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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Open-Label Study of Avelumab (MSB0010718C) Alone or in Combination With Pegylated Liposomal Doxorubicin Versus Pegylated Liposomal Doxorubicin Alone in Patients With Platinum Resistant/Refractory Ovarian Cancer

    Summary
    EudraCT number
    		 2015-003091-77
    Trial protocol
    		 BE   GB   HU   AT   ES   GR   IE   NL   FR   PL   DK   CZ  
    Global end of trial date
    12 Jul 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2023
    First version publication date
    07 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B9991009
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02580058
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pfizer Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, 10017
    Public contact
    ClinicalTrial.gov, Call Center, Pfizer Inc., ClinicalTrial.gov, Call Center, Pfizer Inc., 001 18667181021, ClinicalTrials.gov.inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 18007181021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jul 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jul 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial is to demonstrate that avelumab given alone or in combination with pegylated liposomal doxorubicin (PLD) is superior to PLD alone in prolonging overall survival (OS) in patients with platinum resistant/platinum refractory ovarian cancer; and to demonstrate that avelumab given alone or in combination with PLD is superior to PLD alone in prolonging PFS in patients with platinum resistant/platinum-refractory ovarian cancer.
    Protection of trial subjects
    This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of trial subjects.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Dec 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 3 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Austria: 4
    Country: Number of subjects enrolled
    Belgium: 22
    Country: Number of subjects enrolled
    Canada: 64
    Country: Number of subjects enrolled
    Czechia: 13
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Hong Kong: 1
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Japan: 52
    Country: Number of subjects enrolled
    Korea, Republic of: 40
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Poland: 17
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Singapore: 11
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    Switzerland: 18
    Country: Number of subjects enrolled
    Taiwan: 13
    Country: Number of subjects enrolled
    United Kingdom: 78
    Country: Number of subjects enrolled
    United States: 80
    Worldwide total number of subjects
    566
    EEA total number of subjects
    152
    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)
    349
    From 65 to 84 years
    215
    85 years and over
    2

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of the 717 subjects screened, a total of 566 randomized subjects were enrolled at 199 centers in 24 countries.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avelumab
    Arm description
    		 Avelumab 10 milligram (mg)/kilogram (kg) given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab 10 mg/kg given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles.

    Arm title
    		 Avelumab + PLD
    Arm description
    		 Avelumab 10 mg/kg given as a 1-hour IV Q2W in 4-week cycles + pegylated liposomal doxorubicin (PLD) 40 mg/square meter given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab and PLD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab 10 mg/kg given as a 1-hour IV Q2W + PLD 40mg/m2 given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles.

    Arm title
    		 Pegylated Liposomal Doxorubicin (PLD)
    Arm description
    		 PLD 40 mg/square meter given as a 1-hour IV infusion Q4W in 4-week cycles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    PLD
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    PLD 40mg/m2 given as a 1-hour IV infusion Q4W in 4-week cycles.

    Number of subjects in period 1
    		Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Started
    188
    188
    190
    Treated
    187
    182
    177
    Completed
    0
    0
    0
    Not completed
    188
    188
    190
         Adverse event, serious fatal
    4
    4
    5
         Physician decision
    1
    3
    11
         Consent withdrawn by subject
    4
    7
    31
         Adverse event, non-fatal
    16
    30
    20
         Progressive Disease
    137
    125
    94
         Not Specified
    5
    1
    3
         Non-Compliance With Study Drug
    1
    -
    -
         No Longer Meets Eligibility Criteria
    1
    -
    2
         Global Deterioration of Health Status
    19
    18
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab
    Reporting group description
    		 Avelumab 10 milligram (mg)/kilogram (kg) given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles.

    Reporting group title
    Avelumab + PLD
    Reporting group description
    		 Avelumab 10 mg/kg given as a 1-hour IV Q2W in 4-week cycles + pegylated liposomal doxorubicin (PLD) 40 mg/square meter given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles.

    Reporting group title
    Pegylated Liposomal Doxorubicin (PLD)
    Reporting group description
    		 PLD 40 mg/square meter given as a 1-hour IV infusion Q4W in 4-week cycles.

    Reporting group values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD) Total
    Number of subjects
    		 188 188 190 566
    Age Categorical
    Units: Subjects
        <=18 years
    		 0 0 0 0
        Between 18 and 65 years
    		 111 124 114 349
        >=65 years
    		 77 64 76 217
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 61.0 ( 10.26 ) 59.5 ( 10.05 ) 60.4 ( 10.64 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 188 188 190 566
        Male
    		 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 2 3 1 6
        Not Hispanic or Latino
    		 176 176 183 535
        Unknown or Not Reported
    		 10 9 6 25
    Race (NIH/OMB)
    Units: Subjects
        Black or African American
    		 2 2 6 10
        American Indian or Alaska Native
    		 0 0 1 1
        Asian
    		 34 53 46 133
        Native Hawaiian or Other Pacific Islander
    		 1 0 0 1
        White
    		 148 133 135 416
        Other
    		 1 0 2 3
        Unknown or Not Reported
    		 2 0 0 2
    Region of Enrollment
    Units: Subjects
        North America
    		 49 45 50 144
        Western Europe
    		 78 68 63 209
        Eastern Europe
    		 21 20 26 67
        Middle East
    		 0 0 1 1
        Australasia
    		 10 6 12 28
        Asia
    		 30 49 38 117

    End points

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    End points reporting groups
    Reporting group title
    Avelumab
    Reporting group description
    		 Avelumab 10 milligram (mg)/kilogram (kg) given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles.

    Reporting group title
    Avelumab + PLD
    Reporting group description
    		 Avelumab 10 mg/kg given as a 1-hour IV Q2W in 4-week cycles + pegylated liposomal doxorubicin (PLD) 40 mg/square meter given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles.

    Reporting group title
    Pegylated Liposomal Doxorubicin (PLD)
    Reporting group description
    		 PLD 40 mg/square meter given as a 1-hour IV infusion Q4W in 4-week cycles.

    Primary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    OS is defined as the time from the date of randomization to the date of death due to any cause. OS time was summarized by treatment arm using the Kaplan-Meier method.
    End point type
    Primary
    End point timeframe
    From randomization until the date of first documented progression or date of deaths from any cause, whichever came first, assessed up to 30 months (based on cutoff date: 19 September 2018).
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: months
        median (confidence interval 95%)
    11.8 (8.9 to 14.1)
    15.7 (12.7 to 18.7)
    13.1 (11.8 to 15.5)
    Statistical analysis title
    		 Overall survival comparison versus PLD
    Comparison groups
    Avelumab v Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8253
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.867
         upper limit
    		 1.497
    Statistical analysis title
    		 Overall survival comparison versus PLD
    Comparison groups
    Avelumab + PLD v Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2082
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.672
         upper limit
    		 1.179

    Primary: Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

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    End point title
    		 Progression Free Survival (PFS) Based on Blinded Independent Central Review (BICR) According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    End point description
    PFS is defined as the time from date of randomization to the date of the first documentation of progression of disease (PD) or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method. PFS based on BICR assessment was evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: months
        median (confidence interval 95%)
    1.9 (1.8 to 1.9)
    3.7 (3.3 to 5.1)
    3.5 (2.1 to 4.0)
    Statistical analysis title
    		 PFS comparison versus PLD
    Comparison groups
    Avelumab + PLD v Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0301
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.78
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.607
         upper limit
    		 1.011
    Statistical analysis title
    		 PFS comparison versus PLD
    Comparison groups
    Avelumab v Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects included in analysis
    378
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 > 0.9999
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.31
         upper limit
    		 2.16

    Secondary: ORR Based on Investigator Assessment

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    End point title
    		 ORR Based on Investigator Assessment
    End point description
    Percentage of subjects achieved OR based on investigator assessment is presented for this endpoint. OR is defined as a CR (disappearance of all target lesions) or PR (>=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the RECIST (version 1.1) recorded from randomization until disease progression or death due to any cause. The ORR on each randomized treatment arm were estimated by dividing the number of subjects with OR (CR or PR) by number of subjects randomized to the respective treatment arm.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: percentage of subjects
        number (confidence interval 95%)
    5.3 (2.6 to 9.6)
    18.6 (13.3 to 24.9)
    9.5 (5.7 to 14.6)
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR) Based on BICR Assessment

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    End point title
    		 Objective Response Rate (ORR) Based on BICR Assessment
    End point description
    Percentage of subjects achieved objective response (OR) based on BICR assessment is presented for this endpoint. OR is defined as a complete response (CR, disappearance of all target lesions) or partial response (PR, >=30% decrease under the baseline of the sum of diameters of all target measurable lesions) according to the RECIST (version 1.1) recorded from randomization until disease progression or death due to any cause. Both CR and PR must be confirmed by repeat assessments performed no less than 4 weeks after the criteria for response are first met and before the first documentation of disease progression. Only tumor assessments performed on or before the start date of any further anti-cancer therapies are considered in the assessment of best overall response.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by BICR were conducted at every 8 weeks from screening until documented disease progression (approximately up to 30 months); based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: percentage of subjects
        number (confidence interval 95%)
    3.7 (1.5 to 7.5)
    13.3 (8.8 to 19.0)
    4.2 (1.8 to 8.1)
    No statistical analyses for this end point

    Secondary: Duration of Response (DR) Based on BICR Assessment

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    End point title
    		 Duration of Response (DR) Based on BICR Assessment
    End point description
    DR is defined, for subjects with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR [disappearance of all target lesions] or PR [>=30% decrease under the baseline of the sum of diameters of all target measurable lesions]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    7
    25
    8
    Units: months
        median (confidence interval 95%)
    9.2 (6.4 to 99999)
    8.5 (6.1 to 99999)
    13.1 (5.5 to 99999)
    No statistical analyses for this end point

    Secondary: PFS Based on Investigator Assessment According to RECIST version 1.1

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    End point title
    		 PFS Based on Investigator Assessment According to RECIST version 1.1
    End point description
    PFS is defined as the time from date of randomization to the date of the first documentation of PD or death due to any cause, whichever occurs first. PFS time was summarized by treatment arm using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    From randomization to date of first documentation of PD or death due to any cause whichever was first (up to 30 months); based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: month
        median (confidence interval 95%)
    1.9 (1.8 to 1.9)
    4.7 (3.7 to 6.0)
    3.7 (3.5 to 5.4)
    No statistical analyses for this end point

    Secondary: DR Based on Investigator Assessment

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    End point title
    		 DR Based on Investigator Assessment
    End point description
    DR is defined, for subjects with an OR per RECIST version 1.1, as the time from the first documentation of objective tumor response (CR [disappearance of all target lesions] or PR [>=30% decrease under the baseline of the sum of diameters of all target measurable lesions]) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    10
    35
    18
    Units: months
        median (confidence interval 95%)
    10.4 (3.7 to 99999)
    7.6 (5.6 to 9.1)
    7.4 (3.6 to 11.2)
    No statistical analyses for this end point

    Secondary: Disease Control (DC) Rate Based on BICR Assessment

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    End point title
    		 Disease Control (DC) Rate Based on BICR Assessment
    End point description
    Percentage of subjects achieving DC based on BICR assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or stable disease (SD) according to the RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: percentage of subjects
        number (confidence interval 95%)
    33.0 (26.3 to 40.2)
    57.4 (50.0 to 64.6)
    48.9 (41.6 to 56.3)
    No statistical analyses for this end point

    Secondary: DC Rate Based on Investigator Assessment

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    End point title
    		 DC Rate Based on Investigator Assessment
    End point description
    Percentage of subjects achieving DC based on investigator assessment is presented in this endpoint. DC is a best overall response of CR (disappearance of all target lesions), PR (>=30% decrease under the baseline of the sum of diameters of all target measurable lesions), non-complete response/non-progressive disease or SD according to the RECIST version 1.1.
    End point type
    Secondary
    End point timeframe
    Tumor assessments as assessed by investigator were conducted at every 8 weeks from screening until documented disease progression, up to 30 months; based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: percentage of subjects
        number (confidence interval 95%)
    34.0 (27.3 to 41.3)
    61.7 (54.3 to 68.7)
    54.7 (47.4 to 62.0)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects with Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a clinical investigation patient administered a product or medical device; the event need not necessarily have a causal relationship with the treatment or usage. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect; progression of the malignancy under study. Treatment emergent AEs are those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event is during the on-treatment period.
    End point type
    Secondary
    End point timeframe
    From the time of the first dose of study treatment through a minimum of 30 days + last dose of study treatment, start day of new anti-cancer therapy -1 day (up to 70 months); based on cutoff date: 13 July 2022.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    187
    182
    177
    Units: Subjects
        TEAE
    180
    180
    173
        Treatment emergent SAEs
    72
    74
    51
    No statistical analyses for this end point

    Secondary: Number of Subjects with Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Laboratory Abnormalities
    End point description
    The number of subjects with following laboratory abnormalities meeting any of the Grades 1 to 4 classified according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) toxicity grading version 4.03 were summarized: hematology (anemia, lymphocyte count decreased, neutrophil count decreased; and platelet count decreased) and chemistry laboratory tests (creatinine increased; serum amylase increased and lipase increased).
    End point type
    Secondary
    End point timeframe
    From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    187
    182
    177
    Units: Subjects
        Anemia|Any grade >=1
    135
    155
    144
        Lymphocyte count decreased|Any grade >=1
    89
    148
    107
        Neutrophil count decreased|Any grade >=1
    26
    80
    62
        Platelet count decreased|Any grade >=1
    33
    48
    50
        Creatinine increased|Any grade >=1
    154
    151
    120
        Serum amylase increased|Any grade >=1
    43
    35
    27
        Lipase increased|Any grade >=1
    27
    33
    21
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs - Blood Pressure

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    End point title
    		 Change From Baseline in Vital Signs - Blood Pressure
    End point description
    Vital signs included blood pressure and pulse rate. Changes from baseline in sitting diastolic blood pressure (DBP) and systolic blood pressure (SBP) were summarized.
    End point type
    Secondary
    End point timeframe
    From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    187
    182
    177
    Units: mm Hg
    arithmetic mean (standard deviation)
        DBP Cycle 1 Day 15
    0.1 ( 9.79 )
    -2.2 ( 9.12 )
    0.7 ( 8.89 )
        DBP Cycle 2 Day 1
    -1.1 ( 9.61 )
    -2.8 ( 8.01 )
    -0.1 ( 9.34 )
        DBP Cycle 2 Day 15
    0.1 ( 10.05 )
    -2.8 ( 9.19 )
    -0.1 ( 8.83 )
        DBP Cycle 3 Day 1
    0 ( 10.81 )
    -2.7 ( 8.95 )
    -0.2 ( 8.96 )
        DBP Cycle 3 Day 15
    -0.6 ( 9.25 )
    -2.3 ( 8.56 )
    -0.5 ( 8.67 )
        DBP End of Treatment
    1.1 ( 10.87 )
    -0.3 ( 11.08 )
    0.8 ( 10.40 )
        SBP Cycle 1 Day 15
    -0.9 ( 14.35 )
    -2.3 ( 13.12 )
    -1.0 ( 13.94 )
        SBP Cycle 2 Day 1
    -2.2 ( 14.44 )
    -3.4 ( 13.70 )
    -2.8 ( 13.39 )
        SBP Cycle 2 Day 15
    -0.6 ( 14.11 )
    -3.7 ( 14.78 )
    -1.8 ( 14.98 )
        SBP Cycle 3 Day 1
    -0.2 ( 15.59 )
    -2.7 ( 14.36 )
    -1.5 ( 14.14 )
        SBP Cycle 3 Day 15
    -0.2 ( 13.78 )
    -2.1 ( 15.30 )
    -2.2 ( 13.96 )
        SBP End of Treatment
    -0.9 ( 17.21 )
    -1.0 ( 16.83 )
    -3.2 ( 15.92 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Vital Signs - Pulse Rate

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    End point title
    		 Change From Baseline in Vital Signs - Pulse Rate
    End point description
    Vital signs included blood pressure and pulse rate. Changes from baseline in sitting pulse rate were summarized.
    End point type
    Secondary
    End point timeframe
    From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    187
    182
    177
    Units: bpm
    arithmetic mean (standard deviation)
        Cycle 1 Day 15
    2.9 ( 9.95 )
    1.8 ( 12.10 )
    3.5 ( 10.70 )
        Cycle 2 Day 1
    2.6 ( 10.92 )
    2.9 ( 11.18 )
    1.7 ( 9.71 )
        Cycle 2 Day 15
    2.9 ( 11.19 )
    3.5 ( 11.79 )
    3.2 ( 11.54 )
        Cycle 3 Day 1
    2.4 ( 10.00 )
    2.1 ( 11.78 )
    1.4 ( 11.14 )
        Cycle 3 Day 15
    3.0 ( 12.23 )
    1.4 ( 11.44 )
    2.4 ( 10.41 )
        End of Treatment
    7.7 ( 14.27 )
    7.4 ( 13.70 )
    5.7 ( 14.10 )
    No statistical analyses for this end point

    Secondary: Number of Subjects with Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Number of Subjects with Electrocardiogram (ECG) Abnormalities
    End point description
    Categorical summarization ECG criteria were as follows: 1) QT interval, QTcB, QTcF and QTcP: increase from baseline >30 ms or 60 ms; absolute value > 450 ms, >480 ms and > 500 ms; 2) heart rate (HR): change from baseline >=20 bpm and absolute value <=50 bpm or >=120 bpm; 3) PR interval: absolute value >=220 ms and increase from baseline >=20 ms; 4) QRS: >= 120 ms.
    End point type
    Secondary
    End point timeframe
    From screening to the end of treatment/withdrawal visit, up to 2.7 years, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    187
    182
    177
    Units: Subjects
        QT increase from baseline >30 ms
    26
    40
    47
        QT increase from baseline >60 ms
    5
    9
    4
        QT >450 ms
    6
    10
    5
        QT >480 ms
    1
    2
    2
        QT >500 ms
    1
    1
    1
        QTcB increase from baseline >30 ms
    33
    36
    22
        QTcB increase from baseline >60 ms
    9
    7
    8
        QTcB >450 ms
    56
    63
    45
        QTcB >480 ms
    9
    19
    9
        QTcB >500 ms
    5
    9
    5
        QTcF increase from baseline >30 ms
    19
    24
    13
        QTcF increase from baseline >60 ms
    6
    5
    5
        QTcF >450 ms
    18
    27
    14
        QTcF >480 ms
    4
    8
    5
        QTcF >500 ms
    3
    2
    4
        QTcP increase from baseline >30 ms
    17
    23
    12
        QTcP increase from baseline >60 ms
    6
    5
    4
        QTcP >450 ms
    19
    29
    17
        QTcP >480 ms
    2
    7
    2
        QTcP >500 ms
    1
    2
    2
        Heart rate <=50 bpm and decrease >= 20 bpm
    0
    1
    0
        Heart rate >=120 bpm and increase >= 20 bpm
    5
    5
    3
        PR >=220 ms and increase from baseline >=20 ms
    3
    4
    2
        QRS >=120 ms
    7
    9
    9
    No statistical analyses for this end point

    Secondary: Number of Subjects with % Left Ventricular Ejection Fraction (LVEF) Decrease from Baseline

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    End point title
    		 Number of Subjects with % Left Ventricular Ejection Fraction (LVEF) Decrease from Baseline
    End point description
    LVEF decrease was summarized by multiple-gated acquisition (MUGA)/ echocardiogram (ECHO) parameter. Subjects with a LVEF% >=10 points and >= 15 points decrease from baseline during the on-treatment period were summarized.
    End point type
    Secondary
    End point timeframe
    Screening, Cycle 3 Day 1 (repeated every 2 cycles) to the end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    129
    154
    132
    Units: Subjects
        >= 10 point decrease from baseline|MUGA/ECHO
    8
    22
    13
        >= 15 point decrease from baseline|MUGA/ECHO
    3
    8
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects with CD8 Expression for PFS (Based on BICR Assessment) and for OS

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    End point title
    		 Number of Subjects with CD8 Expression for PFS (Based on BICR Assessment) and for OS
    End point description
    Tumor infiltrating CD8 positive (CD8+) T lymphocytes was assessed by immunohistochemistry. Subjects were considered positive for CD8 T cells if their baseline tissue sample demonstrated presence of >=1% CD8+ cells across the area of the tumor.
    End point type
    Secondary
    End point timeframe
    Biomarkers are measured only at screening.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    165
    171
    164
    Units: Subjects
        Positive
    76
    80
    72
    No statistical analyses for this end point

    Secondary: Number of Subjects with Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL

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    End point title
    		 Number of Subjects with Improved, Stable and Deterioration Based on 10-Point Change for EORTC QLQ-C30 Global QoL
    End point description
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire – Core 30 (EORTC QLQ-C30) is a 30 question survey and includes 5 functional domain subscales, global health status/quality of life, disease/treatment related symptoms, and the perceived financial impact of disease. Higher scores are reflective of a greater presence of symptoms.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1, Day 1 of each subsequent cycle, end of treatment/withdrawal visit and the 30, 60 and 90 days safety follow up visits, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    152
    166
    148
    Units: Subjects
        Deterioration
    46
    65
    46
        Improved
    23
    20
    26
        Stable
    83
    81
    76
    No statistical analyses for this end point

    Secondary: Number of Subjects with PD-L1 Expression for PFS (Based on BICR Assessment) and for OS

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    End point title
    		 Number of Subjects with PD-L1 Expression for PFS (Based on BICR Assessment) and for OS
    End point description
    PD-L1 expression was assessed by immunohistochemistry. Subjects were considered positive for PD-L1 if their baseline tissue sample demonstrated PD-L1 expression on >=1% of tumor cells or >=5% of immune cells.
    End point type
    Secondary
    End point timeframe
    Biomarkers are measured only at screening.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    170
    173
    165
    Units: Subjects
        Positive
    100
    100
    88
    No statistical analyses for this end point

    Secondary: Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28

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    End point title
    		 Time to Deterioration in Abdominal/GI Symptom Subscale of EORTC QLQ-OV28
    End point description
    The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Ovarian Cancer 28 (EORTC QLQ-OV28) is a 28 item instrument with 7 functional domain subscales. Time to deterioration was defined as the time from randomization to the first time the subject's score showed a 15-point or higher increase in the score of the abdominal/GI symptom subscale of the EORTC QLQ-OV28.
    End point type
    Secondary
    End point timeframe
    From Day 1 of Cycle 1 to prior to end of treatment/withdrawal visit, based on cutoff date: 19 September 2018.
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    188
    188
    190
    Units: months
        median (confidence interval 95%)
    00000 (00000 to 99999)
    11.1 (6.5 to 99999)
    10.6 (9.2 to 99999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in EQ-VAS Score at End of Treatment

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    End point title
    		 Change from Baseline in EQ-VAS Score at End of Treatment
    End point description
    The EuroQol- 5 Dimensions- 5 Levels (EQ-5D-5L) questionnaire consists of the EQ-5D-5L descriptive system and a visual analogue scale (the EuroQol-visual analogue scale [EQ-VAS]). The respondent’s self-rated health is assessed on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state) by the EQ-VAS.
    End point type
    Secondary
    End point timeframe
    Baseline and end of treatment/withdrawal visit
    End point values
    		 Avelumab Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    111
    116
    111
    Units: scores on a scale
        arithmetic mean (standard deviation)
    -13.6 ( 20.56 )
    -11.2 ( 19.79 )
    -7.7 ( 22.26 )
    No statistical analyses for this end point

    Secondary: Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose

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    End point title
    		 Serum Trough Concentration (Ctrough) For Avelumab Following Cycle 2 Day 1 Pegylated Liposomal Doxorubicin (PLD) Dose [1]
    End point description
    Ctrough was defined as predose concentration during multiple dosing, and can be observed directly from data.
    End point type
    Secondary
    End point timeframe
    At predose (0 H) on Cycle 2 Day 1.
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab Avelumab + PLD
    Number of subjects analysed
    136
    139
    Units: microgram per milliliter (μg/mL)
        geometric mean (geometric coefficient of variation)
    21.1 ( 89 )
    23.19 ( 74 )
    Statistical analysis title
    		 Ctrough comparison
    Statistical analysis description
    Avelumab was the Reference treatment and Avelumab + PLD was the Test treatment
    Comparison groups
    Avelumab v Avelumab + PLD
    Number of subjects included in analysis
    275
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    110
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 95.4
         upper limit
    		 126.7
    Notes
    [2] - The ratios (and 90% CIs) are expressed as percentages.

    Secondary: Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose

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    End point title
    		 Serum Maximum Concentration (Cmax) For Avelumab Following Cycle 2 Day 1 PLD Dose [3]
    End point description
    Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
    End point type
    Secondary
    End point timeframe
    At postdose (end of infusion, 1H) on Cycle 2 Day 1.
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab Avelumab + PLD
    Number of subjects analysed
    104
    110
    Units: μg/mL
        geometric mean (geometric coefficient of variation)
    231.6 ( 43 )
    207.9 ( 71 )
    Statistical analysis title
    		 Cmax comparison
    Statistical analysis description
    Avelumab was the Reference treatment and Avelumab + PLD was the Test treatment
    Comparison groups
    Avelumab v Avelumab + PLD
    Number of subjects included in analysis
    214
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    90
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 79.5
         upper limit
    		 101.5
    Notes
    [4] - The ratios (and 90% CIs) are expressed as percentages.

    Secondary: Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose

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    End point title
    		 Cmax For Doxorubicin Following Cycle 2 Day 1 PLD Dose [5]
    End point description
    Cmax was defined as maximum observed serum concentration, and can be observed directly from data.
    End point type
    Secondary
    End point timeframe
    From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose.
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    15
    15
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    25850 ( 17 )
    26810 ( 14 )
    Statistical analysis title
    		 Cmax comparison
    Statistical analysis description
    PLD was the Reference treatment and Avelumab + PLD was the Test treatment.
    Comparison groups
    Pegylated Liposomal Doxorubicin (PLD) v Avelumab + PLD
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    96
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 87
         upper limit
    		 106
    Notes
    [6] - The ratios (and 90% CIs) are expressed as percentages. There were 29 subjects in this analysis.

    Secondary: Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose

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    End point title
    		 Area Under The Concentration Time Profile From Time Zero to The Last Quantifiable Concentration (AUClast) For Doxorubicin Following Cycle 2 Day 1 PLD Dose [7]
    End point description
    AUClast was defined as area under the concentration time profile from time zero to the time of the last quantifiable concentration (Clast).
    End point type
    Secondary
    End point timeframe
    From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose.
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    15
    15
    Units: ng*hr/mL
        geometric mean (geometric coefficient of variation)
    2052000 ( 71 )
    2043000 ( 119 )
    Statistical analysis title
    		 AUClast comparison
    Statistical analysis description
    PLD was the Reference treatment and Avelumab + PLD was the Test treatment.
    Comparison groups
    Pegylated Liposomal Doxorubicin (PLD) v Avelumab + PLD
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    100
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 60
         upper limit
    		 168
    Notes
    [8] - The ratios (and 90% CIs) are expressed as percentages. There were 29 subjects in this analysis.

    Secondary: Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose

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    End point title
    		 Area Under The Concentration Time Profile From Time Zero to 336 Hours (AUC336) For Doxorubicin Following Cycle 2 Day 1 PLD Dose [9]
    End point description
    AUC336 was defined as area under the concentration time profile from time zero to 336 hours.
    End point type
    Secondary
    End point timeframe
    From predose (0 H) of Cycle 2 Day 1 through 336 hours postdose.
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    12
    13
    Units: ng*hr/mL
        geometric mean (geometric coefficient of variation)
    2571000 ( 30 )
    2848000 ( 20 )
    Statistical analysis title
    		 AUC336 comparison
    Statistical analysis description
    PLD was the Reference treatment and Avelumab + PLD was the Test treatment.
    Comparison groups
    Pegylated Liposomal Doxorubicin (PLD) v Avelumab + PLD
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    90
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 76
         upper limit
    		 107
    Notes
    [10] - The ratios (and 90% CIs) are expressed as percentages.

    Secondary: Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose

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    End point title
    		 Area Under The Concentration Time Profile From Time Zero to 24 Hours (AUC24) For Doxorubicin Following Cycle 2 Day 1 PLD Dose [11]
    End point description
    AUC24 was defined as area under the concentration time profile from time zero to 24 hours.
    End point type
    Secondary
    End point timeframe
    From 0 through 24 hours postdose.
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab + PLD Pegylated Liposomal Doxorubicin (PLD)
    Number of subjects analysed
    14
    14
    Units: nanogram*hour per milliliter (ng*hr/mL)
        geometric mean (geometric coefficient of variation)
    541700 ( 14 )
    567600 ( 11 )
    Statistical analysis title
    		 AUC24 comparison
    Statistical analysis description
    PLD was the Reference treatment and Avelumab + PLD was the Test treatment.
    Comparison groups
    Pegylated Liposomal Doxorubicin (PLD) v Avelumab + PLD
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 [12]
    Method
    Parameter type
    		 Geometric Mean Ratio (Test/Reference, %)
    Point estimate
    95
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 88
         upper limit
    		 104
    Notes
    [12] - The ratios (and 90% CIs) are expressed as percentages.

    Secondary: Number of Subjects With Treatment-Boosted Anti-Drug Antibody (ADA)

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    End point title
    		 Number of Subjects With Treatment-Boosted Anti-Drug Antibody (ADA) [13]
    End point description
    Treatment-boosted ADA was defined as a positive ADA result at baseline and the titer ≥ 8×baseline titer at least once after treatment with avelumab.
    End point type
    Secondary
    End point timeframe
    At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab.
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab Avelumab + PLD
    Number of subjects analysed
    165
    167
    Units: Subjects
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Induced ADA

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    End point title
    		 Number of Subjects With Treatment-Induced ADA [14]
    End point description
    Treatment-induced ADA was defined as patient who was ADA-negative at baseline and has at least one positive post-baseline ADA result; or if patient did not have a baseline sample, the patient had at least one positive past-baseline ADA result.
    End point type
    Secondary
    End point timeframe
    At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab.
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab Avelumab + PLD
    Number of subjects analysed
    169
    167
    Units: Subjects
    27
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Induced Neutralizing Antibody (nAb)

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    End point title
    		 Number of Subjects With Treatment-Induced Neutralizing Antibody (nAb) [15]
    End point description
    Treatment-induced nAb was defined as patient who was not nAb positive at baseline and had at least one positive post-baseline nAb result; or if patient did not have a baseline sample, the patient had at least one positive past-baseline ADA result.
    End point type
    Secondary
    End point timeframe
    At predose (0 H) of select cycles starting from Cycle 1 through Cycle 24, at end of treatment and 30 days after the last dose of avelumab.
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Statistics are reported for the arms specified
    End point values
    		 Avelumab Avelumab + PLD
    Number of subjects analysed
    173
    169
    Units: Subjects
    5
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first dose of study treatment through a minimum of 30 days + last dose of study treatment, start day of new anti-cancer therapy -1 day (up to 70 months). Based on the cutoff: 13 July 2022.
    Adverse event reporting additional description
    The same event may appear as both an AE and an SAE. However, what is presented are distinct events. An event may be categorized as serious in 1 subject and as non-serious in another subject, or 1 subject may have experienced both a serious and non-serious event during the study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Avelumab
    Reporting group description
    		 Avelumab 10 milligram (mg)/kilogram (kg) given as a 1-hour intravenous (IV) infusion every 2 weeks (Q2W) in 4-week cycles.

    Reporting group title
    Pegylated Liposomal Doxorubicin (PLD)
    Reporting group description
    		 PLD 40 mg/square meter given as a 1-hour IV infusion Q4W in 4-week cycles.

    Reporting group title
    Avelumab + PLD
    Reporting group description
    		 Avelumab 10 mg/kg given as a 1-hour IV Q2W in 4-week cycles + pegylated liposomal doxorubicin (PLD) 40 mg/square meter given as a 1-hour IV infusion every 4 weeks (Q4W) in 4-week cycles.

    Serious adverse events
    		 Avelumab Pegylated Liposomal Doxorubicin (PLD) Avelumab + PLD
    Total subjects affected by serious adverse events
         subjects affected / exposed
    72 / 187 (38.50%)
    51 / 177 (28.81%)
    74 / 182 (40.66%)
         number of deaths (all causes)
    122
    116
    107
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         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
    Deep vein thrombosis
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 187 (0.00%)
    3 / 177 (1.69%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Embolism venous
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Chills
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Administration site extravasation
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complication associated with device
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Fatigue
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease progression
         subjects affected / exposed
    10 / 187 (5.35%)
    2 / 177 (1.13%)
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 177 (0.00%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    Influenza like illness
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Localised oedema
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mucosal inflammation
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 187 (3.74%)
    1 / 177 (0.56%)
    8 / 182 (4.40%)
         occurrences causally related to treatment / all
    5 / 8
    0 / 3
    6 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune-mediated adverse reaction
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Anaphylactic reaction
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Cough
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 187 (1.60%)
    0 / 177 (0.00%)
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 187 (1.07%)
    0 / 177 (0.00%)
    0 / 182 (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
    Pneumonitis
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Productive cough
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Pulmonary embolism
         subjects affected / exposed
    2 / 187 (1.07%)
    2 / 177 (1.13%)
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Respiratory failure
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Product issues
    Device dislocation
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Neutrophil count decreased
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urine output decreased
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Stoma complication
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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 limb fracture
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         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 access complication
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Tremor
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Aphasia
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Clonic convulsion
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 187 (0.00%)
    3 / 177 (1.69%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    9 / 187 (4.81%)
    6 / 177 (3.39%)
    6 / 182 (3.30%)
         occurrences causally related to treatment / all
    1 / 10
    1 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    3 / 187 (1.60%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    2 / 187 (1.07%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    2 / 187 (1.07%)
    1 / 177 (0.56%)
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intussusception
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal pseudo-obstruction
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Intestinal obstruction
         subjects affected / exposed
    11 / 187 (5.88%)
    6 / 177 (3.39%)
    9 / 182 (4.95%)
         occurrences causally related to treatment / all
    2 / 16
    0 / 6
    0 / 9
         deaths causally related to treatment / all
    1 / 3
    0 / 1
    0 / 1
    Ileus
         subjects affected / exposed
    1 / 187 (0.53%)
    2 / 177 (1.13%)
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    4 / 187 (2.14%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    7 / 187 (3.74%)
    3 / 177 (1.69%)
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    1 / 8
    3 / 5
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Subileus
         subjects affected / exposed
    1 / 187 (0.53%)
    2 / 177 (1.13%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    5 / 187 (2.67%)
    2 / 177 (1.13%)
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Obstruction gastric
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Nausea
         subjects affected / exposed
    7 / 187 (3.74%)
    1 / 177 (0.56%)
    4 / 182 (2.20%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mechanical ileus
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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 acute
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Malignant gastrointestinal obstruction
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Proctalgia
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Skin and subcutaneous tissue disorders
    Dermatitis exfoliative generalised
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vasculitic ulcer
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Chronic kidney disease
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Obstructive nephropathy
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Urinary tract obstruction
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Endocrine disorders
    Hypopituitarism
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    2 / 182 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Basedow's disease
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Glucocorticoid deficiency
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 187 (0.00%)
    2 / 177 (1.13%)
    0 / 182 (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
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Cholangitis infective
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Cystitis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Device related infection
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Erysipelas
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    0 / 182 (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
    Infectious pleural effusion
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Influenza
         subjects affected / exposed
    0 / 187 (0.00%)
    2 / 177 (1.13%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymph gland infection
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Medical device site infection
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nail infection
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Oral fungal infection
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Peritonitis bacterial
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 187 (1.60%)
    0 / 177 (0.00%)
    3 / 182 (1.65%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 187 (0.53%)
    1 / 177 (0.56%)
    0 / 182 (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
    Respiratory tract infection
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    Sepsis
         subjects affected / exposed
    0 / 187 (0.00%)
    2 / 177 (1.13%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 187 (0.53%)
    2 / 177 (1.13%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 187 (0.53%)
    0 / 177 (0.00%)
    0 / 182 (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
    Vascular device infection
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic pulmonary embolism
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    0 / 182 (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
    COVID-19 pneumonia
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related bacteraemia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 187 (1.60%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 187 (1.07%)
    1 / 177 (0.56%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 187 (0.00%)
    1 / 177 (0.56%)
    5 / 182 (2.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 187 (0.00%)
    0 / 177 (0.00%)
    1 / 182 (0.55%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 187 (0.00%)
    2 / 177 (1.13%)
    0 / 182 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    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
    		 Avelumab Pegylated Liposomal Doxorubicin (PLD) Avelumab + PLD
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    173 / 187 (92.51%)
    167 / 177 (94.35%)
    176 / 182 (96.70%)
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    18 / 187 (9.63%)
    3 / 177 (1.69%)
    14 / 182 (7.69%)
         occurrences all number
    20
    3
    15
    Fatigue
         subjects affected / exposed
    63 / 187 (33.69%)
    55 / 177 (31.07%)
    77 / 182 (42.31%)
         occurrences all number
    88
    78
    147
    Influenza like illness
         subjects affected / exposed
    6 / 187 (3.21%)
    1 / 177 (0.56%)
    10 / 182 (5.49%)
         occurrences all number
    7
    1
    13
    Asthenia
         subjects affected / exposed
    18 / 187 (9.63%)
    14 / 177 (7.91%)
    30 / 182 (16.48%)
         occurrences all number
    27
    18
    68
    Malaise
         subjects affected / exposed
    5 / 187 (2.67%)
    6 / 177 (3.39%)
    11 / 182 (6.04%)
         occurrences all number
    5
    6
    14
    Mucosal inflammation
         subjects affected / exposed
    4 / 187 (2.14%)
    19 / 177 (10.73%)
    24 / 182 (13.19%)
         occurrences all number
    7
    29
    45
    Oedema peripheral
         subjects affected / exposed
    13 / 187 (6.95%)
    14 / 177 (7.91%)
    24 / 182 (13.19%)
         occurrences all number
    16
    16
    32
    Pyrexia
         subjects affected / exposed
    27 / 187 (14.44%)
    16 / 177 (9.04%)
    36 / 182 (19.78%)
         occurrences all number
    32
    20
    61
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    2 / 187 (1.07%)
    8 / 177 (4.52%)
    12 / 182 (6.59%)
         occurrences all number
    2
    8
    12
    Dyspnoea
         subjects affected / exposed
    34 / 187 (18.18%)
    25 / 177 (14.12%)
    32 / 182 (17.58%)
         occurrences all number
    45
    32
    44
    Cough
         subjects affected / exposed
    17 / 187 (9.09%)
    24 / 177 (13.56%)
    28 / 182 (15.38%)
         occurrences all number
    17
    27
    45
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 187 (3.74%)
    6 / 177 (3.39%)
    10 / 182 (5.49%)
         occurrences all number
    7
    7
    11
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    13 / 187 (6.95%)
    6 / 177 (3.39%)
    13 / 182 (7.14%)
         occurrences all number
    16
    9
    30
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 187 (2.14%)
    2 / 177 (1.13%)
    11 / 182 (6.04%)
         occurrences all number
    5
    4
    20
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 187 (2.14%)
    2 / 177 (1.13%)
    18 / 182 (9.89%)
         occurrences all number
    7
    2
    30
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 187 (2.14%)
    2 / 177 (1.13%)
    16 / 182 (8.79%)
         occurrences all number
    8
    3
    22
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 187 (0.53%)
    4 / 177 (2.26%)
    13 / 182 (7.14%)
         occurrences all number
    1
    4
    54
    White blood cell count decreased
         subjects affected / exposed
    6 / 187 (3.21%)
    15 / 177 (8.47%)
    15 / 182 (8.24%)
         occurrences all number
    7
    41
    70
    Weight decreased
         subjects affected / exposed
    10 / 187 (5.35%)
    13 / 177 (7.34%)
    13 / 182 (7.14%)
         occurrences all number
    11
    19
    19
    Platelet count decreased
         subjects affected / exposed
    5 / 187 (2.67%)
    7 / 177 (3.95%)
    10 / 182 (5.49%)
         occurrences all number
    8
    16
    22
    Neutrophil count decreased
         subjects affected / exposed
    4 / 187 (2.14%)
    9 / 177 (5.08%)
    17 / 182 (9.34%)
         occurrences all number
    10
    33
    84
    C-reactive protein increased
         subjects affected / exposed
    0 / 187 (0.00%)
    3 / 177 (1.69%)
    10 / 182 (5.49%)
         occurrences all number
    0
    3
    13
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    13 / 187 (6.95%)
    14 / 177 (7.91%)
    17 / 182 (9.34%)
         occurrences all number
    17
    14
    20
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 187 (8.02%)
    11 / 177 (6.21%)
    29 / 182 (15.93%)
         occurrences all number
    16
    12
    34
    Dizziness
         subjects affected / exposed
    5 / 187 (2.67%)
    8 / 177 (4.52%)
    17 / 182 (9.34%)
         occurrences all number
    5
    8
    19
    Neuropathy peripheral
         subjects affected / exposed
    2 / 187 (1.07%)
    4 / 177 (2.26%)
    10 / 182 (5.49%)
         occurrences all number
    2
    4
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    32 / 187 (17.11%)
    42 / 177 (23.73%)
    56 / 182 (30.77%)
         occurrences all number
    68
    77
    131
    Neutropenia
         subjects affected / exposed
    1 / 187 (0.53%)
    25 / 177 (14.12%)
    27 / 182 (14.84%)
         occurrences all number
    2
    52
    58
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    12 / 187 (6.42%)
    4 / 177 (2.26%)
    5 / 182 (2.75%)
         occurrences all number
    16
    7
    9
    Abdominal pain upper
         subjects affected / exposed
    10 / 187 (5.35%)
    13 / 177 (7.34%)
    17 / 182 (9.34%)
         occurrences all number
    10
    13
    22
    Abdominal pain
         subjects affected / exposed
    54 / 187 (28.88%)
    38 / 177 (21.47%)
    47 / 182 (25.82%)
         occurrences all number
    69
    48
    67
    Constipation
         subjects affected / exposed
    35 / 187 (18.72%)
    46 / 177 (25.99%)
    48 / 182 (26.37%)
         occurrences all number
    47
    58
    69
    Abdominal distension
         subjects affected / exposed
    14 / 187 (7.49%)
    18 / 177 (10.17%)
    18 / 182 (9.89%)
         occurrences all number
    19
    20
    21
    Vomiting
         subjects affected / exposed
    43 / 187 (22.99%)
    44 / 177 (24.86%)
    43 / 182 (23.63%)
         occurrences all number
    63
    58
    65
    Stomatitis
         subjects affected / exposed
    8 / 187 (4.28%)
    35 / 177 (19.77%)
    53 / 182 (29.12%)
         occurrences all number
    13
    73
    125
    Nausea
         subjects affected / exposed
    53 / 187 (28.34%)
    76 / 177 (42.94%)
    87 / 182 (47.80%)
         occurrences all number
    66
    117
    131
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 187 (4.81%)
    14 / 177 (7.91%)
    9 / 182 (4.95%)
         occurrences all number
    9
    17
    11
    Dyspepsia
         subjects affected / exposed
    7 / 187 (3.74%)
    14 / 177 (7.91%)
    18 / 182 (9.89%)
         occurrences all number
    7
    15
    25
    Diarrhoea
         subjects affected / exposed
    42 / 187 (22.46%)
    32 / 177 (18.08%)
    36 / 182 (19.78%)
         occurrences all number
    61
    45
    57
    Skin and subcutaneous tissue disorders
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 187 (0.53%)
    40 / 177 (22.60%)
    61 / 182 (33.52%)
         occurrences all number
    1
    74
    163
    Dry skin
         subjects affected / exposed
    5 / 187 (2.67%)
    8 / 177 (4.52%)
    23 / 182 (12.64%)
         occurrences all number
    5
    9
    25
    Alopecia
         subjects affected / exposed
    3 / 187 (1.60%)
    7 / 177 (3.95%)
    18 / 182 (9.89%)
         occurrences all number
    3
    7
    18
    Skin hyperpigmentation
         subjects affected / exposed
    0 / 187 (0.00%)
    10 / 177 (5.65%)
    10 / 182 (5.49%)
         occurrences all number
    0
    10
    10
    Erythema
         subjects affected / exposed
    4 / 187 (2.14%)
    5 / 177 (2.82%)
    10 / 182 (5.49%)
         occurrences all number
    4
    7
    15
    Rash maculo-papular
         subjects affected / exposed
    4 / 187 (2.14%)
    11 / 177 (6.21%)
    14 / 182 (7.69%)
         occurrences all number
    5
    19
    40
    Rash
         subjects affected / exposed
    12 / 187 (6.42%)
    21 / 177 (11.86%)
    51 / 182 (28.02%)
         occurrences all number
    21
    26
    126
    Pruritus
         subjects affected / exposed
    13 / 187 (6.95%)
    8 / 177 (4.52%)
    21 / 182 (11.54%)
         occurrences all number
    14
    9
    34
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    9 / 187 (4.81%)
    2 / 177 (1.13%)
    20 / 182 (10.99%)
         occurrences all number
    11
    2
    22
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 187 (10.16%)
    10 / 177 (5.65%)
    17 / 182 (9.34%)
         occurrences all number
    22
    12
    20
    Back pain
         subjects affected / exposed
    22 / 187 (11.76%)
    21 / 177 (11.86%)
    18 / 182 (9.89%)
         occurrences all number
    25
    25
    28
    Myalgia
         subjects affected / exposed
    9 / 187 (4.81%)
    10 / 177 (5.65%)
    14 / 182 (7.69%)
         occurrences all number
    11
    10
    21
    Pain in extremity
         subjects affected / exposed
    4 / 187 (2.14%)
    13 / 177 (7.34%)
    18 / 182 (9.89%)
         occurrences all number
    4
    14
    20
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    15 / 187 (8.02%)
    12 / 177 (6.78%)
    20 / 182 (10.99%)
         occurrences all number
    22
    21
    29
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    36 / 187 (19.25%)
    37 / 177 (20.90%)
    51 / 182 (28.02%)
         occurrences all number
    41
    45
    69
    Hypoalbuminaemia
         subjects affected / exposed
    8 / 187 (4.28%)
    6 / 177 (3.39%)
    13 / 182 (7.14%)
         occurrences all number
    16
    8
    24
    Hypokalaemia
         subjects affected / exposed
    5 / 187 (2.67%)
    11 / 177 (6.21%)
    12 / 182 (6.59%)
         occurrences all number
    12
    19
    17
    Hypomagnesaemia
         subjects affected / exposed
    10 / 187 (5.35%)
    7 / 177 (3.95%)
    8 / 182 (4.40%)
         occurrences all number
    12
    7
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2016
    The protocol amendment 1 included PFS as assessed by blinded independent central review (BICR) as a additional primary objective/endpoint.
    04 Mar 2019
    The protocol amendment 2 explained that the final analysis of the study was completed and the study was planned to remain open to allow the remaining patients currently enrolled in Arm A or B to continue receiving avelumab.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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