / 368 (85.60%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    8 / 373 (2.14%)
    39 / 368 (10.60%)
         occurrences all number
    8
    45
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    12 / 373 (3.22%)
    48 / 368 (13.04%)
         occurrences all number
    13
    59
    BLOOD ALKALINE PHOSPHATASE INCREASED
         subjects affected / exposed
    6 / 373 (1.61%)
    29 / 368 (7.88%)
         occurrences all number
    7
    44
    GAMMA-GLUTAMYLTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 373 (0.80%)
    19 / 368 (5.16%)
         occurrences all number
    3
    21
    WEIGHT DECREASED
         subjects affected / exposed
    16 / 373 (4.29%)
    19 / 368 (5.16%)
         occurrences all number
    17
    22
    Cardiac disorders
    PERICARDIAL EFFUSION
         subjects affected / exposed
    6 / 373 (1.61%)
    58 / 368 (15.76%)
         occurrences all number
    7
    63
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    18 / 373 (4.83%)
    30 / 368 (8.15%)
         occurrences all number
    18
    34
    HEADACHE
         subjects affected / exposed
    19 / 373 (5.09%)
    31 / 368 (8.42%)
         occurrences all number
    19
    39
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    11 / 373 (2.95%)
    45 / 368 (12.23%)
         occurrences all number
    18
    51
    NEUTROPENIA
         subjects affected / exposed
    10 / 373 (2.68%)
    31 / 368 (8.42%)
         occurrences all number
    11
    37
    THROMBOCYTOPENIA
         subjects affected / exposed
    14 / 373 (3.75%)
    61 / 368 (16.58%)
         occurrences all number
    19
    79
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    25 / 373 (6.70%)
    34 / 368 (9.24%)
         occurrences all number
    27
    47
    FACE OEDEMA
         subjects affected / exposed
    5 / 373 (1.34%)
    41 / 368 (11.14%)
         occurrences all number
    5
    48
    FATIGUE
         subjects affected / exposed
    60 / 373 (16.09%)
    91 / 368 (24.73%)
         occurrences all number
    66
    112
    OEDEMA PERIPHERAL
         subjects affected / exposed
    28 / 373 (7.51%)
    93 / 368 (25.27%)
         occurrences all number
    32
    130
    PYREXIA
         subjects affected / exposed
    12 / 373 (3.22%)
    20 / 368 (5.43%)
         occurrences all number
    13
    24
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    14 / 373 (3.75%)
    21 / 368 (5.71%)
         occurrences all number
    14
    24
    CONSTIPATION
         subjects affected / exposed
    35 / 373 (9.38%)
    48 / 368 (13.04%)
         occurrences all number
    37
    57
    DIARRHOEA
         subjects affected / exposed
    35 / 373 (9.38%)
    30 / 368 (8.15%)
         occurrences all number
    39
    35
    DYSPEPSIA
         subjects affected / exposed
    4 / 373 (1.07%)
    20 / 368 (5.43%)
         occurrences all number
    4
    22
    NAUSEA
         subjects affected / exposed
    51 / 373 (13.67%)
    77 / 368 (20.92%)
         occurrences all number
    56
    86
    VOMITING
         subjects affected / exposed
    35 / 373 (9.38%)
    35 / 368 (9.51%)
         occurrences all number
    40
    41
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    43 / 373 (11.53%)
    56 / 368 (15.22%)
         occurrences all number
    47
    69
    DYSPNOEA
         subjects affected / exposed
    39 / 373 (10.46%)
    67 / 368 (18.21%)
         occurrences all number
    41
    82
    PLEURAL EFFUSION
         subjects affected / exposed
    11 / 373 (2.95%)
    76 / 368 (20.65%)
         occurrences all number
    12
    91
    PRODUCTIVE COUGH
         subjects affected / exposed
    11 / 373 (2.95%)
    23 / 368 (6.25%)
         occurrences all number
    12
    27
    Skin and subcutaneous tissue disorders
    DRY SKIN
         subjects affected / exposed
    9 / 373 (2.41%)
    21 / 368 (5.71%)
         occurrences all number
    9
    21
    ERYTHEMA
         subjects affected / exposed
    5 / 373 (1.34%)
    22 / 368 (5.98%)
         occurrences all number
    6
    36
    PHOTOSENSITIVITY REACTION
         subjects affected / exposed
    5 / 373 (1.34%)
    88 / 368 (23.91%)
         occurrences all number
    5
    126
    PRURITUS
         subjects affected / exposed
    17 / 373 (4.56%)
    21 / 368 (5.71%)
         occurrences all number
    18
    25
    RASH
         subjects affected / exposed
    8 / 373 (2.14%)
    24 / 368 (6.52%)
         occurrences all number
    9
    28
    SKIN TOXICITY
         subjects affected / exposed
    6 / 373 (1.61%)
    22 / 368 (5.98%)
         occurrences all number
    6
    24
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    13 / 373 (3.49%)
    33 / 368 (8.97%)
         occurrences all number
    13
    33
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    19 / 373 (5.09%)
    30 / 368 (8.15%)
         occurrences all number
    20
    33
    BACK PAIN
         subjects affected / exposed
    29 / 373 (7.77%)
    22 / 368 (5.98%)
         occurrences all number
    29
    23
    Metabolism and nutrition disorders
    HYPERGLYCAEMIA
         subjects affected / exposed
    3 / 373 (0.80%)
    29 / 368 (7.88%)
         occurrences all number
    4
    32
    DECREASED APPETITE
         subjects affected / exposed
    49 / 373 (13.14%)
    95 / 368 (25.82%)
         occurrences all number
    55
    115
    HYPOALBUMINAEMIA
         subjects affected / exposed
    3 / 373 (0.80%)
    32 / 368 (8.70%)
         occurrences all number
    4
    41
    HYPOKALAEMIA
         subjects affected / exposed
    9 / 373 (2.41%)
    27 / 368 (7.34%)
         occurrences all number
    10
    34

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Feb 2017
    Amendment 1: clarification that best response at Screening is determined by RECIST v1.1; DLL3high defined as > 75% tumor cells staining positive according to the VENTANA DLL3 (SP347) IHC Assay; allowed concomitant dose of prednisone reduced to < 10mg/day; clarification of 12 weeks of non-treatment after 2 dosing cycles; clarification that secondary variable of objective response rate (ORR) is per CRAC and investigator assessment.
    20 Apr 2017
    Amendment 2: exclude subjects with any history of capillary leak syndrome; exclude subjects with known hypersensitivity to pharmaceuticals produced in Chinese hamster ovary cells; strong inhibitors of cytochrome P450 3A4 (CYP3A4) prohibited.
    09 May 2017
    Amendment 3: addition of prospective testing for DLL3 and stratification factor of unknown versus 0% to < 25% versus 25% to < 75% versus 75% or above; clarification that clinical benefit is determined by RECIST v1.1; definition of disease progression clarified with respect to effusions; dose reduction guidelines for unacceptable toxicity included for edema; adverse event (AE) preferred terms (PTs) expected due to SCLC or progression of SCLC updated per Medical Dictionary for Regulatory Activities (MedDRA) v19.1.
    05 Mar 2019
    Amendment 4: primary efficacy endpoints clarified as progression-free survival (PFS) per CRAC and OS in subjects with DLL3high ED SCLC; efficacy endpoints updated to include OS, PFS, and patient-reported outcomes (PROs; physical functioning) in all randomized subjects as secondary, and ORR, clinical benefit rate (CBR), duration of response (DOR), and PROs (except physical functioning) as exploratory; number of planned sites increased from 275 to 300; interim efficacy analysis removed and a futility analysis at 50% of the final OS endpoints added; ED SCLC definition per International Association for the Study of Lung Cancer/Veterans Association added; updated safety and toxicity management (per rovalpituzumab tesirine Investigator Brochure v7), including language around serosal effusions, pneumonitis, edema, and photosensitivity; updated language regarding rovalpituzumab tesirine classification as a hazardous drug.

    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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