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    Clinical Trial Results:
    A Phase III Study to Evaluate the Efficacy and Safety of Pazopanib Monotherapy Versus Placebo in Women Who Have Not Progressed after First Line Chemotherapy for Epithelial Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

    Summary
    EudraCT number
    		 2008-004672-50
    Trial protocol
    		 IE   DE   AT   FR   ES   DK   BE   IT   SE  
    Global end of trial date
    24 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Sep 2018
    First version publication date
    07 Sep 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    110655
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00866697
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Aug 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to determine whether pazopanib (up to 24 months, at 800 mg daily) prolongs PFS compared to placebo in women with non-bulky, FIGO Stage II to IV epithelial ovarian, fallopian tube, or primary peritoneal cancer that had not progressed after first-line chemotherapy
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 May 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 20
    Country: Number of subjects enrolled
    Australia: 65
    Country: Number of subjects enrolled
    Belgium: 38
    Country: Number of subjects enrolled
    China: 72
    Country: Number of subjects enrolled
    Denmark: 12
    Country: Number of subjects enrolled
    France: 178
    Country: Number of subjects enrolled
    Germany: 188
    Country: Number of subjects enrolled
    Hong Kong: 9
    Country: Number of subjects enrolled
    Ireland: 10
    Country: Number of subjects enrolled
    Italy: 91
    Country: Number of subjects enrolled
    Japan: 51
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Spain: 79
    Country: Number of subjects enrolled
    Sweden: 10
    Country: Number of subjects enrolled
    Taiwan: 17
    Country: Number of subjects enrolled
    United States: 33
    Worldwide total number of subjects
    940
    EEA total number of subjects
    637
    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)
    725
    From 65 to 84 years
    214
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study consisted of a screening/baseline period, a treatment period and a posttreatment or follow-up period. Study treatment continued for 24 months unless subjects met any of the criteria for investigational product discontinuation, including withdrawal of consent.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Participants received matching placebo once daily for a maximum of 24 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    matching placebo for pazopanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    tablet administered orally once daily for up to 24 months

    Arm title
    		 Pazopanib 800 mg
    Arm description
    		 Participants received pazopanib 800 milligrams (mg) once daily for a maximum of 24 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    pazopanib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800 mg tablet administered orally once daily for up to 24 months

    Number of subjects in period 1
    		Placebo Pazopanib 800 mg
    Started
    468
    472
    Completed
    254
    244
    Not completed
    214
    228
         Study closed/terminated
    156
    138
         Physician decision
    3
    5
         Consent withdrawn by subject
    33
    57
         Lost to follow-up
    22
    28

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily for a maximum of 24 months.

    Reporting group title
    Pazopanib 800 mg
    Reporting group description
    		 Participants received pazopanib 800 milligrams (mg) once daily for a maximum of 24 months.

    Reporting group values
    		 Placebo Pazopanib 800 mg Total
    Number of subjects
    		 468 472 940
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 357 368 725
        From 65-84 years
    		 110 104 214
        85 years and over
    		 1 0 1
    Age continuous
    Units: years
        median (full range (min-max))
    		 57 (20 to 85) 56 (25 to 80) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 468 472 940
        Male
    		 0 0 0
    Race/Ethnicity, Customized
    Units: Subjects
        African American/African Heritage
    		 1 2 3
        American Indian or Alaska Native
    		 1 1 2
        Central/South Asian Heritage (Her)
    		 1 0 1
        Japanese/East Asian Her/South East Asian Her
    		 102 106 208
        White
    		 363 363 726
    AgeContinuous
    Units: Years
        arithmetic mean (standard deviation)
    		 56.8 ± 10.83 55.8 ± 10.54 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received matching placebo once daily for a maximum of 24 months.

    Reporting group title
    Pazopanib 800 mg
    Reporting group description
    		 Participants received pazopanib 800 milligrams (mg) once daily for a maximum of 24 months.

    Primary: Investigator-assessed Progression-free Survival (PFS)

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    End point title
    		 Investigator-assessed Progression-free Survival (PFS)
    End point description
    PFS is the interval between the date of randomization and the date of progression, defined by Response Evaluation Criteria in Solid Tumors (RECIST), or death due to any cause. Per RECIST, for target lesions (TLs), disease progression (PD) is defined as >=20% increase in the sum of the longest diameters (LD) of TLs, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of >=1 new lesions. For non-target lesions (NTLs), PD is defined as the appearance of >=1 new lesions and/or unequivocal progression of existing NTLs. Participants (par.) who did not progress/die were censored at the date of last adequate assessment (LAA). Par. who started a new anti-cancer therapy (ACT) prior to radiological progression/death were censored at the date of LAA prior to the new ACT. Par. who progressed/died after an extended period (>=12 months) without adequate assessment (AA) were censored at the date of their last visit with AA prior to progression/death.
    End point type
    Primary
    End point timeframe
    From the date of randomization until the date of progression or death due to any cause (median time of follow-up was 17.9 months for pazopanib and 12.3 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    468
    472
    Units: months
        median (confidence interval 95%)
    12.3 (11.8 to 17.7)
    17.9 (15.9 to 21.8)
    Statistical analysis title
    		 PFS
    Comparison groups
    Placebo v Pazopanib 800 mg
    Number of subjects included in analysis
    940
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.0021 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.766
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.643
         upper limit
    		 0.911
    Notes
    [1] - The P-value from the stratified log-rank test was adjusted for the two stratification factors.

    Secondary: Overall Survival - Median

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    End point title
    		 Overall Survival - Median
    End point description
    Overall surival is defined as the interval between the date of randomization and the date of death due to any cause. For participants who did not die, the time to death was censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death due to any cause up to approximately 95 months
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    468
    472
    Units: months
        median (confidence interval 95%)
    64.0 (56.0 to 75.7)
    59.1 (53.5 to 71.6)
    No statistical analyses for this end point

    Secondary: Progression-free Survival per Gynecologic Cancer Intergroup (GCIG) Criteria

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    End point title
    		 Progression-free Survival per Gynecologic Cancer Intergroup (GCIG) Criteria
    End point description
    Progression-free survival by GCIG criteria is defined as the time from the date of randomization to the earliest date of disease progression per GCIG criteria or death due to any cause. Progression is defined according to RECIST but can also be based upon serum CA-125. Progression or recurrence based on serum CA-125 levels are defined on the basis of a progressive serial elevation of serum CA-125, according to the following criteria: (1) participants (par.) with elevated CA-125 pretreatment and normalization of CA-125 must show evidence of CA-125 >=2x the upper normal limit (UNL) on two occasions at least one week apart or; (2) par. with elevated CA-125 pretreatment, which never normalizes, must show evidence of CA-125 >=2x the nadir value on two occasions at least one week apart or; (3) par. with CA-125 in the normal range pretreatment must show evidence of CA-125 >=2x the UNL on two occasions at least one week apart.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of progression per GCIG criteria or death due to any cause (median time of follow-up was 16.8 months for pazopanib and 11.9 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    468
    472
    Units: months
        median (confidence interval 95%)
    11.9 (10.6 to 14.9)
    16.8 (12.6 to 18.1)
    No statistical analyses for this end point

    Secondary: 3-year Progression-free Survival

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    End point title
    		 3-year Progression-free Survival
    End point description
    3-year progression-free survival is defined as the percentage of participants who are progression-free at 3 years from randomization. Progression-free survival is defined as the time from the date of randomization to the earliest date of disease progression (defined by RECIST) or death due to any cause. Per RECIST, for target lesions, disease progression (PD) is defined as at least a 20% increase in the sum of the longest diameters (LD) of target lesions, taking as a reference, the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. For non-target lesions, PD is defined as the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. No analysis was done.
    End point type
    Secondary
    End point timeframe
    Up to 3 years after randomization
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    468
    472
    Units: percentage of participants
    99
    99
    No statistical analyses for this end point

    Secondary: Change from Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in the European Organization for the Research and Treatment of Cancer (EORTC) QLQ-C30 global health status score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The EORTC QLQ-C30 is a self-reported, 30-item cancer-specific instrument that assesses 15 domains: 5 functional scales (physical, role, emotional, cognitive, and social functioning), 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties), and a global health status, or quality of life. Global health status is assessed using a 7-item Likert scale, ranging from 1 to 7 ("poor" to "excellent"). Participants were asked to respond to the following questions using the 7-item Likert scale: "How would you rate your overall health during the past week"; "How would you rate your overall quality of life during the past week?" Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures analysis of covariance (ANCOVA).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    393
    293
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=393, 293|
    0.58 ± 0.821
    -3.82 ± 0.950
        Month 7, n=316, 223|
    0.95 ± 0.962
    -4.65 ± 1.139
        Month 10, n=240, 184|
    1.98 ± 0.972
    -4.28 ± 1.115
        Month 13, n=190, 140|
    0.65 ± 1.200
    -1.80 ± 1.398
        Month 16, n=137, 87|
    1.39 ± 1.370
    0.96 ± 1.702
        Month 25, n=92, 53|
    3.86 ± 1.488
    -1.68 ± 1.934
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module attitude to disease/treatment functional score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module attitude to disease/treatment functional score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV (ovarian)-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses attitude to disease/treatment functional symptoms, among others. Participants were asked to indicate the extent to which they experienced attention to disease/treatment functional problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: How much has your disease been a burden to you?; How much has your treatment been a burden to you?; Were you worried about your future health? Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    378
    291
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=378, 291|
    9.92 ± 1.110
    4.24 ± 1.263
        Month 7, n=299, 223|
    12.10 ± 1.203
    4.94 ± 1.385
        Month 10, n=228, 185|
    14.31 ± 1.310
    8.54 ± 1.467
        Month 13, n=182, 138|
    15.45 ± 1.388
    10.07 ± 1.589
        Month 16, n=133, 88|
    15.81 ± 1.668
    13.25 ± 2.013
        Month 25, n=90, 54|
    16.50 ± 2.021
    5.72 ± 2.565
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module body image functional score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module body image functional score on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses body image symptoms, among others. Participants were asked to indicate the extent to which they experienced body image problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Have you felt physically less attractive as a result of your disease or treatment?; Have you been dissatisfied with your body? Data are transformed to a scale ranging from 0 to 100. Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    386
    297
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=386, 297|
    7.18 ± 1.063
    2.99 ± 1.210
        Month 7, n=312, 230|
    7.88 ± 1.141
    4.26 ± 1.319
        Month 10, n=236, 190|
    8.12 ± 1.319
    4.65 ± 1.482
        Month 13, n=187, 145|
    8.54 ± 1.421
    4.34 ± 1.616
        Month 16, n=133, 91|
    7.68 ± 1.633
    6.21 ± 1.941
        Month 25, n=88, 56|
    10.81 ± 1.856
    3.10 ± 2.281
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module peripheral neuropathy (PN) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module peripheral neuropathy (PN) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses peripheral neuropathy symptoms, among others. Participants were asked to indicate the extent to which they experienced peripheral neuropathy symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have tingling hands or feet?; Have you had numbness in your fingers or toes?; Have you felt weak in your arms or legs? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    388
    297
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=388, 297|
    -3.34 ± 1.038
    -5.22 ± 1.184
        Month 7, n=301, 226|
    -6.12 ± 1.104
    -5.20 ± 1.270
        Month 10, n=235, 188|
    -7.85 ± 1.209
    -5.11 ± 1.361
        Month 13, n=188, 140|
    -8.76 ± 1.301
    -6.37 ± 1.499
        Month 16, n=133, 90|
    -8.66 ± 1.456
    -8.65 ± 1.745
        Month 25, n=91, 55|
    -9.47 ± 1.595
    -8.30 ± 2.010
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module abdominal (AB)/gastrointestinal (GI) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module abdominal (AB)/gastrointestinal (GI) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses AB/GI symptoms, among others. Participants were asked to indicate the extent to which they experienced AB/GI symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have abdominal pain?; Did you have a bloated feeling in your abdomen/stomach?; Did you have problems with your clothes feeling too tight?; Did you experience any change in bowel habit as a result of your disease or treatment?; Were you troubled by passing wind/gas/flatulence?; Have you felt full too quickly after beginning to eat?; Have you had indigestion/heartburn? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    388
    289
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=388, 289|
    0.93 ± 0.673
    6.62 ± 0.777
        Month 7, n=308, 225|
    2.36 ± 0.831
    11.11 ± 0.967
        Month 10, n=232, 187|
    2.74 ± 0.957
    11.33 ± 1.080
        Month 13, n=187, 141|
    3.64 ± 1.027
    12.29 ± 1.181
        Month 16, n=133, 88|
    3.69 ± 1.251
    8.11 ± 1.503
        Month 25, n=91, 54|
    3.82 ± 1.388
    11.86 ± 1.762
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module hormonal/menopausal symptoms score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module hormonal/menopausal symptoms score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses hormonal/menopausal symptoms, among others. Participants were asked to indicate the extent to which they experienced hormonal/menopausal symptoms or problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Did you have hot flashes?; Did you have night sweats? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    398
    299
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=398, 299|
    -0.86 ± 1.026
    -0.95 ± 1.177
        Month 7, n=315, 232|
    -0.38 ± 1.185
    1.29 ± 1.371
        Month 10, n=239, 189|
    -2.17 ± 1.299
    0.83 ± 1.470
        Month 13, n=186, 144|
    -2.77 ± 1.396
    -0.74 ± 1.594
        Month 16, n=136, 91|
    -0.41 ± 1.610
    1.09 ± 1.920
        Month 25, n=92, 55|
    -1.58 ± 1.798
    -0.68 ± 2.280
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module sexuality functional on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module sexuality functional on Day 1 of Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses sexual functioning symptoms, among others. Participants were asked to indicate the extent to which they experienced sexual functioning problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: To what extent were you interested in sex?; To what extent were you sexually active?; If sexually active, to what extent was sex enjoyable for you?; If sexually active, did you have a dry vagina during sexual activity? Higher scores represent better functioning (better quality of life). Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. Data were not analyzed due to low compliance (<50% at Baseline).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: scores on a scale
        least squares mean (standard error)
    ±
    ±
    Notes
    [2] - Data were not analyzed due to low compliance (<50% at Baseline).
    [3] - Data were not analyzed due to low compliance (<50% at Baseline).
    No statistical analyses for this end point

    Secondary: Change from Baseline in QLQ-OV-28 module other chemotherapy side effects (SE) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in QLQ-OV-28 module other chemotherapy side effects (SE) symptoms score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The OV-28 module is a 28-item addition to the EORTC QLQ-C30 that focuses on issues specific to ovarian cancer. It assesses other chemotherapy SE symptoms, among others. Participants were asked to indicate the extent to which they experienced other chemotherapy SE symptoms/problems in the week prior to assessment. Participants responded on a scale of 1-4 (1=not at all, 2=a little, 3=quite a bit, 4=very much) to the following questions: Have you lost any hair?; If yes, were you upset by the loss of your hair?; Did food/drink taste different from usual?; Did you have aches or pains in your muscles or joints?; Did you have problems with hearing?; Did you urinate frequently?; Have you had skin problems (e.g., itchy, dry)? Data are transformed to a scale from 0 to 100. Lower scores represent better health (fewer symptoms) for symptom scales. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA. Data were not analyzed due to low compliance (<50% at Baseline).
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: scores on a scale
        least squares mean (standard error)
    ±
    ±
    Notes
    [4] - Data were not analyzed due to low compliance (<50% at Baseline).
    [5] - Data were not analyzed due to low compliance (<50% at Baseline).
    No statistical analyses for this end point

    Secondary: Change from Baseline in the EuroQOL EQ-5D (five dimensions) thermometer score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in the EuroQOL EQ-5D (five dimensions) thermometer score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The EuroQol (EQ-5D) questionnaire is a 2-page, generic, preference-based quality of life measure comprised of a 5-item health status measure and a visual analogue scale (VAS) and is used to generate two scores: the utility score and the thermometer score The thermometer score is based on a vertical VAS. The VAS is designed like a thermometer scale on which the best health state the participant can imagine is referenced at 100, and the worst health state the participant can imagine is marked by 0. Based on how good or bad the current health state is, the participant is asked to draw a line across the thermometer scale. For example, a line drawn across 46 on the scale of 0 to 100 would be coded 46. A negative adjusted mean change from Baseline represents a worsening of quality of life. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    371
    288
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=371, 288|
    1.35 ± 0.876
    1.20 ± 0.993
        Month 7, n=301, 220|
    3.00 ± 0.929
    1.69 ± 1.076
        Month 10, n=225, 179|
    3.68 ± 1.048
    0.98 ± 1.179
        Month 13, n=179, 136|
    2.92 ± 1.194
    2.49 ± 1.369
        Month 16, n=127, 87|
    3.30 ± 1.219
    3.51 ± 1.451
        Month 25, n=86, 53|
    6.87 ± 1.534
    1.71 ± 1.937
    No statistical analyses for this end point

    Secondary: Change from Baseline in the EQ-5D (five dimensions) utility score at Week 13 and Months 7, 10, 13, 16, and 25

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    End point title
    		 Change from Baseline in the EQ-5D (five dimensions) utility score at Week 13 and Months 7, 10, 13, 16, and 25
    End point description
    The EQ-5D utility score captures health status across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety and/or depression. Participants indicated the level of perceived problems in each of the five dimensions on three levels: 1, no problems; 2, some problems; 3, an extreme problem. Unique health states were defined by combining response levels from each of the five dimensions. For example, state 11111 indicates no problem on any of the five dimensions, whereas state 11223 indicates no problems with mobility or self-care; some problems with performing usual activities, moderate pain/discomfort; and extreme anxiety/depression. Responses are typically converted into health utilities or valuations on a scale ranging from 0 (worst health) to 1 (perfect health). A negative adjusted mean change from Baseline represents a worsening of quality of life. Mean changes from Baseline were calculated via mixed model-repeated measures ANCOVA.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 13; Months 7, 10, 13, 16, and 25
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    376
    293
    Units: scores on a scale
    least squares mean (standard error)
        Week 13, n=376, 293|
    0.00 ± 0.009
    -0.04 ± 0.010
        Month 7, n=303, 226|
    0.00 ± 0.010
    -0.04 ± 0.012
        Month 10, n=228, 181|
    0.01 ± 0.011
    -0.04 ± 0.012
        Month 13, n=185, 138|
    0.01 ± 0.011
    -0.01 ± 0.013
        Month 16, n=129, 87|
    -0.00 ± 0.014
    0.03 ± 0.017
        Month 25, n=88, 56|
    0.00 ± 0.016
    -0.02 ± 0.020
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated Grade 2, 3, and 4 on-therapy adverse events occurring in >=10% of participants in either treatment arm

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    End point title
    		 Number of participants with the indicated Grade 2, 3, and 4 on-therapy adverse events occurring in >=10% of participants in either treatment arm
    End point description
    An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. AEs were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the AE. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. Each tx group had 1 subject who did not receive treatment. 5 subjects randomized to placebo received pazopanib. Total subjects in pazopanib=477
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    461 [6]
    472 [7]
    Units: participants
        Hypertension, G2|
    52
    95
        Hypertension, G3|
    25
    139
        Hypertension, G4|
    0
    0
        Diarrhoea, G2|
    22
    97
        Diarrhoea, G3|
    5
    38
        Diarrhoea, G4|
    0
    1
        Nausea, G2|
    15
    42
        Nausea, G3|
    0
    4
        Nausea, G4|
    0
    0
        Headache, G2|
    6
    36
        Headache, G3|
    3
    8
        Headache, G4|
    0
    0
        Fatigue, G2|
    19
    42
        Fatigue, G3|
    1
    7
        Fatigue, G4|
    0
    0
        Neutropenia, G2|
    17
    51
        Neutropenia, G3|
    2
    29
        Neutropenia, G4|
    2
    3
        Dysgeusia, G2|
    0
    16
        Dysgeusia, G3|
    0
    0
        Dysgeusia, G4|
    0
    0
        Abdominal pain, G2|
    21
    26
        Abdominal pain, G3|
    5
    5
        Abdominal pain, G4|
    0
    0
        Alanine aminotransferase increased, G2|
    4
    22
        Alanine aminotransferase increased, G3|
    0
    24
        Alanine aminotransferase increased, G4|
    1
    4
        Hair color changes, G2|
    0
    13
        Hair color changes, G3|
    0
    0
        Hair color changes, G4|
    0
    0
        Decreased appetite, G2|
    2
    19
        Decreased appetite, G3|
    0
    1
        Decreased appetite, G4|
    0
    0
        Vomiting, G2|
    8
    21
        Vomiting, G3|
    1
    4
        Vomiting, G4|
    0
    0
        Aspartate aminotransferase increased, G2|
    3
    22
        Aspartate aminotransferase increased, G3|
    0
    10
        Aspartate aminotransferase increased, G4|
    1
    3
        Arthralgia, G2|
    13
    19
        Arthralgia, G3|
    3
    5
        Arthralgia, G4|
    0
    0
        Abdominal pain upper, G2|
    3
    20
        Abdominal pain upper, G3|
    1
    1
        Abdominal pain upper, G4|
    0
    1
        Asthenia, G2|
    8
    28
        Asthenia, G3|
    0
    6
        Asthenia, G4|
    0
    0
        Palmar-plantar erythrodysaesthesia syndrome, G2|
    2
    42
        Palmar-plantar erythrodysaesthesia syndrome, G3|
    1
    9
        Palmar-plantar erythrodysaesthesia syndrome, G4|
    0
    0
        Thrombocytopenia, G2|
    1
    15
        Thrombocytopenia, G3|
    1
    6
        Thrombocytopenia, G4|
    2
    3
        Hypothyroidism, G2|
    9
    19
        Hypothyroidism, G3|
    0
    0
        Hypothyroidism, G4|
    0
    0
        Constipation, G2|
    20
    12
        Constipation, G3|
    1
    1
        Constipation, G4|
    0
    0
    Notes
    [6] - Each tx group had 1 subject who did not receive treatment.
    [7] - 1 sub=no tx. 5 subjects randomized to placebo received pazopanib. Total subject=477
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated on-therapy hematology grade shifts from Baseline grade

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    End point title
    		 Number of participants with the indicated on-therapy hematology grade shifts from Baseline grade
    End point description
    Hematology toxicities were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. Participants with a missing Baseline grade were assumed to have a Baseline grade of 0. WBC=White blood cell.
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    456
    466
    Units: participants
        Hemoglobin, Any grade increase, n=456, 466|
    44
    68
        Hemoglobin, Increase to Grade 3, n=456, 466|
    0
    0
        Hemoglobin, Increase to Grade 4, n=456, 466|
    0
    0
        Lymphocytes, Any grade increase, n=453, 461|
    75
    91
        Lymphocytes, Increase to Grade 3, n=453, 461|
    1
    13
        Lymphocytes, Increase to Grade 4, n=453, 461|
    0
    0
        Neutrophils, Any grade increase, n=455, 462|
    80
    236
        Neutrophils, Increase to Grade 3, n=455, 462|
    2
    44
        Neutrophils, Increase to Grade 4, n=455, 462|
    0
    5
        Platelets, Any grade increase, n=456, 465|
    25
    167
        Platelets, Increase to Grade 3, n=456, 465|
    1
    8
        Platelets, Increase to Grade 4, n=456, 465|
    1
    4
        WBC count, Any grade increase, n=456, 465|
    77
    236
        WBC count, Increase to Grade 3, n=456, 465|
    0
    11
        WBC count, Increase to Grade 4, n=456, 465|
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated on-therapy chemistry grade shifts from Baseline grade

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    End point title
    		 Number of participants with the indicated on-therapy chemistry grade shifts from Baseline grade
    End point description
    Hematology toxicities were graded according to the Common Terminiology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death. Participants with a missing Baseline grade were assumed to have a Baseline grade of 0.
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    456
    465
    Units: participants
        Albumin, Any grade increase, n=450, 455|
    33
    50
        Albumin, Increase to Grade 3, n=450, 455|
    0
    0
        Albumin, Increase to Grade 4, n=450, 455|
    0
    0
        Creatinine, Any grade increase, n=456, 465|
    27
    42
        Creatinine, Increase to Grade 3, n=456, 465|
    0
    1
        Creatinine, Increase to Grade 4, n=456, 465|
    0
    0
        Hypercalcemia, Any grade increase, n=456, 462|
    33
    16
        Hypercalcemia, Increase to Grade 3, n=456, 462|
    0
    0
        Hypercalcemia, Increase to Grade 4, n=456, 462|
    0
    0
        Hyperglycemia, Any grade increase, n=446, 453|
    117
    128
        Hyperglycemia, Increase to Grade 3, n=, 446, 453|
    10
    2
        Hyperglycemia, Increase to Grade 4, n=446, 453|
    0
    0
        Hyperkalemia, Any grade increase, n=455, 464|
    39
    38
        Hyperkalemia, Increase to Grade 3, n=455, 464|
    2
    1
        Hyperkalemia, Increase to Grade 4, n=455, 464|
    0
    2
        Hypermagnesemia, Any grade increase, n=439, 447|
    11
    20
        Hypermagnesemia, Increase to Grade 3, n=439, 447|
    1
    6
        Hypermagnesemia, Increase to Grade 4, n=439, 447|
    1
    0
        Hypernatremia, Any grade increase, n=455, 463|
    26
    25
        Hypernatremia, Increase to Grade 3, n=455, 463|
    0
    0
        Hypernatremia, Increase to Grade 4, n=455, 463|
    0
    0
        Hypocalcemia, Any grade increase, n=456, 462|
    21
    52
        Hypocalcemia, Increase to Grade 3, n=456, 462|
    0
    2
        Hypocalcemia, Increase to Grade 4, n=456, 462|
    0
    0
        Hypoglycemia, Any grade increase, n=446, 453|
    25
    41
        Hypoglycemia, Increase to Grade 3, n=446, 453|
    2
    0
        Hypoglycemia, Increase to Grade 4, n=446, 453|
    2
    2
        Hypokalemia, Any grade increase, n=455, 464|
    31
    40
        Hypokalemia, Increase to Grade 3, n=455, 464|
    1
    2
        Hypokalemia, Increase to Grade 4, n=455, 464|
    1
    0
        Hypomagnesemia, Any grade increase, n=439, 447|
    55
    65
        Hypomagnesemia, Increase to Grade 3, n=439, 447|
    3
    1
        Hypomagnesemia, Increase to Grade 4, n=439, 447|
    0
    2
        Hyponatremia, Any grade increase, n=455, 463|
    37
    45
        Hyponatremia, Increase to Grade 3, n=455, 463|
    5
    9
        Hyponatremia, Increase to Grade 4, n=455, 463|
    0
    0
        Phosphate, Any grade increase, n=409, 401|
    33
    24
        Phosphate, Increase to Grade 3, n=409, 401|
    4
    0
        Phosphate, Increase to Grade 4, n=409, 401|
    0
    1
    No statistical analyses for this end point

    Secondary: Number of participants with the indicated treatment-emergent thyroid-stimulating hormone (TSH) elevations above 5 million units per liter (MU/L)

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    End point title
    		 Number of participants with the indicated treatment-emergent thyroid-stimulating hormone (TSH) elevations above 5 million units per liter (MU/L)
    End point description
    Participants were assessed for thyroid function abnormalities. Clinical hypothyroidism is defined as 5 <TSH <=10 MU/L and T4 <lower limit of normal (LLN).
    End point type
    Secondary
    End point timeframe
    From the date of the first dose of study drug to the date of the last dose plus 28 days (average of 9.8 months for pazopanib and 12.6 months for placebo)
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    42
    157
    Units: participants
        5 <TSH <=10 MU/L|
    34
    94
        10 <TSH <=20 MU/L|
    4
    36
        TSH >20 MU/L|
    4
    27
    No statistical analyses for this end point

    Secondary: Overall Survival - Hazard Ratio

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    End point title
    		 Overall Survival - Hazard Ratio
    End point description
    Overall surival is defined as the interval between the date of randomization and the date of death due to any cause. For participants who did not die, the time to death was censored at the time of last contact.
    End point type
    Secondary
    End point timeframe
    From the date of randomization until the date of death due to any cause up to approximately 95 months
    End point values
    		 Placebo Pazopanib 800 mg
    Number of subjects analysed
    468
    472
    Units: deaths
        deaths
    253
    241
        censored, follow up ended
    215
    231
    Statistical analysis title
    		 hazard ratio
    Comparison groups
    Placebo v Pazopanib 800 mg
    Number of subjects included in analysis
    940
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6431
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.805
         upper limit
    		 1.145

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV).  All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit up to approximately 95 months
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group title
    Pazopanib
    Reporting group description
    		 Pazopanib

    Serious adverse events
    		 Placebo Pazopanib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    51 / 461 (11.06%)
    121 / 477 (25.37%)
         number of deaths (all causes)
    0
    3
         number of deaths resulting from adverse events
    0
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenoma benign
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal proliferative breast lesion
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant lymphoma unclassifiable low grade
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm of unknown primary site
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to abdominal cavity
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid adenoma
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcerated haemangioma
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arterial thrombosis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 461 (0.00%)
    8 / 477 (1.68%)
         occurrences causally related to treatment / all
    0 / 0
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 461 (0.00%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fibrosis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 461 (0.22%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia
         subjects affected / exposed
    1 / 461 (0.22%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ill-defined disorder
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 461 (0.43%)
    9 / 477 (1.89%)
         occurrences causally related to treatment / all
    1 / 3
    9 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sarcoidosis
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Female genital tract fistula
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 461 (0.00%)
    18 / 477 (3.77%)
         occurrences causally related to treatment / all
    0 / 0
    19 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 461 (0.00%)
    7 / 477 (1.47%)
         occurrences causally related to treatment / all
    0 / 0
    8 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 461 (0.00%)
    5 / 477 (1.05%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 461 (0.00%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural complication
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery insufficiency
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cranial nerve disorder
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intercostal neuralgia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Presyncope
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transverse sinus thrombosis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 461 (0.22%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 461 (0.22%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    1 / 1
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vitreous detachment
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous floaters
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal mass
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 461 (0.65%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal haemorrhage
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 461 (0.43%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocele
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer perforation
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    3 / 461 (0.65%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 461 (0.22%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    3 / 461 (0.65%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 461 (0.43%)
    4 / 477 (0.84%)
         occurrences causally related to treatment / all
    0 / 2
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 461 (0.00%)
    3 / 477 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erythema multiforme
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    2 / 461 (0.43%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myalgia intercostal
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    1 / 461 (0.22%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious colitis
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngotonsillitis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 461 (0.00%)
    2 / 477 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pyelonephritis
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    3 / 461 (0.65%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 461 (0.00%)
    1 / 477 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 461 (0.22%)
    0 / 477 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Pazopanib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    381 / 461 (82.65%)
    462 / 477 (96.86%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    29 / 461 (6.29%)
    23 / 477 (4.82%)
         occurrences all number
    30
    24
    Hypertension
         subjects affected / exposed
    87 / 461 (18.87%)
    256 / 477 (53.67%)
         occurrences all number
    131
    442
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    55 / 461 (11.93%)
    66 / 477 (13.84%)
         occurrences all number
    62
    78
    Fatigue
         subjects affected / exposed
    66 / 461 (14.32%)
    133 / 477 (27.88%)
         occurrences all number
    82
    171
    Mucosal inflammation
         subjects affected / exposed
    10 / 461 (2.17%)
    32 / 477 (6.71%)
         occurrences all number
    10
    43
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    20 / 461 (4.34%)
    24 / 477 (5.03%)
         occurrences all number
    24
    27
    Dyspnoea
         subjects affected / exposed
    21 / 461 (4.56%)
    31 / 477 (6.50%)
         occurrences all number
    21
    34
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    27 / 461 (5.86%)
    24 / 477 (5.03%)
         occurrences all number
    27
    24
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    25 / 461 (5.42%)
    73 / 477 (15.30%)
         occurrences all number
    33
    86
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 461 (5.21%)
    66 / 477 (13.84%)
         occurrences all number
    29
    76
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 461 (0.65%)
    24 / 477 (5.03%)
         occurrences all number
    3
    26
    Blood bilirubin increased
         subjects affected / exposed
    1 / 461 (0.22%)
    29 / 477 (6.08%)
         occurrences all number
    1
    36
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 461 (0.22%)
    32 / 477 (6.71%)
         occurrences all number
    1
    36
    Neutrophil count decreased
         subjects affected / exposed
    11 / 461 (2.39%)
    36 / 477 (7.55%)
         occurrences all number
    16
    61
    Platelet count decreased
         subjects affected / exposed
    1 / 461 (0.22%)
    30 / 477 (6.29%)
         occurrences all number
    1
    40
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    22 / 461 (4.77%)
    26 / 477 (5.45%)
         occurrences all number
    24
    27
    Dysgeusia
         subjects affected / exposed
    13 / 461 (2.82%)
    95 / 477 (19.92%)
         occurrences all number
    13
    103
    Headache
         subjects affected / exposed
    70 / 461 (15.18%)
    135 / 477 (28.30%)
         occurrences all number
    130
    211
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    5 / 461 (1.08%)
    44 / 477 (9.22%)
         occurrences all number
    7
    66
    Neutropenia
         subjects affected / exposed
    23 / 461 (4.99%)
    103 / 477 (21.59%)
         occurrences all number
    34
    172
    Thrombocytopenia
         subjects affected / exposed
    8 / 461 (1.74%)
    48 / 477 (10.06%)
         occurrences all number
    8
    60
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    94 / 461 (20.39%)
    88 / 477 (18.45%)
         occurrences all number
    112
    128
    Abdominal pain upper
         subjects affected / exposed
    30 / 461 (6.51%)
    67 / 477 (14.05%)
         occurrences all number
    49
    78
    Constipation
         subjects affected / exposed
    72 / 461 (15.62%)
    38 / 477 (7.97%)
         occurrences all number
    94
    43
    Diarrhoea
         subjects affected / exposed
    79 / 461 (17.14%)
    252 / 477 (52.83%)
         occurrences all number
    92
    514
    Dyspepsia
         subjects affected / exposed
    17 / 461 (3.69%)
    24 / 477 (5.03%)
         occurrences all number
    18
    25
    Nausea
         subjects affected / exposed
    81 / 461 (17.57%)
    174 / 477 (36.48%)
         occurrences all number
    100
    222
    Stomatitis
         subjects affected / exposed
    7 / 461 (1.52%)
    27 / 477 (5.66%)
         occurrences all number
    10
    33
    Vomiting
         subjects affected / exposed
    39 / 461 (8.46%)
    71 / 477 (14.88%)
         occurrences all number
    47
    105
    Skin and subcutaneous tissue disorders
    Hair colour changes
         subjects affected / exposed
    8 / 461 (1.74%)
    95 / 477 (19.92%)
         occurrences all number
    8
    98
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    7 / 461 (1.52%)
    61 / 477 (12.79%)
         occurrences all number
    7
    98
    Rash
         subjects affected / exposed
    22 / 461 (4.77%)
    42 / 477 (8.81%)
         occurrences all number
    26
    55
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    8 / 461 (1.74%)
    40 / 477 (8.39%)
         occurrences all number
    12
    51
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    15 / 461 (3.25%)
    49 / 477 (10.27%)
         occurrences all number
    15
    53
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    68 / 461 (14.75%)
    71 / 477 (14.88%)
         occurrences all number
    96
    84
    Back pain
         subjects affected / exposed
    38 / 461 (8.24%)
    30 / 477 (6.29%)
         occurrences all number
    55
    37
    Muscle spasms
         subjects affected / exposed
    20 / 461 (4.34%)
    35 / 477 (7.34%)
         occurrences all number
    23
    44
    Myalgia
         subjects affected / exposed
    34 / 461 (7.38%)
    45 / 477 (9.43%)
         occurrences all number
    35
    49
    Pain in extremity
         subjects affected / exposed
    18 / 461 (3.90%)
    38 / 477 (7.97%)
         occurrences all number
    21
    41
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    33 / 461 (7.16%)
    32 / 477 (6.71%)
         occurrences all number
    46
    44
    Viral upper respiratory tract infection
         subjects affected / exposed
    24 / 461 (5.21%)
    27 / 477 (5.66%)
         occurrences all number
    30
    34
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    15 / 461 (3.25%)
    79 / 477 (16.56%)
         occurrences all number
    19
    87

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Jul 2009
    - Provided additional tests for safety monitoring (ie, ECG and phosphorus); - expanded eligibility to ECOG 2 patients and added exclusion criterion regarding other (secondary) malignancies active within the last 5 years; - changed the trigger for more frequent CT/MRI scans; - changed requirement for separation by 24 hrs of the two blood pressure evaluations at Screening (exclusion criterion #6); - changed the grading of AEs from NCI CTCAE v3 to v4; - updated dose modification guidelines;
    14 Dec 2009
    France : -Added requirements that, whenever identified, abnormal levels of electrolytes (ie, calcium, magnesium, potassium) should be brought to normal for the subject to (continue to) be eligible for the study. - Added a requirement that potassium levels should be repeated at the start of IP administration if the last assessment was performed > 72 hours before treatment start. - Added changes in QTc from Baseline of >60msec as a criterion for interrupting the investigational product. - Added an Appendix listing medications known to be associated with prolongation of the QTc interval or TdP (to be used with caution). - Added an Appendix providing a corrective formula for calcium levels when albumin levels are low.
    28 Sep 2010
    -The treatment period was adjusted to 24 months throughout the document - Added additional (mainly safety) assessments at the previously-existing visits M16, M19, M25, and M31. - Statements added to explain that all patients should be considered for extension and outlining the algorithm for continued therapy.
    23 Jul 2012
    -Replaced the OS condition on the timing of the data cutoff for purposes of the primary analysis with a condition of completion of study treatment. - Re-spaced the OS interim analyses, to occur first, at the same time as the final PFS analysis, and second, when ~60% (ie, 330) of the required number of OS events (551) have been reported. - Eliminated unnecessary protocol requirements (eg, CT/MRI scans and CA-125 assessments) following the achievement of the data cut-off for the primary analysis.
    09 May 2016
    -Added a third OS interim analysis for futility at 80% information fraction (when approximately 441 OS events are reported. -Added additional OS follow-up for subjects whose last contact date is more than 6 months older at the time when 540 events are reported if the study continues after the third interim analysis or at the time when the decision is made to close the study after the third interim analysis.
    16 Jun 2016
    Deleted or replaced references to GSK or its staff with that of Novartis/Novartis and its authorized agents. Made administrative changes to align with Novartis processes and procedures.

    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.
    Study was closed following 3rd OS interim analysis as planned per protocol, which confirmed futility
    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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